21 Other idiopathic choreic syndromes

Chorea is the major neurological feature of several idiopathic disorders which may be inherited. The commonest cause of inherited chorea is Huntington's disease and this has been dealt with separately in Chapter 20. Other inherited chorea disorders include benign hereditary chorea, paroxysmal kinesiogenic chorea, choreoacanthocytosis, and ataxia-telangiectasia. The latter two conditions are associated with systemic abnormalities which reflect the generalized nature of the inherited defect (see Table 21.1). Those infrequently producing chorea are only referenced. There are also the so-called Huntington's disease look like syndromes and these have also been dealt with in Chapter 21. There are, furthermore, a number of other inherited disorders in which there is a recognized associated biochemical abnormality in the blood. In most of these, chorea can occur but dystonia is usually the major movement disorder. These are covered in Chapters 40 and 41 in the section on dystonic syndromes. This distinction is rather artificial and as the underlying causes of the idiopathic disorders are known, some may be more appropriately included in the symptomatic groups.

Benign hereditary chorea and paroxysmal kinesiogenic chorea (see later and Chapter 51) stand apart from the others in that they are not associated with additional major signs and do not show gradual progression with development of widespread ‘degeneration’ of the nervous system but may even improve with age. They are perhaps the closest choreic anaology to the primary or idiopathic dystonias. Paroxysmal kinesiogenic chorea is dealt with under ‘Paroxysmal movement disorders’, Chapter 49.

Spontaneous oro-facial chorea, which may be present in the elderly, is an idiopathic disorder. Although it is of uncertain cause and included in Table 21.1, it is unlike the other disorders in being acquired. Because of this and its relation to tardive dyskinesia it is discussed with the latter condition in Chapter 23 under the ‘Symptomatic choreic syndromes’.

While it is possible that earlier cases of this disorder may have been misclassified and regarded as a variant of Huntington's disease, this disorder was delineated as a separate condition only relatively recently, although whether this is a syndrome or true entity has long been debated (Schrag et al. 2000). Perhaps the first description is that of Velander (1931) in which he reported three families with non-progressive chorea commencing in early childhood. The chorea particularly involved the mouth and tongue, but there was variation within families. There were additional cerebellar signs but no evidence of intellectual impairment.

In 1966 and 1967 Haerer et al. and Pincus and Chutorian independently described further kindreds with benign hereditary chorea. These patients displayed maximal involvement of the upper limbs, but the face and tongue were also affected. Since then more and more families have been reported, and subsequent publications reported results from genetic work-up.

Strict criteria for the delineation of this syndrome have not been developed. Several features, however, appear common to the cases reported and establish the disorder as a separate entity. These are 1) its hereditary nature, 2) the onset of chorea in infancy or childhood, 3) the absence of other major neurological features, including mental impairment, and 4) the relative stability of the signs once they have developed. The precise boundaries of this disorder and the possible existence of various subtypes remain to be clarified.

A family has been reported that displayed the above features except the involuntary movements were rather more sudden and shock-like (Refsum and Sjaastad 1973). Although these patients were regarded as having benign hereditary myoclonus the authors have expressed doubts as to whether this is a separate condition. It has been suggested that benign hereditary chorea may really be misinterpreted as benign hereditary myoclonus or that there is a continuum and one disorder may flow into the other (Sjaastad 1981). Benign hereditary chorea has, however, been (genetically) identified as a distinctive choreic syndrome by so many independent authors that it is unlikely it is merely a variant of benign hereditary myoclonus. It seems as though the clinical features of these two disorders may occasionally overlap, as may those of the latter disorder and myoclonic dystonia (Quinn 1988, Asmus et al. 2007). There was also some debate whether some cases said to have benign hereditary chorea may actually have mobile dystonia and may be a manifestation of idiopathic familial dystonia (Quinn 1993). Occasional families said to have benign hereditary chorea show progression of chorea, which may become severe enough to limit function (Schady and Meara 1988) and in other families onset may be delayed until the teens or early adult life (Suchowersky et al. 1986).

A disorder entitled ‘familial inverted choreoathetosis’ has been described as a separate entity (Fisher et al. 1979). The basis for separation is the predominant involvement with myoclonus affecting the legs, possible progression with age, and extensor plantar responses in some patients. These patients, however, displayed chorea in the upper limbs, trunk, and tongue and it is uncertain at present whether this is a separate entity or a variant of benign hereditary chorea. Although it may eventually establish itself as an independent disorder, it is included here as one of the ‘benign hereditary choreas’. A broad nomenclature of this disorder or group of disorders has been used and patients have been described under a number of headings, including ‘hereditary non-progressive chorea of early onset’, choreoathetosis, benign early onset’, ‘familial non-progressive involuntary movements of children’, and ‘hereditary chorea without dementia’. Apart from the possible exceptions mentioned above, however, they all seem to describe the same clinical entity. Neurophysiological, neurochemical, and neuropathological data are often not available in the historical reports to assist with classification.

Most reported cases have a dominant mode of inheritance (Fig. 21.1). Although father-to-son transmission is absent from some large pedigrees (Haerer et al. 1967), it has been reported (Pincus and Chutorian 1967, Behan and Bone 1977) confirming that the disorder is autosomal. Examples of passage through clinically unaffected subjects and the wide range of clinical involvement reflect considerable variation in genetic penetrance (Haerer et al. 1967, Schady and Meara 1988). However, Harper et al. (1978) reported a nearly complete penetrance in males and 0.75 penetrance

in females. Since its identification by Haerer et al., more than 30 families have been reported to have this disorder reviewed by Bruyn and Myrianthopoulos 1986; Wheeler et al. 1993; Kleiner-Fisman and Lang 2007).

Involuntary movements may first appear at any time from infancy to early childhood and have occurred as early as 4 weeks of age (Nutting et al. 1969). Frequently they become apparent when the child begins to walk (Haerer et al. 1967). The age of clinical onset varies between kinships but is relatively constant within one pedigree.

The disorder may insidiously progress for several years before entering a more or less static stage. Several reports suggest there may be gradual improvement with age (Haerer et al. 1967, Sadjadpour and Amato 1973). Some patients, however, have shown continued deterioration (Behan and Bone 1977, Schady and Meara 1988) and this was a feature of the family with predominant lower limb involvement reported by Fisher et al. (1979). One member of this family required hand controls to drive a car and was unable to work because of the movements. A few other patients have become limited by the disorder (Schady and Meara 1988) but most have shown relatively little functional disability.

Most patients have predominant involvement of the hands and arms, although the face, tongue, and neck may be moderately affected (Fig. 21.2). The lower limbs are usually least involved. Mild cases may merely be passed off by aquaintances as being ‘nervous’ or clumsy. As with other forms of chorea, the abnormal movements are exacerbated by mental effort, stress, or fatigue and disappear with sleep. Difficulty with gait, stumbling, and falling occur occasionally (Haerer et al. 1967) and may cause delay in walking until 3–6 years of age (Sadjadpour and Amato 1973, Fisher et al. 1979). Dysarthria may occur but is only occasionally marked. It seems likely that it is due to chorea and not an independent mechanism. Dysphagia has seldom been noted (Schady and Meara 1988). In most cases incoordination is also secondary to chorea but intention tremor has been reported in a few patients (Velander 1931, Pincus and Chutorian 1967). The presence of intention tremor in occasional family members unaffected by chorea confirms that it is not a misinterpretation of the latter movement disorder. Hypotonia and ‘hung-up’ reflexes due to delayed relaxation have been reported. Other physical signs are usually absent although extensor plantar responses have been reported in patients with predominant lower limb involvement (Fisher et al. 1979) and congenital deafness has occurred in one family. Although the absence of dementia has been stressed in order to separate this condition from Huntington's disease, there has been the clinical impression of border-line or mild mental subnormality in some patients and slightly low measured intelligence in others (Haerer et al. 1967, Sadjadpour and Amato 1973, Fisher et al. 1979). In a family reported by Leli et al. (1984) members with benign hereditory chorea had lower verbal intelligence and impaired verbal abstract concept formation compared with unaffected relatives. This intellectual impairment seems to be constitutional and there has been no evidence of progressive mental change. Most patients, however, are probably of normal intelligence.

The issue of the differential diagnosis of benign hereditary chorea is a vexed one. In this regard the extensive review by Schrag et al. (2000) is instructive. The authors analyzed all the published reports of families with benign hereditary chorea and contacted the authors to get follow-up information. They obtained information

on 11 of 42 reported families including three their group had seen earlier. They further reviewed seven new families and four sporadic cases in whom the diagnosis of benign hereditary chorea had been considered at some stage by them. The reason for getting follow-up data was to assess whether these cases had features that might suggest an alternative diagnosis. The videotapes of these families were reviewed by three independent raters and the diagnosis was changed in 9 of the 11 families reported in the literature. In the remaining two families atypical features were clear in the original description, thus suggesting an alternative diagnosis. Benign hereditary chorea was also not reported equivocally in any of their own seven families or sporadic cases after the review of videotapes. The authors also closely examined the reported clinical data of the remaining 31 families and found that atypical features were present in most, suggesting an alternative diagnosis. The most common other diagnosis was myoclonic dystonia or mobile dystonia and essential myoclonus. One of the families reported as benign hereditary chorea had an atypical presentation of ataxia telengiectasia (Klein et al. 1996) and another glutaric academia type 1 (Shafrir et al. 1994). Thus, the overall conclusion was that benign hereditary chorea was not a diagnosis but a syndrome which required further investigation and, apart from the test for Huntington's disease, other conditions mentioned above should be looked for in a given patient (Schrag et al., 2000). Genetic analysis to test for TITF1 gene mutations will confirm the diagnosis of benign hereditary chorea (see later).

Haematology, plasma biochemistry, urinary amino acid screening, cerebrospinal fluid (CSF) analysis, electroencephalography, and radiology have shown no consistent abnormality. Thyroid function may be abnormal. A mild excess of slow activity in the electroencephalogram (Sadjadpour and Amato 1973) and slight dilatation of the lateral ventricles (Behan and Bone 1977) on pneumoencephalography have been reported in isolated cases but seem unlikely to be significant. CT and MRI imaging of the brain showed no notable abnormalities. Positron emission tomography (PET) using fluorodeoxyglucose may show hypometabolism in the caudate (Suckowersky et al. 1986). Mahajnah et al. (2007) performed brain single photon emission computed tomography (SPECT) after intravenous injection of technetium 99m ethyl cysteinate dimer and detected alterations in two of three childen from one family. Of these, one showed markedly decreased uptake in the right striatum and the right thalamus. Another child had mildly reduced uptake in the right putamen and the left thalamus. Pathology assessment showed no significant gross or histological abnormalities (Kleiner-Fisman et al. 2003).

Benign hereditary chorea was shown not to be allelic to Huntington's disease (Yapijakis et al. 1995, Hageman 1996). Subsequently, by means of a genome-wide linkage study in one large four-generation Dutch family reported to have benign hereditary chorea, evidence for the responsible gene defect suggested localization to chromosome 14q (de Vries et al. 2000). In 2002, Breeveld et al. identified mutations in the gene encoding thyroid transcription factor-1 (TITF1; also referred to as TTF, NKX2.1, and T/ebp)located on chromosome 14q13 as a cause of benign hereditary chorea. The families had onset in infancy and childhood, chorea, and absence of mental deterioration, and other variable features such as gait difficulties, pyramidal signs, slow saccades, and abnormal reflexes. With identification of the gene and its function, the clinical spectrum of the disorder has expanded to include abnormalities in the thyroid and lung (Devriendt et al. 1998; Asmus et al. 2005). Mutations in the TTIF1 gene are, however, not relevant to other forms of sporadic or familial chorea (Bauer et al. 2006).

As the disorder is usually mild and functional disability slight or absent it is best to concentrate on rehabilitative measures, training patients to adapt to their problem. In general, drugs that modify dopamine receptor activity are the most successful agents in the treatment of chorea. The side effects of long-term therapy with such agents are substantial and in most instances of benign hereditary chorea their use is not justified. Where they have been tried they seem to have had little if any effect on the involuntary movements. It has been suggested that high dose prednisolone lessens

the chorea (Robinson and Thornett 1985), but movements would have to be severe to warrant a trial of such therapy.

Acanthocytes are erythrocytes with numerous spiny projections protruding from their external surfaces. These short, stubby spines consist of deformations of the cell membrane (Fig. 21.3).

Acanthocytosis has been discovered in several different neurological disorders including neurochoreoacanthocytosis, McLeod's syndrome, and pantothenate kinase-associated neurodegeneration/Hallervorden–Spatz disease. Some previously described disorders (like the HARP syndrome – hypoprebetalipoproteinaemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) were later, after genes were identified, found to be allelic disorders.

In 1950, Bassen and Kornzweig described a disease which has come to eponymously bear their names. This is an autosomal recessive disorder associated with absence of beta-lipoproteins in the plasma which is reflected in a very low blood cholesterol concentration. Within the first few years of life these patients may develop abdominal distention with steatorrhoea, and later in childhood progressive clumsiness and ataxia appear. Wasting and weakness, with particular emphasis on the lower limbs and shoulder girdles, proprioceptive loss, and areflexia are often prominent. Extensor plantar responses, cutaneous ‘glove and stocking’ sensory impairment, pes cavus, and kyphoscoliosis may occur. Visual impairment with retinitis pigmentosa and mental impairment complete the picture [see Bruyn (1977[b]) for a review]. Athetoid movements have rarely been reported (Singer et al. 1952) but seem likely to have been pseudoathetosis secondary to proprioceptive loss. It is now known that the neurological damage is due to malabsorption of vitamin E.

Hypobetalipoproteinaemia is another neurological disorder associated with acanthocytosis. In 1967 Mars et al. described a patient with a progressive but fluctuating neurological disorder, involving weakness, lower limb dysaesthesiae, impaired gait, and difficulty with the control of her sphincters. Mixed cerebellar and pyramidal signs predominated. She and her relatives had hypobetalipoproteinaemia and acanthocytosis. In fact most cases of hypobetalipoproteinaemia are not associated with acanthocytosis even though they may show neurological features. Conversely some of these patients showing acanthocytosis do not have a neurological disorder. It is usually inherited as an autosomal dominant disease. Involvement of the nervous system is not dissimilar to the Bassen-Kornzweig syndrome (Bassen-Kornzweig 1950) and presents with a predominantly spinocerebellar picture. Clumsiness, ataxia, and weakness develop. It may be associated with hyper-reflexia and extensor plantar responses. Loss of tendon reflexes and a ‘glove-stocking’ sensory impairment may develop. Additional features are mental impairment and epilepsy [see Bruyn (1977[a]) for a review].

Homozygotes are clinically indistinguishable from those with abetalipoproteinaemia, although neurological involvement may not be so severe (Herbert et al. 1983). A small number of cases of pantothenate kinase-associated neurodegeneration/Hallervorden–Spatz disease have been associated with hypobetalipoproteinaemia, acanthocytosis, and retinitis pigmentosa, in addition to pallidal degeneration (HARP syndrome) (Higgins et al. 1992, Orrell et al. 1995). This is discussed further in Chapter 11. A fourth neurological disorder associated with acanthocytosis is choreoacanthocytosis and further discussion is limited to this.

In 1960 and 1964 Levine presented papers entitled ‘An Hereditary Neurological Disease with Acanthocytosis’ to the American Academy of Neurology. In 1968 Critchley et al. drew attention to the occurrence of acanthocytosis, chorea and other neurological features in a family. Later the same year Levine et al. published further material on the family they had originally described, drawing attention to chorea in some of these patients.

Subsequently, other cases have been identified in Japan, the USA, and Europe (Critchely et al. 1970, Aminoff 1972, Bird et al. 1978, Itoga et al. 1978, Kamakura et al. 1979, Kito et al. 1980, Sakai et al. 1981, Yamamoto 1982, Sotaniemi 1983, Brin et al. 1985, Gross et al. 1985, Serra et al. 1986, Hardie et al. 1991). The exact situation is confused as some Japanese cases have been reported more than once without clear reference being made to this fact (Ohnishi et al. 1981, Sakai et al. 1981, Limos et al. 1982).

Recessively inherited tic, parkinsonism, peripheral weakness, wasting, lower motor neuron signs, and acanthocytosis were reported by Spitz et al. in 1985. In 1982 Schwartz et al. noted some patients with the McLeod phenotype, which is associated with acanthocytosis and splenomegaly, developed choreiform and dystonic movements, with areflexia and wasting of peripheral muscles as a late feature. However, the majority of those with McLeod's syndrome do not have a movement disorder. The exact relationship of McLeod's syndrome to choreoacanthocytosis had been debated. However, it is now clear that the two are genetically distinct disorders. McLeod syndrome is due to an X-linked disorder caused by mutations of the XK gene (Ho et al. 1994, 1996). It had been postulated that the gene responsible for choreoacanthocytosis may lie nearby (Hardie et al. 1991); however, this has been linked to a separate locus on chromosome 9q21 (Rubio et al. 1997) (see later). Further discussion is limited to the choreoacanthocytosis rather than these associated conditions, unless specifically stated.

Choreoacanthocytosis has been described under a variety of different names including chorea-acanthocytosis, hereditary neurologic disease with acanthocytosis, familial degeneration of the basal ganglia with acanthocytosis, normolipoproteinaemic acanthocytosis and multiple tics, amytrophic chorea with acanthocytosis, and neuroacanthocytosis. No definite diagnostic criteria have been established. The disorder is usually familial although sporadic cases have been reported. In kinships with this disease there may be a few individuals who have neurological stigmata without acanthocytosis and vice versa. The vast majority, however, display both of these features (Critchely et al. 1968, Levine et al. 1968). Although the New England family reported by Levine (1964, 1968) and Estes et al. (1967) was originally reported by Kuo and Bassett (1962) as having decreased alpha and beta lipoproteins, further studies have disproved this. All reported cases have had normal lipid and lipoprotein levels apart from one with a low serum total cholesterol and decreased betalipoproteins.

Hypobetalipoproteinaemia was not only present in the index case reported by Kito et al. (1980) but also in the patient's child who had acanthocytosis, however, in the absence of neurological features. Choreoacanthocytosis may thus be defined as occurring in an individual or a pedigree that displays 1) acanthocytosis, 2) normal lipoprotein concentrations, and 3) a progressive neurological syndrome characterized by involuntary movements (particularly orofacial dyskineisia as well as more generalized chorea) and a predominently motor neuropathy, which is variably associated with mild dementia and epilepsy.

Occasional cases of choreoacanthocytosis have come to autopsy (Bird et al. 1978, Sakuta et al. 1980, Iwata et al. 1984, Rinne et al. 1994[a]). These have shown marked atrophy of the caudate nucleus and putamen with loss of small and medium sized neurons and preservation of a few large neurons (Fig. 21.4). The caudate may have been more severely affected than the putamen.

There was also shrinkage of the globus pallidus, which in some cases has been almost as marked as that in the striatum. In the first cases to be reported there was no evidence of neuronal loss in the cerebral cortex, subthalamic nucleus, thalamus, substantia nigra, hypothalamus, or other areas, including the spinal cord and spinal nerve roots. There appeared to be marked gliosis in the neostriatum and mild gliosis in the globus pallidus and white matter of the cerebral hemispheres. A definite increase in the number of glial cells was, however, not demonstrated. The histology was so similar to some cases of Huntington's disease, in which cortical atrophy is not marked, that Bird et al. (1978) felt the two disorders could not be distinguished on histological grounds alone. Unlike Huntington's disease, however, the concentrations of glutamic acid decarboxylase and choline acetyltransferase were not reduced in the caudate and putamen. In two other cases, in whom the major movement disturbance at the time of death was dystonic, there was a decrease in dopamine and its metabolites from most brain areas, but especially the neostriatum and pallidum. There was also marked elevation of noradrenalin in the putamen and globus pallidus and a striking reduction of substance P in the neostriatum, globus pallidus, and substantia nigra. Serotonin was diminished in the caudate nucleus and substantia nigra. Gamma-aminobutryic acid (GABA) was decreased in the putamen and globus pallidus, but normal in other brain regions examined (de Yebenes et al. 1988). The reasons for the biochemical differences compared with Huntington's disease, in the presence of similar histology, remain unexplained. Subsequent studies, however, have shown that in some cases the medial thalamic nuclei, which project to the striatum, show atrophy and gliosis (Rinne et al. 1994[a]), and that in patients with parkinsonism there is loss of neurons in the substantia nigra with some extra-cellular pigment, but no Lewy bodies. The ventrolateral nigra is most affected, as in Parkinson's disease. Lack of involvement of the subthalamic nucleus, cerebral cortex, cerebellum, pons, and medulla has been confirmed (Rinne et al. 1994[a], [b]). The preservation of these areas helps to distinguish it from Huntington's disease.

There may be reduction in numbers of anterior horn cells in the spinal cord, loss of myelinated axons in the ventral nerve roots, and axonal sprouting. These changes may be more marked in the cervical than the lumbar region. There may also be a decrease in large myelinated fibres in the dorsal roots, but this is relatively mild (Sobue et al. 1986, de Yebenes et al. 1988, Rinne et al. 1994[a]). Two brothers reported by Spencer et al. (1987) suffered from a similar choreic, amyotrophic, and dementing syndrome associated with a spherocytic haemolytic anaemia without acanthocytosis. One brother showed neuronal loss in the caudate and putamen, with gliosis, spheroid bodies, and numerous iron deposits. The globus pallidus contained minimal iron and spheroid body formation but was otherwise normal. There was a mild cell loss and gliosis in the substantia nigra and degeneration of anterior horn cell neurons. The other brother subsequently developed CSF and blood antibodies against glial fibrillary acidic protein, which was felt to be due to a secondary autoimmune response (Lagreze et al. 1988). The status of these two cases is uncertain, but they did have splenomegaly and cardiomegaly, both of which are common in McLeod syndrome, and their Kell blood group was not reported.

Little is known about the neurophysiological processes underlying the distinctive involuntary movements in this disorder. They do, however, show features that distinguish them from those of Huntington's disease. The chorea is decreased by concentration during mental arithmetic and by voluntary muscle contraction at a distant site. Individual choreic movements are preceded by a slow cortical negativity similar to the so-called cortical readiness potential which proceeds voluntary movement in normals. These prechoreic potentials are not seen in Huntington's disease, suggesting that the neuronal circuits activated in the production of chorea are different in these two disorders (Shibaski et al. 1982). On the other hand, the intracortical inhibition of the motor cortex in patients with chorea due to neuroacanthocytosis (or Huntington's disease) is normal, unlike that in patients with parkinsonism or dystonia (Hanajima et al. 1999).

It seems likely that cell membrane abnormalities underlie the erythrocyte and neurological abnormalities (see ‘Laboratory tests’).

The disorder is genetically heterogenous. Historically, there are some reports of choreoacanthocytosis inherited as an autosomal dominant trait with variable penetrance (Critchley et al. 1968, Levine et al. 1968).

However, is is now generally considered a recessive disorder and linkage to chromosome 9 was claimed through linkage studies on 11 families of diverse origin including several British ones, with the responsible gene located on 9q21 (Rubio et al. 1997). Later, mutations in the VPS13A gene, which encodes chorein, were identified (Rampoldi et al. 2001). Accordingly, some kinships show only a single generation resulting from a consanguinous marriage being affected (Bird et al. 1978, Sakai et al. 1981). Sporadic cases are not infrequent (Critchley et al. 1970, Ohnishi et al. 1981, Limos et al. 1982). For review see Gandhi et al. 2008.

Furthermore, analysis of published cases showed a marked lack of father-to-son transmission, raising the possibility of an X-linked gene, and there is a related disorder which is that of McLeod syndrome with some overlapping features. The latter is characterized by absence of the Kx antigen and reduced expression of Kell system antigens and caused by hemizygosity for mutations in the XK gene located on chromosome Xp21.

The involuntary movements which give the disorder its name are the most conspicuous neurological feature but are not invariable. In fact, in the family reported by Levine et al. (1968), only three had chorea and one had chorea gravidarum out of 19 patients with evidence of neurological disease. The original description of this family omitted to mention chorea (Levine 1964). Chorea has been a more consistent feature in other kinships and it has been present in the majority of cases (Hardie et al. 1991). The movements usually

commence in adolescence or early adult life (range 8–62 years) as an oro-facial dyskinesia, often dystonic in nature. Grimacing, tongue protrusion, and jaw movements are particularly frequent (Figs 21.5 and 21.6). Unlike Meige's syndrome, Huntington's disease, and most other choreic disorders, tongue, lip, and cheek biting is frequent and often leads to marked tissue destruction due to severe tongue protrusion dystonia in some cases, and even amputation of the tongue and parts of the lips may occur (Fig. 21.7) (Critchley et al. 1970, Schneider et al. 2006). In this respect, the disorder is similar to the Lesch–Nyhan syndrome. Such self-mutilation, however, has been uncommon in some pedigrees (Hardie et al. 1991). Dysarthria is common and is largely due to choreic involvement of the muscles of speech and respiration and pseudobulbar disturbance. Grunts, snorts, and other repetitive noises are frequent. In addition echolalia and explosive utterances occur but are seldom obscene as in Gilles de la Tourette syndrome. Dysphagia may result from uncontrollable lingual movements and incoordination of the tongue, palate, and pharynx with loss of normal pharyngeal peristalsis (Critchley et al. 1970). Drooling may occur.

Chorea usually spreads to involve the neck, trunk, and limbs with clumsiness and ataxia. Incoordination and intention tremor are absent and difficulty with balance and falling seem to be the result of chorea. In some patients the abnormal movements are more intermittent and jerky than those of chorea, resembling multi- focal myoclonus and tics. Sudden head drops may occur (Schneider et al. 2010b). In others, the picture may be dominated by dystonia (Hardie et al. 1991). Dystonic protusion of the tongue induced by chewing and attempted swallowing referred to as ‘feeding dystonia’ can be particularly bothersome (Stevenson and Hardie 2001).

The other consistent features relate to the neuropathy. Muscle wasting may become prominent, particularly around the neck, shoulders, pectoral muscles, hands, and legs (Fig. 21.8), but neuropathy may be more common in McLeod syndrome. Fasiculations have been reported in a few cases. Weakness, hypotonia, and areflexia are common. Corticospinal tract signs were reported in a patient who was in a kinship displaying the typical disorder. She was said to have only a few acanthocytes and a disorder resembling Friedreich's ataxia without involuntary movements, but with cerebellar signs, a neuropathy, extensor plantar responses, and deafness (Critchley et al. 1968). It seems difficult, however, to escape from the conclusion that she had a variant of choreoacanthocytosis or a distinct disorder. Extensor plantar responses and hearing impairment have been occasionally found in other cases (Hardie et al. 1991). Pes cavus has been reported infrequently (Aminoff 1972, Bird et al. 1978). Sensory changes are mild and although distal impairment of vibration is common, cutaneous sensory loss is infrequent (Levine et al. 1968). Some series have shown no consistent sensory changes (Hardie et al. 1991).

Dysarthria and involuntary movements may make mental status difficult to assess and may give the erroneous impression of impairment. Nonetheless, cognitive impairment, psychiatric features, and organic personality change occur not infrequently (Critchely et al. 1968, 1970, Levine et al. 1968, Sakai 1981, Hardie 1989, Hardie et al. 1991) and have been considered by some authors to be similar to those seen in Huntington's disease (Medalia et al. 1989, Kartsounis and Hardie 1996). Dysphoria, anxiety disorders, obsessive-compulsive syndromes, and marked emotional lability have been prominent, particularly in patients with self- mutilation behaviour including head banging (Wyszynski et al. 1989, Stevenson and Hardie 2001). In other patients intellect is preserved (Aminoff 1972, Kito 1980). Predominant psychiatric manifestation with depression or bipolar disorder has been described in five males of a family with McLeod syndrome due to a novel point mutation of the XK gene (Jung et al. 2001).

Seizures have been reported in choreoacanthocytosis (Sakai et al. 1981, Vita et al. 1989). They occurred in one third of the cases of Hardie et al. (1991), and rarely epilepsy may be the presenting feature (Schwartz et al. 1992, Kazis et al. 1995). The neurological features are gradually progressive and may eventually cause significant disability with behavioural changes, communication and feeding difficulties, clumsiness, and frequent falls.

In the two brothers with a similar clinical picture reported by Spitz et al. (1985) parkinsonism replaced multiple tics and supranuclear palsy developed. Parkinsonism has occasionally been reported to replace chorea in otherwise typical cases of choreoacanthocytosis (Saki et al. 1981, Rinne et al. 1994[b]). Rarely, parkinsonism may be the presenting feature (Peppard et al. 1990). Cardiac involvement has been reported (Critchley et al. 1968), but one such case was subsequently found to have the McLeod phenotype, in which cardiomyopathy is common (Faillace et al. 1982).

The presence of acanthocytosis is the main laboratory feature of the disorder. As mentioned, however, affected individuals in pedigrees with this disease may not show acanthocytosis invariably. It is thus recommended to repeat the blood smear on three independent occasions in order not to miss the characteristic cells. Patients with the clinical features of this disorder and striatal atrophy have been reported in whom red cells have been morphologically normal but have developed acanthocytosis easily with stimulation. Thus, unfixed wet blood preparations of isotonically diluted blood, in vitro aging, or contact with glass have promoted these changes but had no effect on blood from normals (Feinberg et al. 1991). The mechanism underlying the formation of the stubby protrusions from the erythrocytes is not fully understood. It has been suggested that the presence or absence of a plasma factor may cause the acanthocytosis and Aminoff (1972) found that incubation of group-compatible donor cells in patients’ plasma resulted in 30% developing this deformed appearance. Similar findings have not been obtained using plasma from other cases (Kito et al. 1980). Incubation of patients’ acanthocytes in normal serum does not restore normal shape, although the addition of 20% albumin or the non-ionic detergent Tween 80 does do this (Critchley et al. 1970). There has thus been a suggestion that the major abnormality causing acanthocytosis is in the plasma rather than in the erythrocyte, but most evidence suggests it is the latter. Studies of erythrocyte membrane lipids have revealed no consistent abnormality (Estes et al. 1967, Aminoff 1972, Villegas et al. 1987), although abnormal proportions of covalently bound fatty acids have been noted (Sakai et al. 1991). Alterations in the degree of phosphorylation of membrane proteins and abnormal flux of chloride or sulphate anions have also been reported (Olivieri et al. 1997). Ultrastructural abnormalities of the membraneous skeleton have been observed using freeze-fraction electron microscopy (Ueno et al. 1982, Terada et al. 1999).

Anaemia and evidence of homolysis may be present, but these are usually mild. In vitro tests may show an increase in erythrocyte fragility (Estes et al. 1967) and a decrease in membrane fluidity (Oshima et al. 1985). The proportion of acanthocytes may vary from about 1% to 50% of the total number of erythrocytes in different patients. The presence of acanthocytes can also vary from time to time in individual patients. Blood platelets are morphologically normal but may show increased adenosine diphosphate induced aggregation and electrophoretic mobility (Betts et al. 1970). Although the exact mechanism underlying these haematological changes and their relationship to the neuropathology has yet to be clearly delineated, it seems likely that they are both due to the same basic biochemical defect and that this may express itself through an abnormality of cell membranes.

Mild elevations of serum glutamic oxaloacetic transaminase, serum glutamic pryruvate transaminase, lactic acid dehydrogenase, and creatinine phosphokinase have been reported (Kito et al. 1980, Hardie et al. 1991). By contrast serum lipid and lipoprotein values have been normal except in the cases mentioned above under ‘Definition’. Urinary excretion of 3,4-dihydroxyphenyl acetic acid (DOPAC) and CSF noradrenaline have been found to be increased in a case. This is in contrast to Huntington's disease where urinary DOPAC is usually decreased (Kitto et al. 1980). This evidence of increased nor-adrenaline turnover is of interest in view of the preservation of enzymes connected with GABA and acetylcholine metabolism (see earlier under ‘Neuropathology and neurochemistry’).

Unlike the Lesch–Nyhan syndrome, the activity of erythrocytes hypoxanthine guanine phosphoribosyl transferase and the concentration of plasma uric acid are normal. CSF examination has been reported to show reduced levels of homovanillic acid and methoxy-hydroxy-phenylglycol (de Yebenes et al. 1988).

Neurophysiological tests show normal or minimally reduced nerve conduction velocities and sensory action potential amplitudes but a ‘neurogenic’ pattern on electromyography, consistent with axonal loss (Sakai et al. 1981, Limos et al. 1982, Sotaniemi 1983, Vita et al. 1989, Hardie et al. 1991). Some reports have suggested a demyelinating process, but these changes were probably secondary to axonal degeneration (Ohnishi et al. 1981, Sobue et al. 1981). One case reported had a large fibre axonal neuropathy and antibodies to GM1 ganglioside, although it appears likely that this was an inflammatory response secondary to the axonal degeneration (Hirayama et al. 1997). Although central nucleation and fibre splitting have been reported on muscle biopsy these ‘myopathic’ findings may be secondary to chronic denervation but are outweighed by the more prominent histological evidence of ‘neurogenic’ atrophy (Limos et al. 1982, Vita et al. 1989). Similar changes in cases of the McLeod syndrome have been interpreted as showing mild myopathy in addition to neurogenic degeneration (Witt et al. 1992). Muscle involvement in this disorder may be more significant and cardiomyopathy is a frequent feature. A selective pattern of fatty infiltration mainly of the posterior compartment of the leg with sparing of the gracilis, semitendinosis, and the lateral heads of the gastrocnemi has been found on CT scan of muscles both in McLeod syndrome and cases of choreoacanthocytosis (Ishikawa et al. 2000). Sural nerve biopsy in choreoacanthocytosis has shown substantial reduction in the population of large myelinated fibres (Serra et al. 1966, Ohnishi et al. 1981, Hardie et al. 1991) especially distally (Vita et al. 1989, Malandrini et al. 1993), but these sensory changes are mild compared with those in motor nerves (Sobue et al. 1986).

The most specific finding on CT or MRI brain scanning is atrophy of the caudate nucleus (Henkel et al. 2006, 2008). Generalized dilation of the lateral ventricles is also frequently reported, but cortical atrophy has been noted occasionally (Critchley 1968, Bird 1978, Kito et al. 1980, Sotaniemi 1983, Malandrini et al. 1993). Increased signal on T2-weighted MRI in the caudate and putamen can also occur (Spitz et al. 1985, Tanaka et al. 1998). PET scanning may show decreased metabolism of glucose in the caudate and putamen and frontal cortex (Hosokawa et al. 1987, Dubinsky et al. 1989, Tanaka et al. 1998) and decreased D₂-receptor binding sites, especially in the former structure (Brooks et al. 1991). [18F]-dopa uptake is reduced in the posterior part of the putamen. These changes in dopamine receptors and dopa uptake have been regarded as being consistent with the chorea and the extrapyramidal rigidity seen in this disorder (Peppard et al. 1990, Brooks et al. 1991). Striatal and frontal blood flow has been reported to be reduced (Brooks et al. 1991, Delecluse et al. 1991).

Frontal hypoperfusion, reduced striatal glucose metabolism, as well as decreased D₂ receptor binding in the striatum also occurs in McLeod syndrome (Danek et al. 1994, Takashima et al. 1994, Oechsner et al., 2001).

There is no treatment to alter the gradual progression of the disease. Dopamine receptor blocking drugs (haloperidol), anticholinergics (trihexyphenidyl hydrochloride), and benzodiazepines (diazepam) have had minimal, if any, effect on the abnormal movements (Critchley et al. 1968, Bird et al. 1978).

Bilateral thalamotomy in a patient has been reported as ‘markedly diminishing the choreiform movements and the oro- linguo-facial dyskinesia’ (Limos et al. 1982). Another patient has had unilateral pallidotomy which apparently helped similarly (Fujimoto et al. 1997). However, these benefits are likely to be short term and do not alter the disease progression per se. Deep brain stimulation has also been tried in individual patients, however, overall with disappointing results (Wihl et al. 2001).

The first report of the disorder, which has subsequently become known as ataxia-telangiectasia, was published in French by Syllaba and Henner in 1926. They did not, however, distinguish it as a separate disease but thought it a variant of congenital athetosis. Review of their case material has confirmed that the patients did have ataxia-telangiectasia (Henner 1968). The second report was also published in French by Louis-Bar in 1941, without reference to the earlier publication. Both of these papers were largely ignored until three independent descriptions of the disease were published in 1957 (Biemond 1957, Boder and Sedgwick 1957, Wells and Shy 1957). These emphasized the essential clinical components of the illness, namely a progressive neurological syndrome with cerebellar features and involuntary movements, oculocutaneous telangiectasiae, and frequent respiratory tract infections. Widespread recognition of the disease followed quickly and within 6 years at least 101 cases had been published (Boder and Sedgewick 1963). In 1958 the liability to infection was partially explained by the finding of hypogammaglobulinaemia (Boder and Sedgewick 1958, Centerwall and Miller 1958) and selective deficiencies in specific immunoglobulins were soon discovered (Thieffry et al. 1961, Fireman et al. 1964). At the same time it became apparent that cellular immunity was disturbed with diminished delayed hypersensitivity responses (Peterson et al. 1963). These disturbances in immunity were attributed to hypoplasia or absence of the thymus, which had been noted in earlier reports (Good et al. 1964). At about the same time Boder and Sedgewick (1963) noted in a literature review that there was an increased incidence of malignancy, particularly involving the lymphoreticular system. In 1966 an increased incidence in malignancy, particularly lymphoma and leukaemia, was documented amongst the relatives of ataxia-telangectasia patients (Reed et al. 1966). In the same year transformation of the patients’ lymphocytes, when cultured with phytohaemagglutinin, was found to be abnormal (Leikin et al. 1966). Subsequently increased incidence of chromosomal breakage and abnormal sensitivity to ionizing radiation, along with a number of other abnormalities discussed below, have been discovered.

Clinically the diagnosis is based on the presence of 1) a progressive neurological syndrome characterized by cerebellar signs, chorea, or dystonia, abnormal eye movements, and the late development of spinal and peripheral nerve involvement, and 2) telangiectasiae involving particularly the eyes and face. Laboratory findings which strongly support the diagnosis include various tests demonstrating cellular and hormonal immunodeficiency and elevated levels of carcinoembryonic antigen, alpha-fetoprotein, or beta-fetoprotein. The increased serum alpha-fetoprotein level is present in 95% of cases with increasing levels over time. Further laboratory confirmation of the diagnosis is based on increased in vitro radiosensitivity; decreased or absent levels of intracellular ataxia telangiectasia mutated (ATM) protein levels on Western blotting; and mutations in the ATM gene (Chun et al. 2004, Taylor et al. 2005)

Ataxia-telangiectasia does not fit comfortably into most classifications of neurological disorders. Although it could be classified with the neurocutaneous disorders, it is perhaps best placed among the spinocerebellar atrophies (Sedgewick and Boder 1972). Although the choreic and dystonic movements are usually not as prominent as the cerebellar features, they may be the predominent neurological signs, particularly in later stages although extrapyramidal features as a presenting sign have also rarely been described (Wells and Shy 1957, Bodensteiner et al. 1980, Carrillo et al. 2009). Thus, the disorder is included here under the inherited choreas although the character of the involuntary movements is such that it could also be included under the dystonias.

The clinical picture of ataxia-telangiectasia is remarkably stereotyped and, although there are variations in emphasis from case to case, there are no distinct sub-types or sub-classification.

Large bizarre cells with big hyperchromatic nuclei were first discovered in ataxia-telangiectasia in the anterior pituitary, but have subsequently been identified in many tissues including thyroid, adrenal, liver, spleen, and kidney. While unusual, this nuclear atypicality is not specific for ataxia-telangiectasia and may be found in malignancy, normal aging, and occasionally without other association (Aguilar et al. 1968).

The major pathological findings are in the nervous system. There has been debate about whether the central nervous system shows vascular changes which parallel those of the conjunctivae and skin and some authors have been unable to demonstrate abnormality (Hassler 1967, Solitare and Lopez 1967, Aguilar et al. 1968). Dilated meningeal and parenchymal vessels, however, do occur (Boder and Sedgewick 1958, Solitare and Lopez 1967) and may occasionally be extensive, resembling their cutaneous counterparts (Amromin et al. 1979, Agamanolis and Greenstein 1979).

Subarachnoid haemorrhage from an angiographically visible arteriovenous malformation has been reported (Paula-Barbosa et al. 1983), but vascular changes are usually minor (Hassler 1967) and are not the cause of the neurological degeneration. The cerebellum bears the brunt of the disease with severe cortical degeneration involving particularly Purkinje cells (Gatti and Vinters 1985), but also the granular and basket neurons to a lesser extent. Both vermis and cerebellar hemispheres are damaged and cerebellar white matter may show mild gliosis. Loss of cells also occurs in the dentate olivary and vestibular nuclei. Other brainstem changes include the formation of glial nodules and axonal ‘spheroids’. Similar findings may occur in the spinal cord, where later in the course of the disease there may be axonal degeneration and demyelination in posterior and lateral columns. The anterior horns are involved late, with neuronal degeneration and the appearance of ‘ghost cells’ (Aguilar et al. 1968). Peripheral nerves may show minor changes, particularly in the Schwann cells, but without conspicuous demyelination (Gardener and Goodman 1969). Histology of the atrophic muscle suggests ‘neurogenic’ atrophy (Goodman et al. 1969), although a contribution from direct involvement of muscle has not been excluded.

Changes in the cerebral cortex are minor (Centerwall and Miller 1958) or absent. Similarly little pathology has been demonstrated in the basal ganglia and usually they are reported as normal. Minor atrophy of the caudate nucleus (Amromin et al. 1979) with some loss of large cells (Osetowska and Traczynska 1964) and haemosiderotic glial nodules in the globus pallidus (Terplan and Krauss 1969) have been described. Macroscopically there may be mild cell loss in the substantia nigra (Centerwall and Miller 1958, Solitare and Lopez 1967), but occasionally it is severe and intracytoplasmic eosinophic inclusions (Lewy bodies) may be present (DeLeon et al. 1976, Agamanolis and Greenstein 1979). Occasionally there are minor thalamic and hypothalamic changes (Amromin et al. 1979). [For a review of pathology see Sedgewick and Boder (1972).]

There has also been a review of cases with ataxia-telangiectasia who had prominent movement disorders (Koepp et al. 1994). This revealed that in 10 of 17 reported cases the basal ganglia or brainstem nuclei were affected. The substantia nigra was most consistently affected, with varying degrees of neuronal loss with depigmentation (Terplan 1969, DeLeon 1976, Koepp et al. 1994). Neuronal loss in striatal and pallidal neurons has also been reported. In line with this is the finding of one patient with prominent dystonia who showed lesions in the lentiform nuclei in neuroimaging studies, the nature of which remained unclear.

Non-neurological autopsy findings include major abnormalities in the lymphoid system with generalized underdevelopment. Thus, the lymph nodes are reduced in number and size, showing poor development of lymphoid collars surrounding the germinal centres. There is associated reticular cell hyperplasia. The tonsils, adenoids, and thymus are markedly hypoplastic or absent. If a thymic remnant is present it resembles the foetal gland prior to its development into a lymphoid organ and is thus largely epithelial with a few scattered lymphocytes, but lacks cortex and Hassall's corpuscles. Other post-mortem findings are related to respiratory infections, endocrine complications, or associated malignancy (see later).

Perry et al. (1984) reported neurochemical changes in a single autopsy case. They attributed moderate reduction in the putative cerebellar neurotransmitters glutamate and taurine to loss of cortical granule and stellate neurons respectively.

Binding to GABA receptors, which are thought to reside predominantly on the granule cells, was greatly reduced. Markedly decreased GABA content in the dentate nucleus seemed to reflect degeneration of the afferent projection from the Purkinje cells which use this as their neurotransmitter.

These findings appeared to mirror the histological changes. An unexplained finding was a substantial reduction in phosphoethandamine levels in the cerebellar cortex, inferior olivary nucleus, and a wide variety of extracerebellar brain regions.

The neurochemical and neurophysiological changes underlying the involuntary movements are unknown.

Ataxia-telangiectasia is inherited as an autosomal recessive condition. It is now known that it is caused by mutations of the ataxia-telengiectasia gene (designated ATM) on chromosome 11q23 (Savitsky et al. 1995) (for genetic defects in the so-called ataxia-telangiectasia-like disorders see later). Although the prevalence of the disorder is uncertain, it has been variously estimated at 0.3 per 100,000 Caucasian births (Woods et al. 1990), 1 per 100,00 births (Swift 1985), and 2.4 per 100,000 children between the ages of 5 and 12.5 years (Sedgewick and Boder 1972). The low rate of parental consanguininity suggests that heterozygotes may be more common than is sometimes assumed. The neurological features usually commence in infancy and produce clumsiness and ataxia. Gradual progression results in most patients being chair-bound by 10 or 12 years of age although strength at this stage may still be reasonable. Death usually occurs in the teens from infection or malignancy, though patients have survived into the fourth and fifth decades (Goodman et al. 1969, Woods and Taylor 1992). Rarely the disorder may have a more benign course and not commence until the teens (Terenty et al. 1978, Carrillo et al. 2008).

The frequency of clinical features is listed in Table 21.4. Usually the first sign of the disease is ataxia, which appears when, or shortly after, the child learns to walk. The upper limbs may be clumsy and the head unsteady. These cerebellar features gradually progress and intention tremor may develop. Involuntary movements occurring at rest appear later and can easily be overlooked because of the predominant cerebellar features.

These involuntary movements may involve the face, neck, limbs, and trunk. Normal expressive facial movements are diminished so that the patient appears sad and thoughtful. This mask-like appearance is interrupted by facial contortions, grimaces, and tongue movements. In the limbs the movements can be typically choreic, fast and brief, or slower, undulating, and more dystonic, or a combination of the two (Fig. 21.9). Although chorea usually becomes more pronounced in later childhood, it may sometimes predominate the picture from an early stage. Rarely, pronounced dystonia may mask the cerebellar features (Bodensteiner et al. 1980, Carrillo et al. 2008). Ataxia and loss of facial expression have been reported to occur in all cases, chorea in 97%, and dystonia in 79% (Woods and Taylor 1992). Disturbed ocular motility is virtually always present and may occur quite early. The first abnormality is a delay in initiating ocular movements, but, as the disorder progresses, marked hypometria of saccades occurs (Baloh et al. 1978, Stell et al. 1989) and corrective movements may produce nystagmoid jerking (Fig. 21.10). This is unlike patients with most other forms of cerebellar atrophy where hypermetria is more common. If the head is not restrained, eye movements are often accompanied by head thrusts similar to those seen in oculomotor apraxia (Cogan 1952, DeLeon et al. 1976). The head overshoots the target and then gradually returns so that it is in line with the point of fixation, while the eyes remain fixed on the new object utilizing the oculovestibular reflex (Fig. 21.11). Unlike congenital oculomotor apraxia, in which only horizontal eye movements are affected, vertical deviation is also impaired. Blinking frequently accompanies ocular refixation. This disturbance in eye movement with accompanying head thrusts and blinking is similar to the disturbance that can occur in Huntington's disease (Avanzini et al. 1979, Leigh et al. 1983), but, unlike that condition, the velocity of the saccades is not reduced in ataxia-telangiectasia (Baloh 1978, Stell et al. 1989). Involuntary saccades (i.e. the fast components of vestibular and optokinetic nystagmus) have normal velocity but may be hypometric and the eyes show a curious tonic deviation in the direction of the slow component (Stell et al. 1989). Optokinetic nystagmus and smooth pursuit may be absent and vestibular responses may be hyperactive (Stell 1989). A combination of cerebellar and basal ganglia disturbance has been suggested to underlie these disturbances in eye movements (Baloh et al. 1978. In some patients, however, it is definitely present and may be predominantly alternating (Stell et al. 1989).

Nystagmus has been described in a number of reports (McFarlin et al. 1972), but it is not always clearly distinguished from the fixation nystagmus which accompanies ocular dysmetria, and some studies which have concentrated solely on oculomotor dysfunction have made no mention of it (Baloh et al. 1978). In some patients, however, it is definitely present and may be periodically alternating (Stell et al. 1989). Strabismus is common (McFarlin et al. 1972).

Dysarthria is very frequent and usually cerebellar in type although oral dyskinesia may also break up the pattern of speech. Talking may be difficult to initiate so there is delay replying. Tongue protrusion dystonia has been described (Carrillo et al. 2008). Pooling of saliva with drooling is common and has been reported to occur in 93% of cases (Woods and Taylor 1992), although dysphagia is not usually a problem until in the late stages of the disease.

Radiographic studies of oesophageal function have been normal (Fireman et al. 1964). Aspiration may occur in advanced cases.

In the later stages spinal cord and lower motor neuron signs may develop and are present in most patients surviving beyond the mid-teens. Weakness and wasting may be fairly generalized but have a distal emphasis. Fasiculation may be present (Goodman et al. 1969). Gatti et al. (1991) pointed out that a significant proportion of older patients in their 20s and 30s have a spinomuscular atrophy- type wasting affecting mostly the hands and feet and dystonia often causing flexion/extension-type of contractures of the fingers. By the time these signs are obvious the patient is often chair-bound by severe cerebellar deficits. Diminution or loss of tendon reflexes usually occurs fairly early by the age of 8 or so. Peripheral neuropathy has been reported to occur in over 70% of cases (Woods and Taylor 1992). Although the corticospinal element may be submerged by lower motor neuron involvement extensor plantar responses are occasionally found (McFarlin et al. 1972).

Sensory involvement is less common and when it occurs the emphasis is on impairment of vibration and proprioception rather than cutaneous sensation (McFarlin et al. 1972, Woods and Taylor 1992). It has been commented that patients with ataxia-telangiectasia often have an equable disposition, being friendly, helpful, and relatively contented. This may help them make a good social adjustment to their disability (Sedgewick and Boder 1972). Mental deficiency occurs in approximately a third to a half of patients but is usually mild and develops in the later stages of the disease. Motor disability, slowness in intitiating speech, and dysarthria make formal assessment of intelligence difficult. To some extent a gradual diminution in intelligence quotient may reflect failure to improve compared with age-matched controls, rather than absolute deterioration in performance (Sedgewick and Boder 1972). These relatively mild changes may reflect the minor nature of the cerebral hemisphere damage.

There is a gradual loss of motor skills and increase in disability. Woods and Taylor (1992) found that the ability to write was lost at the mean age of 8 years and walking ceased at a mean age of 10 years, although there were occasional patients still on their feet in the third and fourth decades. All of the 70 cases, however, needed help with feeding and dressing and most required assistance with washing and toileting.

Although neurological abnormalities are the most disabling feature of the disease, there are a number of other important systemic changes. The most prominent cutaneous abnormality is the telangiectatic vessels. These usually appear between 3 and 6 years of age and follow the neurological features by several years. The diagnosis may be obscure prior to these vascular changes. Occasionally, however, they may be present from birth.

They are symmetrical and affect particularly the conjunctivae (Fig. 21.12), eyelids, sides of the bridge of the nose, cheeks, ears, neck, and antecubital plus popliteal fossae. Less often they are present over the dorsal surfaces of the hands and feet. They may also be found in the mouth, particularly on the palate (Carrillo et al. 2008). They thus tend to be distributed in regions of exposure or minor trauma. This latter aspect is demonstrated by a tendency to linear distribution in skin folds of the neck and at the elbows and knees. These dilated vessels give the appearance of ‘blood shot’ eyes and a prominant butterfly rash. They blanch on pressure.

Occasional epistaxis has been reported but these vessels are otherwise asymptomatic. The cutaneous vessels are branches of the subcapillary venous plexus whereas the conjunctival ones are dilated connecting venules (Smith and Cogen 1959, Thieffry et al. 1961). Other cutaneous abnormalities include the appearance of premature aging with loss of subcutaneous tissue, atrophy of skin, mottled hypo- and hyperpigmentation, senile keratosis, and basal cell carcinomas (Reed et al. 1966). Premature greying of the hair adds to the progeric appearance. Seborrheic dermatitis is not infrequent. These cutaneous changes occur in the same general distribution as the telangiectasiae suggesting that they may result from exposure to sunlight.

There is a marked increase in the incidence of infections, particularly those involving the upper and lower respiratory tracts. Rhinitis, sinusitis, otitis media, pneumonia, chronic bronchitis, bronchiectasis, and eventual pulmonary fibrosis are all increased in frequency and, individually or in combination, occur in 60–80% of cases (Woods and Taylor 1992). Occasionally destructive pulmonary disease may result in digital clubbing. The organisms involved tend to be the common bacterial respiratory pathogens (Peterson and Good 1968). Pulmonary disease was found to be the cause of death in 67% and a contributary cause in a further 21% of published autopsies reviewed by Sedgewick and Boder (1972).

Deficiencies in cellular and humoral immune mechanisms underlie this susceptibility to infection, and deficiency of IgA in respiratory secretions is probably of particular importance in sino-pumonary disease (see later).

Several endocrine abnormalities have been identified in ataxia-telangiectasia. Hypogonadism is common and its expression may be more prominent in females, in whom it is an almost consistent finding. Absence of hypoplasia of ovaries with infantile Fallopian tubes and uterus plus absence of secondary sexual characteristics are usual (Miller and Chatten 1967). In the few cases in which menstruation occurs it is usually scanty and the menarchy is delayed. Pubertal changes are usually delayed in the male and secondary sexual development is incomplete. The testes are not absent but may show minor histological abnormalities (Aguilar et al. 1968). The relationship between these gonadal changes and the histological abnormalities in the pituitary are uncertain. It has been suggested that the prognosis may be better in females who undergo puberty (Sedgwick and Boder 1991).

Carbohydrate intolerance was found in over half the patients examined by McFarlin et al. (1972) and is due to abnormal peripheral resistance to insulin in the face of high circulating insulin levels. This frequently results in frank diabetes mellitus. Tests of pituitary and thyroid function are usually normal and a reported abnormality in growth hormone (Ammann et al. 1969) has not been confirmed. Growth retardation is present in about three quarters of patients and becomes more prominent with increasing age. Average height is reduced and only occasional patients reach the 50th percentile (Sedgewick and Boder 1972). The mechanism underlying this dwarfing is uncertain although hypoplasia of the thymus and recurrent infection may play a part (Good et al. 1964). Excessive thinness has been reported in over three quarters of patients (Woods and Taylor 1992) and may be partially contributed to by neuropathy.

Skeletal abnormalities, other than short stature, are uncommon although kyphoscoliosis and flexion contractures may occur late in the disease. Craniostenosis, hemivertebrae, and spina bifida occulta have been reported but may be no more than a chance occurrence (Boder and Sedgewick 1958, Robinson 1962, Dunn et al. 1964).

There is an increased incidence of neoplasia and although a review of published autopsies showed it was the cause of death in only 9%, it was a contributory factor in many other cases and malignancies were present in almost half the cases (Sedgewick and Boder 1972). Malignancies of the lymphoreticular system predominate with lymphosarcoma, reticulum cell sarcoma, and Hodgkin's disease being particularly prominent. Malignant lymphomas of all types made up about 90% of tumours. Lymphocytic leukaemia is not uncommon (Lampert 1969). Primary intracranial tumours (Young et al. 1964, Shuster et al. 1966), gastric carcinoma, and miscellaneous other malignancies have been reported (see Table 21.5). The failure of suppression of DNA production following exposure to ionizing radiation and the increased incidence of chromosomal abnormalities (Taylor 1978, Painter and Young 1980) may reflect defects in the control of nucleic acids, which may underlie the tendency to malignancy (see later).

Heterozygotes also have an increased incidence of cancer, with an estimated relative risk of 2.3 for men and 3.1 for women. The relative risk for breast cancer in women, however, may be as high as 6.8 (Swift et al. 1987, Swift 1990).

Minor hepatic changes may occur in the latter stages of the disease with minimal periportal inflammation and fatty infiltration (McFarlin et al. 1972). The cause of these changes has not been established, but injury secondary to recurrent infection has been postulated. Sarcoidosis has been reported (Fleck et al. 1986), but it has not been established that this is more than a chance association.

Ataxia telengiectasia is caused by mutations in the ATM gene encoding a protein involved in the cellular DNA damage response and cell cycle checkpoint control. Numerous mutations of the gene have been described. For example, in one study of 41 Nordic families with ataxia-telengiectasia 37 mutations were detected, of which 25 had not been previously reported (Laake et al. 2000). Overall, more than 400 mutations of the ATM have already been identified (Chun et al. 2004); most of these are unique to single families (Concannon et al. 1997). Because of the large size of the gene of about 150 kb in 66 exons, genetic screening can be extensive and limits the utility of direct mutation screening as a diagnostic tool. It is for this reason also that genetic screening remains unsuccessful in 5–15% of cases (Buzin et al. 2003, Perlman et al. 2003).

Patients’ cell lines in culture show an increased incidence in chromosomal breakage and translocation especially of chromosomes 7 and 14 (Aurias et al. 1980, Hecht and Hecht 1985). Chromosome 14 is involved in immunoglobulin heavy chain production including IgA and IgE (see later). The frequency of additional chromosomal abnormalities and cell death after exposure to ionizing radiation is also increased (Friedberg et al. 1979). Phytohaemagglutinin stimulated DNA synthesis is normally inhibited by such radiation, but this effect is less in ataxia telangiectasia and has been suggested as the basis of a laboratory test for the disease (Jaspers et al. 1981). This continued DNA synthesis may be the reason why there is less radiation-induced miotic delay than in normal cells and it has been postulated that they move forward into division before genetic repair can be performed (Painter and Young 1980, Scott and Zambetti-Bosseler 1980). In addition, cultured cells are abnormally sensitive to cytotoxic chemical damage (Waldermann et al. 1983). There is, however, considerable variation in the sensitivity of cells between different patients, suggesting a degree of genetic heterogeneity (Taylor et al. 1987).

The above findings have led to two hypotheses regarding pathogenesis. The first is that there is a basic defect in organ maturation resulting in impaired function, such as occurs in the immune system. The second is that defective DNA repair or synthesis induced by radiation or chemicals produces cell damage. These theories are not mutally exclusive (Waldermann et al. 1983). Both lack of autoantigen recognition, with failure to suppress potential neoplastic cells, and the increased effect of radiation and cytotoxic chemicals have been suggested to underlie the increased rate of malignancy.

Furthermore, there are so-called ataxia telangiectasia-like disorders and genes responsible for these variants have also been identified. This includes the Nijmegen Breakage syndrome due to mutations in the NBS1 gene on chromosome 8q21 (Carney et al. 1998, Varon et al. 1998). There is some overlap in clinical features including immunodeficiency, chromosomal instability, hypersensitivity to ionizing radiation, and high risk for cancer (Uhrhammer et al. 1998). However, these patients do not have ataxia or telangiectasia but microcephaly and learning difficulties. A second variant is due to mutations in the MRE11 gene causing the ataxia telangiectasia-like disorder (ATLD) with a similar phenotype with early onset ataxia and increased radiosensitivity (Hernandez et al. 1993, Klein et al. 1996, Stewart et al. 1999). Finally, the differential diagnoses to consider are ataxia with ocular motor apraxia types 1 and 2 which can clinically mimic ataxia telangiectasia. However, in AOA1, alpha fetoprotein levels are normal, and in AOA2, ATM levels are normal, so these tests may be useful for differentiation (see later).

Increased blood levels of alpha fetoprotein, beta fetoprotein, and carcinoembryonic antigen have been reported (Waldermann and McIntire 1972, Boder 1975, Sugimoto et al. 1978). The former is the most regular abnormality and has been found to be elevated in 100% of cases (Waldermann et al. 1983).

Routine haematology shows lymphopenia in a third of patients with a reduced proportion of cells carrying certain T-cell markers. A neutrocytosis may be present in response to infection. Plasma biochemistry is usually unremarkable apart from possibe evidence of glucose intolerance in over 50% and hepatic dysfunction in 40–50%. Elevations of serum alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvate transaminase, and lactic acid dehydrogenase have been reported along with abnormal retention of bromsulphalein (McFarlin et al. 1972). There may be evidence of gonadal dysfunction including diminished excretion of 17 ketosteroids (Smith and Conerly 1985).

Serum protein electrophoresis and immunoglobulin estimations usually reveal a dysgammaglobulinaemia. The most common abnormalities are decreased or absent IgA and IgE (Ammann et al. 1969). Total IgG is usually normal or slightly reduced, but decreased subclass IgG-2 is present in most patients (Oxelius 1982). Total IgM may be normal or increased, although an abnormal low molecular weight IgM and a sedimentation coefficient of 8S is usually present (McFarlin et al. 1972). IgA is usually deficient in secretions including those of the respiratory tract, tears, and saliva. This is accompanied by a marked decrease in the number of plasma cells containing IgA in mucosal surfaces.

Cellular immunity is diminished and cutaneous delayed hypersensitivity responses to a variety of stimuli are absent or reduced. Lymphocytes show a variety of abnormalities with in vitro testing, and blast transformation in response to various antigens, phytohaemagglutinin, and pokeweed mitogen is deficient (McFarlin et al. 1972). The production of antibody is severely reduced and lymphocytes are unable to increase this normally when stimulated by specific antigens and by non-specific means. There is inability to produce antigen-specific cytotoxic killer cells.

Immature B-lymphocytes are coded to enable production of IgM and IgD, but with differentiation they may discard a piece of DNA and the gap is sealed (switch recombination) to allow the formation of IgG, IgA, or IgE. Similarly immature T-lymphocytes have antigen receptors on their surface, which are composed soley of gamma or delta chains, and with development they may switch to having receptors with alpha and beta chains. These processes in B- and T-lymphocytes may be derived from the same ancestral gene, and abnormality of this may be why IgG, IgA, IgE, and T-lymphocytes, with alpha and beta antigen receptors, are deficient in this disease (Carbonari et al. 1990, Peterson and Funkhouser 1990).

The CSF is usually normal although non-diagnostic pleocytosis and protein elevation have occasionally been reported (Boder and Segewick 1958, Goodman et al. 1969).

Several radiological abnormalities may be found in ataxia telangiectasia. Skull and chest X-rays may reveal sinus or pulmonary pathology. The absence of adenoid and tonsillar tissues may be evident in views of the nasopharynx. CT scanning of the chest may show an absence of thymic tissue and views through the posterior fossa may display cerebellar atrophy (Scharnetzky et al. 1980).

Electroencephalography may show minor non-specific changes in a minority of cases with a diffuse increase in the amount of slow activity. Visual and somatosensory evoked potentials are frequently abnormal and such abnormalities may precede clinical manifestations of involvement. By contrast, brainstem auditory evoked potentials are usually unaffected (Sridharan and Mehta 1985, Taylor et al. 1985, Kwast and Ignatowicz 1990).

Nerve conduction studies are usually normal, but advanced disease may show minor slowing suggestive of a disproportionate loss of larger fibres. Motor and sensory recordings can both be affected (Kwast and Ignatowicz 1990). At this stage electromyography may show ‘neurogenic’ changes (Engel et al. 1966, Goodman et al. 1969).

Sural nerve biopsy has shown minor changes including lipid accumulation in Schwann cells and some axonal degeneration (Gardner and Goodman 1969, Barbieri et al. 1986). Muscle biopsy shows ‘neurogenic’ atrophy (Engel et al. 1966, Goodman et al. 1969). Although features suggestive of myopathy have also been occasionally observed (Goodman et al. 1969), it seems unlikely that there is significant myopathic change in most cases.

The disorder is gradually progressive and little treatment is available. The major neurological disability results from cerebellar degeneration and this is not amenable to therapy. In cases where involuntary movements predominate, dopamine receptor modulating drugs may produce relief (Bodensteiner et al. 1980), although few reports actually mention the results of such treatment. Unless chorea or dystonia are causing significant disability it is probably best to avoid these drugs. Rehabilitative measures aimed at maximal utilization of existing function are important.

Vigorous treatment of respiratory infections with antibiotics and physiotherapy is the mainstay of treatment. Parenteral gammaglobulin and administration of fresh or freshly frozen plasma has also been recommended if recurrent infections prove troublesome. Bone marrow transplantation and the use of transfer factor have also been reported to be helpful, but at present must be regarded as experimental (Berkel et al. 1977).

In view of the increased risk of developing malignancies, patients should be screened regularly. When treating malignancy the abnormal sensitivity to radiation and chemotherapy should be remembered and reduced dosage is appropriate. Fatal reactions to radiotherapy have been reported (Gotoff et al. 1967, Morgan et al. 1968, Eyre et al. 1988).

Genetic advice should be offered to the parents. As it is an autosomal recessive disorder, any of their children will have a 25% chance of being homozygous and thus having the disease as well as a 50% chance of being heterozygous for the ATM gene mutation. although by itself it would be unlikely to influence parents not to have further children. The increased incidence of malignancy in heterozygotes should be borne in mind.

The classification of spinocerebellar degenerations remains contentious. There is very considerable phenotypic variation, not only between but also within pedigrees, which casts doubts on the validity of many of the classifications that have been proposed. Historically, there is that of Harding (1982) in which she defines autosomal dominant cerebellar ataxia (ADCA) of late onset into four types. Type 1 encompasses all of the cases with ophthalmoplegia, optic atrophy, dementia, amyotrophy, and extrapyramidal features, which do not show a pigmentary retinal degeneration. Type 2 consists of patients who have cerebellar degeneration but in addition have a pigmentary retinal degeneration. They may also have ophthalmoplegia, dementia, and extrapyramidal features. Type 3 consists of a pure cerebellar syndrome without ocular features, dementia, or extrapyramidal signs. Such cases generally commence after 60 years of age. Type 4 includes patients with myoclonus and deafness. The pathology associated with types 1 and 2 are those of olivopontocerebellar atrophy, but there is nearly always abnormality elsewhere in the nervous system, including the basal ganglia, spinal cord, and peripheral nerves.

Molecular geneticists have documented the genetic heterogeneity of the autosomal dominant ataxias which are labelled as spinocerebellar ataxia (SCA) and are followed by a number assigned for each new gene locus. Some of the SCAs have been identified to be trinucleotide repeat expansion disorders, for example spinocerebellar ataxia type 1 (SCA1). However, not all SCAs are due to this molecular mechanism, for example it is not a feature of patients with type 2 (Enevoldson et al. 1994, Giunti et al. 1994). Genotype-based classification of the list of SCA mutations has grown to about 30 and it is likely that more will be discovered (Subramony 2001). Chorea is a rare manifestation of these conditions, being described in SCA1 (Schols et al. 2000), with SCA2 (Subromony 2001), SCA 3 (Schols et al. 2000), and SCA17 (Schneider et al. 2006[b]), as well as dentatorubro-pallidoluysian atrophy (see later and Chapter 20 under Huntington's disease look like-4 disease).

Older classifications (Holmes 1907) tended to define three main varieties of inherited cerebellar ataxias, namely hereditary spastic ataxia, olivopontocerebellar atrophy, and cerebellar atrophy. We have chosen to adopt this older classification here, not because we think it is correct, but because many of the descriptions of choreic and athetotic movements within such pedigrees date from earlier times and have used such a system. In addition, there are the issues of dominantly inherited spastic paraplegia and the more recently described ataxia-ocular motor apraxic syndrome. Because of the latter's close resemblance to classical ataxia telangiectasia, it is described first, so it is juxtaposed to the section on the latter disease. Descriptions for the others follow.

In 1988 Aicardi et al. described a disorder that bore striking clinical resemblance to ataxia telangiectasia, had a tendency to late onset, and demonstrated no evidence of involvement with other systems. In particular, there was no tendency to frequent infections, and immunoglobulins, alpha fetoprotein, T- and B-lymphocyte markers, and chromosomes 7 and 14 were normal in all of the patients who were tested. In addition, the cases did not demonstrate telangiectasia. There was evidence of parental consanguinity in some cases and siblings were involved. The authors felt it was most likely the disorder was inherited as an autosomal recesssive condition.

The condition commenced in childhood and typically started between 2 and 7 years of age. Ataxia of gait was the initial symptom and this tended to be followed by incoordination of the upper limbs and an unstable sitting posture. The disorder was slowly progressive, although most patients could still walk independently in their early to mid-teens. All of the cases had choreic and athetotic movements in addition to cerebellar ataxia. Chorea was particularly prominent in some of the patients. Tremor of the upper limbs and hypomimia occurred in a small number.

All of the patients exhibited abnormal head movements, which usually commenced a few years after the appearance of the ataxia and were felt to be due, at least in part, to the abnormal eye movements, which were clinically indistinguishable from oculomotor apraxia. Saccades, particularly those carried out to command, were extremely slow and hypometric. Usually several saccades in succession were required to make a movement and in some patients it took several seconds. Horizontal movements were impaired in all patients and vertical saccades were affected in the majority. Head thrusts and exaggerated blinking were used to achieve fixation. Optokinetic nystagmus was absent or abnormal in most patients. Ice-water caloric tests were abnormal in the subjects tested.

Deep tendon reflexes were reduced or absent in almost all the patients, particularly in the lower limbs, but there was no loss of muscle bulk or weakness. Impairment of posterior column function was seen in a few cases. Pyramidal tract signs occurred occasionally. Approximately half the patients had mild mental subnormality. CT showed slight atrophy of the vermis in some cases. Motor nerve conduction velocity was reported to be occasionally slowed in the lower limbs.

The patients originated from widely separate geographical areas and from different backgrounds. The authors considered that it formed a distinctive syndrome separate from ataxia-telangectasia and that it was a form of spinocerebellar degeneration.

Genetically, two forms can be distinguished: ataxia oculomotor apraxia syndrome type 1 and type 2. Of these, the former is caused by mutation in the gene encoding aprataxin (APTX) which is located on chromosome 9p13 (Date et al. 2001). The second form is due to mutations in the senataxin (SETX) gene located on chromosome 9q34 (Moreira et al. 2004).

A variety of involuntary movements, including chorea and athetosis, have been noted in some types of spinocerebellar degneration. Movements associated with the largely spinal form, familial spastic paraplegia, are mentioned in Chapter 41 as most descriptions emphasize dystonic features.

Hereditary spastic ataxia is a somewhat uncertain entity and while some have classified it along with olivoponto-cerebellar atrophy (Pratt 1967), others (Eadie 1975[a]) have envisaged it as a link between spinal and cerebellar forms of spinocerebellar degeneration. Delineation as a separate disorder is based largely on descriptions of a single family reported by Sanger Brown in 1892. In 22 affected individuals onset varied between 11 and 45 years of age. Cerebellar signs with ataxia and incoordination initially predominated, but later pyramidal tract signs became prominent. Optic atrophy with progressive visual failure was common and ptosis occurred occasionally. Dysarthria was frequent and few patients developed dysphagia. As the disorder progressed involuntary choreic-like movements became marked. ‘When the patient attempts to talk the tongue appears to move in every conceivable position without being protruded; the face undergoes various incoordinate movements, the head is repeatedly bent forward and moved from side to side, there is protrusion of the chin, and the arms were flexed and moved forwards and backward. The movements are highly suggestive of chorea, but less rapid’ (Brown, 1892). The mean life expectancy from onset was 15 years (Barker 1903, Brown 1892). The most conspicuous neuropathological feature was degeneration of posterior columns and dorsal spinocerebellar tracts, but there were minor changes in the brainstem and cerebellum. Anatomical reports, however, were not complete. While there have been a few reports of families similar to that described by Brown (1892), in most, involuntary movements have been absent and none seems to fit exactly into the same category (Eadie 1975[a]).

Olivoponto-cerebellar atrophy is sometimes associated with involuntary movements. The inherited variety (Menzel type) was well described by Menzel (1891) and one of his patients had chorea in an arm, facial contortions, torticollis, and jactitation of the feet, as well as dysarthria, incoordination, and ataxia.

The disorder is usually inherited as an autosomal dominant condition. Degeneration is frequently most marked in the cerebellum, pons, medulla (especially the olivary nuclei), posterior columns, and spinocerebellar tracts. More widespread changes, however, are often present. Onset is usually in early or mid adult life, commencing with ataxia and incoordination. Dysarthria develops and dysphagia may occur (Menzel 1891, Aring 1940, Schut 1950). Paralysis of bulbar muscles and fasiculation of the tongue may be present. Optic atrophy, pupillary abnormalities, and a variety of eye movement disturbances sometimes occur. Pyramidal tract signs and sphincteric involvement are seen in some patients. Dementia occurs occasionally [for a review of clinical features see Eadie (1975[b])].

Involuntary movements include orofacial dyskinesia (Gallemaerts et al. 1939, Chandler and Bebin 1956), slow (Aring 1940) or rapid (Fickler 1911, Rosenhagen 1943, Locke and Foley 1960) head movements, torticollis (Menzel 1891), chorea (Menzel 1891, Hassin and Harris 1936, Rosenhagen 1943, Chandler and Bebin 1956,), athetosis (Adams et al. 1961, Tyrer et al. 1964, Konigsmark and Weiner 1970), and hemiballismus (Titica and van Bogaert 1946). Parkinsonian features with hypokinesia, bradykinesia, fixed posture, and rest tremor are occasionally seen. The disorder is gradually progressive and survival is approximately 15 years from onset, although there is a considerable range (Eadie (1975[b]).

The sporadic variety (Dejerine–Thomas type) of olivopontocerebellar atrophy is frequently associated with parkinsonian features, but involuntary movements, other than tremor, are seldom a feature (Eadie 1975[d]). Dystonia has rarely been reported (Janati et al. 1989).

By contrast with inherited olivopontocerebellar atrophy, both dominantly and recessively inherited cerebellar forms of spinocerebellar degeneration (Holmes’ type), in which degeneration is largely restricted to cerebellar cortex and olivary nuclei, seldom show involuntary movements other than tremor (Eadie 1975[c]). Dystonia has only occasionally been reported (Ferguson and Critchley 1924, Harding 1984). However, one of Hall et al.'s (1941, 1945) patients possibly had athetosis. Fraser (1880) described siblings with progressive cerebellar signs, optic atrophy, and strabismus. One patient had chorea. Autopsy showed atrophy of the cerebellum with thinning of the cortex, but pathological details were scanty. The classification of this family is uncertain, but the presence of optic atrophy makes it unlike the Holmes’ type of cerebellar atrophy although temporal pallor of the optic discs has occasionally been noted in this latter disorder (Richter's 1940).

Other variants of cerebellar atrophy have occasionally been reported to have involuntary movements. The family described by Weiner et al. (1967) had 27 members over five generations affected with progressive ataxia, choroidoretinitis, optic atrophy, impaired ocular movements, pyramidal signs, and late onset dementia. Facial dyskinesia, athetosis, and occasionally chorea were prominent. Degeneration of the cerebellum, olivary nuclei, and striatum was present in a patient who had progressive dementia, ataxia, ‘choreo-athetoid’ movements, and hypogenitalism. A brother was similarly affected (Altschul and Kotlowski 1956).

In 1946 Titeca and van Bogaert described a 47-year-old Belgian male who had presented with chorea, ataxia, and dysarthria. His sister had suffered a similar illness with ataxia and dementia. Their mother had died at 68 years of age and was not known to have been affected. Post-mortem of the index case showed marked atrophy of the dentatorubral and pallidoluysian systems. In 1958 Smith et al. described a patient with ataxia, dysarthria, opsoclonus, chorea, and dystonia. They defined the neuropathology as resulting from ‘combined dentatorubral and pallidoluysian degeneration’. In the same year Verhaart (1958) published details of a 50–year-old who had combined degeneration of the dentate nuclei, globus pallidus, and subthalamic nuclei. There was a lesser degree of damage in the red nuclei, tegmentum, and medium longitudinal fasiculus. The following year Neumann reported on two additional cases who showed neuronal loss and gliosis involving chiefly the globus pallidus and dentate nucleus, with a lesser degree of alteration in the red nucleus and subthalamic nucleus (corpus Luysi). Minor changes were also present in the spinal column. Delineation of the entity of dentatorubro-pallidoluysian atropy as a separate disease entity had begun. Examples of this disorder remained extremely rare, however, until almost 20 years later when reports of familial cases with similar pathology, but rather varied clinical phenotype, began to appear from Japan (Takahata et al. 1978, Goto et al. 1982, Naito and Oyanagi 1982). Subsequently it has become apparent that the disorder has a particular predilection for Japanese (Iizuka et al. 1984, Takahashi et al. 1988), although further case reports have appeared from Europe (Warner et al. 1994, Munoz et al. 1999, Destee et al. 2000, Filla et al. 2000) and in African-Americans (Burke et al. 1994[a]). In the latter group it has sometimes been referred to as the Haw River syndrome. On the other hand, it seems to be rare or not occur in the Asian Indian and Chinese populations (Basu et al. 2000, Tang et al. 2000).

The pathological hallmark of this disease is combined degeneration of the dentatofugal and pallidofugal systems. There is thus severe cell loss and gliosis of the dentate and red nuclei, as well as the globus pallidus, particularly the lateral segment, and the subthalamic nucleus. Sometimes there is widespread deposition of lipofuscin (Goto et al. 1982, Iizuka et al. 1984, Horner et al. 1994, Munoz et al. 1999). The cerebellar changes are usually more marked than those involving the pallidum and subthalamic nucleus (Iizuka et al. 1984, Takahashi et al. 1988). Occasionally it has been the internal rather than the external segement of the globus pallidus which has shown most atrophy. Such cases may be more likely to show a parkinsonian-like clinical picture (Goto et al. 1982). In patients with chorea, the major histo-pathological change may be in the external segment (Kosaka et al. 1977). Lesser degrees of damage can also occur in the caudate, putamen [with loss of large neurons and proliferation of glia (Naito and Oyanagi 1982)], substantia nigra, inferior olivary nucleus, and thalamus, particularly laterally (Pfeiffer and McComb 1990). Neuronal loss in the substantia nigra has perhaps been more common in sporadic than familial cases (Warner et al. 1994). In addition, degeneration of the fastigio-vestibular system is common and particularly involves demyelination of the uncinate fasciculus, juxtarestiform body (Iizuka et al. 1984), and vestibular nuclei (Takahashi et al. 1988). Damage to the midbrain tegmentum and the adjacent pons seems to correlate with ocular motor abnormalities. There has been atrophy of the pontine and midbrain reticular formation, central tegmental tracts, central grey matter, and superior colliculi, and has been mainly reported in cases of the ataxic-choreoathetoid type (Iizuka et al. 1984).

In addition, in a few cases there has been spinal cord involvement, rather reminiscent of that seen in Friedreich's ataxia, with degeneration of corticospinal pathways or posterior columns (Goto et al. 1982, Iizuka et al. 1984, Pfeiffer and McComb 1990, Warner et al. 1994). Demyelination in spinocerebellar tracts may also occur (Titeca and van Bogaert 1946, Naito and Oyanagi 1982, Iizuka et al. 1984). Infrequently, the anterior horns of the spinal cord may be affected. In rare cases the changes have been suggestive of motor neuron disease (Gray et al. 1981, 1985), but the exact classification of such patients and their relationship to the more typical disorder is quite uncertain. Degeneration of the posterior roots and neuronal loss in the dorsal root ganglia has been an occasional feature (Pfeiffer and McComb 1990) and there has been evidence of axonal loss on sural nerve biopsy (Goto et al. 1982). In most patients the cerebellar cortex has been normal or only slightly involved, but more severe degeneration has been reported (Takahashi et al. 1988). Usually cerebral cortex has been unaffected, but occasionally there have been mild changes (Warner et al. 1994). The basal nucleus of Meynert has been found to be uninvolved (Takahashi et al. 1988).

The biochemical changes associated with this disorder are not well known. GABA concentrations in the internal segment of the globus pallidus and the substatia nigra are reduced. Substance P concentration is diminished in the same areas, with the nigra being affected to a greater extent (Kanazawa et al. 1985). CSF levels of the dopamine metabolite homovanillic acid are low, whereas those of the serotonin metabolite 5-hydroxyindoleacetic acid are normal (Goto et al. 1982). Choline acetyltransferase activity tends to be reduced in the caudate and putamen (Kanazawa et al. 1985).

Linkage and candidate gene analysis in Japanese families has shown that the disorder is associated with an expanded trinucleotide repeat sequence (CAG) on chromosome 12p (Koide et al. 1994, Nagafuchi et al. 1994). This repeat segement is polymorphic in a control population with between 7 and 23 repeats. In patients suffering from dentatorubro-pallidoluysian atrophy it is expanded to between 49 and 75 repeats with no overlap between normal and affected subjects. There has been a dominant mode of inheritance. (Warner et al. 1995; Potter et al. 1995; Burke et al. 1994[a]). Dentatorubral and pallidoluysian atrophy (DRPLA) is thus one of the family of neurodegenerative diseases caused by expansion of a polyglutamine tract. The DRPLA gene product is called atrophin-1 and is widely expressed, and is found in both the nuclear and cytoplasmic compartments of neurons (Yazawa et al. 1995, Schilling et al. 1999). Truncated fragments of atrophin-1 accumulate in neuronal nuclei both in a transgenic mouse model of DRPLA and in human postmortem brain tissue (Schilling et al. 1999, Yamada et al. 2001), and may underlie the disease phenotype.

A deficit of in vivo mitochondrial oxidative metabolism and thus a role for mitochondrial dysfunction as a factor involved in the pathogenesis of both Huntington's disease and DRPLA has also been suggested by 31P-magnetic resonance spectroscopy (MRS) studies (Lodi et al. 2000).

As in Huntington's disease, the size of the expansion is inversely correlated to the age of onset, so that those with the most trinucleotides tend to develop symptoms earlier than those with short expansions. The similarity extends even further and the clinical features of dentatorubro-pallidoluysian atrophy tend to depend on the age of onset, with progressive myoclonus and epilepsy being more common in those whose symptoms commence early, and ataxia, choreoathetosis, and dementia being observed more frequently in patients with later onset of symptoms (see later). Like Huntington's disease the condition shows a marked tendency for anticipation, so that succeeding generations usually develop symptoms at a progressively younger age. This is related to instability of the expanded allele, particularly when inherited from the father. In 80% of paternal tranmissions there is an increase of more than 5 CAG repeats. Maternal transmissions, however, may show either a decrease or an increase in length of fewer than 5 repeats (Ikeuchi et al. 1995, Komure et al. 1995, Potter 1995). Earlier onset and greater severity of disease has been noted in homozygotes (Ikeuchi et al. 1995).

As mentioned above, the disorder appears to be more common in Japanese, in whom the prevalence is estimated at approximately 1 case per million (Miwa 1994), than in those of European and African descent, in whom the condition is thought to be exceedingly rare. Le Ber et al. (2003) estimated the frequency of DRPLA in Europe as 0.25% in both familial and sporadic cases, based on a sample of 809 patients with ataxia.

It has been suggested that this may be because normal Japanese have a greater number of CAG repeats in the allele for this disease than these other races, and mutation with an expansion in the number of repeats to beyond the critical length may thus be easier. Burke et al. (1994[b]) claimed that the proportion of Japanese with alleles larger than 19 repeats (7.4%) is greater than that in whites (0%) and African-Americans (1%), although the number of chromosomes (610) in this study was relatively small. More recently, four Portuguese families with DRPLA were found to have two intragenic single nucleotide polymorphisms in introns 1 and 3 of the DRPLA gene, in addition to the CAG repeat, and all these families shared the same haplotype which was also identical to Japanese DRPLA chromosomes. It was suggested that in view of that this haplotype is the most frequent in Japanese normal alleles, but rare in Portuguese controls, and this may explain the relatively high frequency of DRPLA in Japan compared to Europe (Martins et al. 2003).

It has also been suggested that in occasional families, the genetic abnormality responsible for dentatorubro-pallidoluysian atropy is linked to the long arm of chromosome 14 (Cancel et al. 1994). The significance of this, however, remains uncertain as a clinically similar ataxic syndromes, namely Machado-Joseph disease or spinocerebellar ataxia (SCA3), is localized to this same area and it is possible such families represent variants of this disorder, rather than being true examples of dentatorubro-pallidoluysian atrophy.

From the clinical point of view dentatorubro-pallidoluysian atrophy has been divided into three types (Iizuka et al. 1984), although such subclassification has been thought by others to be inappropriate and potentially misleading (Warner et al. 1994). The patterns of clinical abnormality that have been defined are as follows:

Spinal lesions resembling those of Friedreich's ataxia have been reported in all of these three clinical types (Iizuka et al. 1984).

There is a very wide spectrum of the clinical phenotype with a range of different combinations of signs and symptoms, rather than three clearly delineated groups. While there is a tendency for the pattern to be different in those with younger from those with older onset, the whole range can be seen within single families (Takahashi et al. 1988, Warner et al. 1994).

Psychomotor retardation may be noted in infants (Takahashi et al. 1988) and childhood onset cases, but early development is usually normal. Myoclonus and epilepsy subsequently develop and tend to be resistent to therapy. The myoclonus may be stimulus sensitive and induced by touch, change of posture, or light. Onset prior to 21 years of age is associated with myoclonus (96%) and epilepsy (96%) much more frequently than those in whom the disease first appears over 40 (myoclonus approximately 25% and epilepsy approximatley 12%). There is an intermediate prevalence (approximately 50%) of both of these two symptoms in those with onset between 21 and 40 years. On the other hand, commencement after 40 years of age is associated with choreoathetosis (80%) and psychiatric symptoms (80%) in the majority of cases, whereas these are much less frequent in those with onset under 21 years. Ataxia and dementia, however, are very commonly seen whatever the age of onset (Fig. 21.13).

Psychiatric symptoms are very variable, including mood instability, irritability, euphoria, soliloquy, hypereroticism, delirium, delusions, visual and auditory hallucinations, and suicidal tendencies (Ikeuchi et al. 1995). Dementia has been claimed to be ‘subcortical’ in nature (Morita and Naito 1986), but precise neuropsychological details are uncertain.

A variety of ocular motor abnormalities have been reported, including supranuclear conjugate gaze palsy (particularly vertical), loss of convergence, horizontal gaze nystagmus, which can be monocular, ‘nystagmoid jerks’, impaired voluntary and pursuit saccades, and ‘slow eye movements’ (Verhaart 1958, Neumann 1959, Goto et al. 1982, Iizuka et al. 1984). Opsoclonus (Smith et al. 1958) and ptosis (Iizuka et al. 1984) have also been descibed.

Dysarthria is common (Warner et al. 1994) and dysphagia can be a problem, particularly terminally. Incoordination may be more pronounced in the lower extremities and gait ataxia can become marked (Iizuka et al. 1984). Chorea and dystonia are common, particularly the former, and they involve the face, neck, trunk, and limbs. At times the movements may be ballistic. In some patients

the clinical picture is dominated by parkinsonism, with or without superadded dystonia (Warner et al. 1995). Evidence of pyramidal involvement may be present with hypertonia, ankle clonus, hyper-reflexia, including a brisk jaw-jerk, and extensor plantar responses (Goto et al. 1982, Iizuka et al. 1984, Takahashi et al. 1988, Warner et al. 1994). Conversely, there may be hypotonia and diminished or absent tendon reflexes (Goto et al. 1982, Pfeiffer and McCombe 1990, Warner et al. 1994). Impairment of sensation is usually absent or mild, but defects in spinothalamic and posterior column sensory modalities have been reported occasionally (Goto et al. 1982, Pfeiffer and McCombe 1990).

Gradual progression usually results in the patient becoming bedridden, sometimes in a state of spastic tetraparesis. Premature death may result from the effects of immobility or occasionally from uncontrolled seizures.

The clinical spectrum of dentatorubro-pallidoluysian atrophy overlaps with that of Huntington's disease, progressive myoclonic epilepsy, and spinocerebellar degenerations such as Friedreich's ataxia, so that misdiagnosis is not uncommon (Pfeiffer and McComb 1990, Warner et al. 1995).

Routine haematological, biochemical, and CSF evaluations are unhelpful in establishing diagnosis. Reported abnormalities of CSF neurotransmitters have been mentioned above, but are not specific enough to allow diagnosis and overlap with the normal range. One study has reported that high-amplitude somatosensory evoked potentials were not present in any of their genetically proven 12 DRPLA patients as compared to patients with Unverricht Lundborg syndrome. Moreover, brainstem auditory evoked responses were also absent in seven out of the 12 patients. The authors suggested that these results suggest differences in pathophysiology between DRPLA, which predominantly affects the brainstem and subcortical regions, and progressive myoclonic epilepsy characterized by cortical hyperexcitability (Kasai et al. 1999). CT and MRI brain scan may show atrophy of the cerebellum and brainstem, particularly the midbrain and pons. There can also be a degree of cerebral atrophy. Degeneration of the globus pallidus may be apparent and it can show high intensity signals on proton and T2-weighted MRI images (Imamura et al. 1994). Similar changes have been reported in subcortical white matter (Potter et al. 1995, Munoz et al. 1999). Chromosomal evaluation with identification of an abnormally enlarged CAG repeat sequence is clearly the most definitive test.

Management should include genetic advice, counselling, and support, as has been outlined in Chapter 20 for Huntington's disease. Specific therapy is unavailable and treament has to be symptomatic, aimed at controlling seizures, ballismus, severe chorea, and troublesome dystonia, in addition to physiotherapy, occupational therapy, and nursing. The general principles of this are similar to those applied to Huntington's disease and generalized primary dystonia, which have been covered elsewhere.

Degeneration of retinal pigment epithelium and choroid is occasionally associated with involuntary movements. Fundus flavimaculatus is one of a miscellaneous group of disorders encompased by the ‘flecked retina syndrome’ (Krill and Klien 1965). Fundus flavimaculatus is an allelic subtype of Stargardt disease, the most common hereditary recessive macular dystrophy, with an estimated incidence of 1 in 10,000. Stargardt disease, which has been associated with mutations in the ABCA4 gene and the RDS gene, shows juvenile to young adult age of onset; fundus flavimaculatus often displays later age of onset and slower progression.

The yellowish-white retinal spots of fundus flavimaculatus may be widespread or grouped posteriorly. The optic nerve, visual fields, and dark adaptation are normal or show only minor changes. Both sporadic and familial forms have been described. Friemann (1955) reported siblings with choreic movements of the face and limbs and ‘flavial dystrophy’. The fundal photographs suggest fundus flavimaculatus, a term introduced subsequent to Friemann's (1955) report (Franceschetti 1962).

Richardson et al. (1981) reported serpiginous choroiditis, unilateral hemiplegic dystonia, and intention tremor in a sporadic case.

Calcification of the basal ganglia occurs in a wide variety of unrelated medical conditions including a variety of infections, metabolic and genetic syndromes, and intracranial diseases and can also be an incidental finding in the elderly. It may be inherited in disorders such as pseudohypoparathyroidism and tuberous sclerosis. In addition, several pedigrees have been reported in which idiopathic intracranial calcification, involving the neostriatum and globus pallidus, has been associated with a movement disorder (Fritzsche 1935, Matthews 1957, Schafroth 1958, Sala and Savoldi 1959, Moskowitz et al. 1971, Boller et al. 1977, Francis 1979, Kuroiwa and Mayron 1982, Manyam et al. 1992).

It is uncertain whether such families have the same disorder, as clinical features vary quite markedly. Both autosomal dominant and recessive modes of inheritance have been noted, but many earlier reports have not utilized CT brain scan, making it possible intracranial calcification was overlooked in some cases, leading to a pseudo-recessive pattern. Calcification in these families has been described in the caudate putamen, globus pallidus, cerebral and cerebellar gyri, and dentate nucleus and vermis (Boller et al. 1977, Kuroiwa and Mayron 1982, Manyam et al. 1992). The term bilateral striopallidentate calcinosis or Fahr's disease has been used to describe some idiopathic familial cases (Manyam et al. 1992). Most of these usually have an autosomal dominant type of inheritance. A gene locus on chromosome 14q has been identified in one such family with idiopathic basal ganglia calcification. The index case and other family members had a combination of chorea, dystonia, and tremor presenting in the mid 20s (Geschwind et al. 1999).

Although calcification may appear in childhood or adolesence, the appearance of symptoms is usually delayed until adult life. Mental deterioration seems almost invariable, with many cases progressing to dementia (Boller et al. 1977). In occasional families the predominant picture may be schizophreniform psychosis (Francis 1979). Epilepsy occurred in some patients (Sala and Savoldi 1959). Dysarthria is common and may occur alone or in association with incoordination and ataxia (Matthews 1957, Boller et al. 1977). Occasional patients have had ‘pyramidal’ features.

The commonest movement disorder is parkinsonism with hypomimia and bradykinesia. Many patients, however, have had chorea of the face, neck, and all limbs. Manyam and collegues (2001) in 61 cases with idiopathic striopallidodentate calcification found that parkinsonism was the commonest clinical feature in 57%, followed by chorea in 19%, followed by tremor and dystonia (8% each). Frequently these movements have been labelled as ‘choreoathetotic’ (Moskowitz et al. 1971, Boller et al. 1977, Francis 1979, Kuroiwa and Mayron 1982). For further descriptions see Chapters 14 and 41.

Both familial and sporadic cases of this disorder have been reported. Cutaneous marmorata is frequently associated. Onset has occurred from childhood to adult life. There is extensive angiomatosis of leptomeninges and adjacent cerebral cortex with progressive demyelination of cerebral white matter. Clinical features include dementia, epilepsy, and neurological deficit due to haemorrhage. Involuntary movements, including chorea, athetosis, and myoclonus have occasionally been described (Divry and van Bogaert 1946, van Bogaert and Colle 1967). The type of movement disturbance may alter and in one patient there was transition from a cerebellar-myoclonic syndrome to choreoathetosis and eventually to rigidity with dystonia. (van Bogaert and Colle 1967)

A family with 18 affected members (ten males and eight females) with a novel autosomal dominant disorder characterized by adventitious movements that sometimes appear choreiform and that are associated with perioral and periorbital myokymia has been described (Fernadez et al. 2001). The disorder starts in early childhood or adolescence. The involuntary movements are paroxysmal at early ages, increase in frequency and severity, and may become constant in the third decade. Thereafter, there is no further deterioration, and there may even be improvement in old age. The adventitious movements are worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease is socially disabling, but there is no intellectual impairment or decrease in lifespan. The authors excluded linkage to genes for conditions known to cause chorea including Huntington disease, dentatorubral-pallidoluysian atrophy, choreoacanthocytosis, benign hereditary chorea locus, as well as paroxysmal dystonic choreoathetosis and episodic ataxias and suggesting that a novel gene underlies this condition.

In 1983 Woodhouse and Sakati described a distinctive autosomal recessive neuroendocrine syndrome in six Saudi Arabian patients from two inbred families. Since then a handful of reports of similar cases have been published (Gul et al. 2000, Al-Swailem et al. 2006, Medica et al. 2007, Al Semari and Bohlega 2007, Koshy et al. 2008,

Schneider and Bhatia 2008, Alazami et al. 2008, Alazami et al. 2010, Steindl et al. 2010). The disorder is characterized by the combination of alopecia, hypogonadism, diabetes mellitus, mental retardation, sensory neural deafness and extrapyramidal features. Seizures, polyneuropathy, thyroid dysfunction, keratoconus and syndactyly of hand or feet have been described in some of the cases.

A literature review by Schneider and Bhatia (2008) revealed that involuntary movements occurred in about half of the cases and were mostly characterized by a combination of chorea and dystonia with onset in adolescence or adulthood with focal limb onset, but spread of symptoms was common causing gait difficulties and immobility as the disease progresses. Severe dystonic scoliosis can occur. A patient with cogwheel rigidity in the absence of dystonia and chorea has also been reported (Al Semari and Bohlega 2007). Eye movements were normal even in late stages. Alopecia is progressive and typically begins in the fronto- parietal region. (Fig. 21.14) It also affects body hear including eyelashes and in the pubic area. Body stature is often eunochoid due to abnormal sexual hormones and both hypo- and hypergonadtropic hypogonadism have been described. Diabetes mellitus may be either insulin-dependent (type I) or –independent (type II) and work-up has demonstrated reduced levels of insulin-like growth factor 1. (Al Semari and Bohlega 2007) Investigations have furthermore shown white matter lesions on MRI and T-wave electrocardiogram abnormalities. (Fig. 21.15 and see Schneider and Bhatia 2008 for review). Table 21.7 shows a summary of the clinical and investigational findings.

The underlying gene defect of the disorder, which thus phenotypically resembles a mitochondriopathy, was identified by Alazami et al. (2008) who detected mutations in the C2orf37 gene localized on chromosome 2q31 in eight families of Saudi origin. In addition to this initial founder mutation, further mutations have since been reported in independent families including Caucasian cases (Alazami et al. 2010, Steindl et al. 2010).