14 Basal ganglia calcification

Calcification in the brain occurs in various tumours, infarcts, haematomas, arteriovenous malformations, hamartomas, tuberous sclerosis, Sturge–Weber syndrome, cysticercosis, toxoplasma and cytomegalic inclusion disease, tuberculomas, etc. Such focal calcification in sites of brain injury (metastatic calcification) is not the subject of this chapter. Nor do we consider microscopic calcification in the brain. We are concerned with macroscopic calcification in the basal ganglia.

In 1930 Fahr described a single 55-year-old patient who died in coma after a series of seizures. At autopsy the brain showed striking calcification of the blood vessels penetrating the white matter of the cerebral hemispheres, but not of the basal ganglia. Historical inaccuracy has led to the use of the term ‘Fahr's disease’ to describe basal ganglia calcification, although Bamberger (1855) first described this finding in autopsy material. Radiological identification of basal ganglia calcification, and in the dentate nucleus of the cerebellum and the white matter of the cerebellum and cerebral hemispheres, was reported in 1935 by Kasanin and Crank, and by Fritzsche. The association of basal ganglia (and more widespread) calcification with hypoparathyroidism was recognized by Camp (1947) and Lowenthal (1948). Subsequent reports in the radiological literature suggested that about two-thirds of cases with basal ganglia calcification on plain skull X-rays had hypoparathyroidism or, more rarely, pseudo-hypoparathyroidism (Bennett et al. 1959; Palubinskas et al. 1959).

Other patients with basal ganglia calcification on skull X-rays, however, were found not to have hypoparathyroidism or similar disorders. Sometimes this condition was familial. So was born the erroneous concept of ‘Fahr's disease’. Subsequently, the development of new investigations established that many of these cases had other metabolic disorders or other recognizable inherited conditions. Harrington et al. (1981) listed 24 conditions associated with basal ganglia calcification, to which others have subsequently been added (Tables 14.1 and 14.2). Nevertheless, there are still some cases of familial basal ganglia calcification of unknown cause despite full investigation, inherited usually as an autosomal dominant trait.

The situation was complicated further by the advent of the computed tomography (CT) brain scan, which was more sensitive for the detection of brain calcification than plain skull X-rays (Table 14.3). Calcification in the basal ganglia has been found in about 0.5% of routine brain scans, particularly in those over the age of 50 years. In the vast majority of such cases, the calcification is confined to the basal ganglia (nearly always in the globus pallidus) and is of no significance (it is similar to calcification in the choroid plexus and pineal gland). In a minority, however, the calcification extends beyond the globus pallidus to involve the striatum (caudate and putamen), thalamus, dentate nucleus, and white matter of the cerebellum, and white matter of the cerebral hemispheres. Such extensive brain calcification is likely to be pathological, although often it is not associated with neurological symptoms, at least initially. It is more properly described as striatopallido-dentate calcification (Lowenthal and Bruyn 1968) which requires appropriate full investigation. Although widely used in the literature, even this description is inadequate, for such calcification frequently also involves the white matter of the cerebral and cerebellar hemispheres and the thalamus.

Against this background we will first discuss incidental basal ganglia calcification. Then we will describe the various pathological causes of striatopallido-dentate calcification. Finally, we will put forward a scheme for investigation of pathological basal ganglia calcification.

Calcium has CT absorption coefficients from 40–500 µm so that its density is easily detected on CT brain scans. CT is far more sensitive than plain skull X-rays. In a retrospective survey of 31 years’ experience at the Mayo Clinic, only 38 cases of basal ganglia calcification were found on skull films (Muenter and Whisnant 1968). Among 14 cases of basal ganglia calcification detected by CT brain scans in 4219 studies, only one was identified on plain skull X-ray (Koller et al. 1979). Skull X-rays identified only four out of 40 cases of basal ganglia calcification seen on CT scan by Murphy (1979) and one out of 26 cases reported by Fénelon et al. (1993).

Table 14.3 summarizes nine papers reporting the incidence of basal ganglia calcification in routine CT brain scans; incidence varied between 0.2 and 2.0%. The calcification was usually bilateral and symmetrical. At least two-thirds of cases were aged 50 years or more, but no sex difference was noted. Where the exact site of the calcification was described, the globus pallidus was almost invariably involved (in 349 of 377), as has also been found in neuropathological studies (Neumann 1963) (Fig. 14.1). Indeed, microscopic calcification is evident in the globus pallidus (and dentate nucleus) in 40–72% of routine autopsies (Strassman 1949; Slager and Wagner 1956), usually without significant loss of neurons or myelin. Calcification on CT scan was bilateral in the majority of cases, but was unilateral in 25 of the patients described by Förstl et al. (1992). Unilateral involvement was more common (16%) in the 30 cases of Fénelon et al. (1993), which was also unusual in that in 26% of patients a cause was detected. In the vast majority of such patients the calcification in the globus pallidus is of no clinical relevance [see, for example, Koller et al. (1979) and Förstl et al. (1992)]. Indeed, unilateral or bilateral calcification of the globus pallidus on CT brain scan in those aged 50 years or more should be considered a normal, physiological finding akin to calcification

in the choroid plexus and pineal gland. Generally it requires no investigation.

The mechanism of such basal ganglia calcification is not quite clear. Neuropathological studies suggest that physiological deposition of calcium granules occurs with age within the media and adventitia of arterioles, in the perivascular spaces and surrounding capillaries (Slager 1955; Slager and Wagner 1956; Friede et al. 1961). As the deposits enlarge, the granules coalesce, encircling the vessels, but the lumen and surrounding brain parenchyma are not affected until late in the process. There has been a recent suggestion that physiological bilateral basal ganglia calcification may actually be the result of a quiet Ebstein–Barr (EB) or other viral infection. In this regard Morishima et al. (2002) analyzed lymphocyte subsets and cytokines in the peripheral blood in ten adult patients said to have physiological basal ganglia calcification, following up a report of altered immune response hypersensitivity with elevation of serum levels of gamma interferon and natural killer (NK) cell proliferation in peripheral blood of children with EB infection-related bilateral basal ganglia calcification (Morita et al. 1998). They found an increased number of NK cells in seven of the ten adults as well as tumour necrosis factor-alpha in the sera of five and interferon-gamma in one. They concluded that NK cell propagation releasing circulating cytokines, particularly tumour necrosis factor-alpha, may be involved and EB virus or the like may be associated in the aetiology of physiological basal ganglia calcification.

If isolated calcification in the globus pallidus over the age of 50 years can be ignored, what if it occurs in younger individuals or is more widespread? Calcification in the globus pallidus apparently of no significance sometimes does occur in young adults, but it is extremely rare in children. It seems wise to investigate those with such calcification under the age of 50 years. Young adults should be screened for parathyroid abnormalities. Children should be investigated more extensively. Only 6 out of 18,000 CT scans of children reported by Kendall and Cavanagh (1986) had idiopathic basal ganglia calcification and all of these had neurological symptoms.

Calcification outside the pallidus provokes a similar problem. If extending only into the caudate or putamen in elderly subjects it probably can be ignored. However, if it involves the dentate nucleus or white matter of the cerebral hemispheres, it should be investigated. In such cases magnetic resonance imaging (MRI) may show hyperintensities in grey and white matter outside the regions of calcification on CT, and these have been interpreted as areas of brain damage (Avrahami et al. 1994).

Since Camp (1947) recognized hypoparathyroidism as a cause of symmetrical bilateral basal ganglia calcification, many similar cases have been described (Illum and Dupont 1985).

Primary hypoparathyroidism is characterized by hypocalcaemia and hyperphosphataemia, with absent or low levels of parathormone

but no dysmorphism or skeletal abnormality. There is a normal response to parathormone infusion, as judged by the increase in urinary output of cyclic adenyl monophosphate (cyclic AMP) and of phosphate.

The typical manifestations of primary hypoparathyroidism are tetany, cataracts, and epilepsy. In long-standing cases, cognitive impairment and dementia may occur. A variety of movement disorders have been described less commonly, including parkinsonism, chorea, and dystonia (sometimes paroxysmal) (Table 14.4) (Muenter and Whisnant 1968).

Mild rigidity and bradykinesia with a slow gait associated with severe dysarthria and dysphagia has been described in long-standing hypoparathyroidism, despite treatment (Cheek et al. 1990). CT brain scans show bilateral calcification in the basal ganglia, especially in the globus pallidus and putamen, and often in the thalamus, cerebellar dentate nucleus, and cortical white matter (Vaamonde et al. 1993) (Fig. 14.2). MRI is less impressive, although there is reduced signal on T2 weighted images due to the low proton density of calcium and other minerals (Fig. 14.2). In addition, MRI may reveal pathological tissue surrounding calcification. Progressive cerebral calcification has been reported in hypoparathyroidism, despite maintenance of normocalcaemia (Smits et al. 1982).

Secondary hypoparathyroidism follows destruction or removal of the parathyroid glands, most commonly after thyroid surgery. The biochemical changes are similar to those of the primary form. Basal ganglia calcification may follow 10–40 years after thyroid surgery (Frame 1965; Klawans et al. 1976; Berendes and Dörstelmann 1978; Forman et al. 1980) and may be associated with parkinsonism, as well as the usual tetany. Such parkinsonism has not usually responded to levodopa therapy (Frame 1965; Klawans et al. 1976; Berendes and Dörstelmann 1978). The occasional patient, however, has shown some improvement (Vaamonde et al. 1993). Serial CT brain scans have documented the development of basal ganglia calcification in post-operative hypoparathyroidism (Posin et al. 1979; Spiegel et al. 1982; Freilich 1985). The duration of the hypoparathyroidism and the degree of its control appear to be of little importance in its development. More extensive calcification on CT brain scan has been described, involving the basal ganglia, corona radiata, and cerebellum, after surgical removal of the parathyroids (Bhimani et al. 1985).

In pseudo-hypoparathyroidism (Table 14.5), the plasma calcium also is low and the phosphate is high, but parathormone levels are normal or high. Parathormone infusion produces little or no increase in urinary excretion of cyclic AMP (although urinary phosphate may increase), indicating end-organ unresponsiveness. Such patients often are dysmorphic with short stature, short metacarpals (particularly the 4th) and metatarsals, and a round face. They may exhibit subcutaneous calcification and obesity. Skeletal X-rays confirm the short metacarpals, and may show changes of secondary hyperparathyroidism. Symptoms of hypocalcaemia usually present after the age of 5 years. The condition may be inherited and mutations in the GNAS gene have been described.

Mental retardation often is present, as are cataracts. Basal ganglia calcification may extend into cerebral white matter and the cerebellum. Parkinsonism without observable basal ganglia calcification on CT has also been noted (Evans and Donley 1988).

Beall et al. (1989) reported an unusual patient (with two other affected siblings) who had striatopallido-dentate calcification, pseudo-hypoparathyroidism, and porphyria cutanea tarda with a refractory anaemia. She developed a change in personality, spasticity, and incontinence in middle-life, followed by seizures and parkinsonism, all of which progressed quite rapidly. At autopsy she had widespread deposition of iron in the brain and other organs, due to iron overload.

Such patients exhibit the dysmorphic features of pseudo-hypoparathyroidism, but show no biochemical abnormalities of calcium metabolism, normal parathormone levels, and a normal response to infusion of parathormone. They do not develop symptoms of hypocalcaemia. The condition is inherited as an X-linked or influenced autosomal dominant trait.

Hyperparathyroidism may infrequently be encountered with basal ganglia calcification. Clinical features include l-dopa unresponsive parkinsonism and gait apraxia (Margolin et al. 1980).

Human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS) is associated with a variety of intracranial infections, including toxoplasmosis, which can cause intracranial calcification. In addition, HIV itself can result in calcification of the basal ganglia in infants, children, and adults (Belman et al. 1986; Fénelon et al. 1993). The mechanism for these changes is uncertain, but mineralization of vessel walls as a consequence of immune complex deposition and vasculitis has been noted in the early stages of infection (Belman et al. 1986; Gray et al. 1992). Deposition of calcium occurs in small globular deposits around capillaries or in thickened arteriolar walls.

Basal ganglia calcification following cerebral irradiation therapy has been described in several reports (Bennett et al. 1959; Harwood-Nash and Reilly 1970; Numagachi et al. 1975; Lee and Suh 1977; Murphy 1979). The total radiation dose has varied from 4000 to over 9000 rads. The interval between irradiation and detection of the calcification has ranged from 3 to 20 years. Radiation leads to fibrinoid necrosis of blood vessel walls, with endothelial and periadventitial fibroblastic proliferation, and telangiectatic dilatation of capillaries (Rubinstein 1972). Calcification occurs in such areas of delayed radiation-induced change.

Subsequent to the introduction of intrathecal chemotherapy for childhood leukaemia, basal ganglia calcification was recognized (Flament-Durant et al. 1975; Mueller et al. 1976; Peylan-Ramu et al. 1978). The combination of intrathecal methotrexate and cranial irradition has been implicated, causing a necrotizing leucoencephalopathy (Rubinstein et al. 1975). Microscopically, there are necrotic foci and a reactive gliosis in the cerebral white matter. Calcification occurs in degenerating axons and in the cerebral debris in a perivascular distribution. Most patients develop a subacute encephalopathy with seizures, progressive cognitive impairment, and focal neurological deficits. The intrathecal methotrexate has been held responsible, with radiation increasing brain methotrexate concentrations by impairing the blood–brain barrier.

The Kearns–Sayre syndrome of external ophthalmoplegia plus retinitis pigmentosa, cardiac conduction defects, and a high cerebrospinal fluid (CSF) protein may be associated with basal ganglia and more widespread calcification (Castaigne et al. 1971; Robertson et al. 1979; Seigel et al. 1979; Yoda et al. 1984), sometimes with hypoparathyroidism (Pellock et al. 1978). Widespread cerebral calcification also occurs in other forms of mitochondrial disorders including A3243G and the G1606A mutation of mitochondrial DNA (Markesbery 1979; Egger et al. 1981; Truong et al. 1990; Lien et al. 2002; Saacconi et al. 2002) (see also Chapter 4 and Fig. 14.3).

A small number of cases of presenile dementia, associated with aphasia, parkinsonism, and terminal tetraplegia in flexion associated with calcification of the globus pallidus and localized atrophy of the temporal and temporo-frontal lobes, have been described in the literature. The histological findings have included widespread neurofibrillary tangles (NFT) in cerebral cortex without Pick's bodies or significant numbers of senile plaques and pre-amyloid deposits. However, Terada et al. (2001) detected what they called a novel histopathological abnormality of ‘plaque-like structures’ (PLS). These appeared as oval, slightly eosinophilic masses of up to 100 µm in diameter. With methenamine silver stain, the PLS were argyrophilic, and thread-like structures were observed in and around them. Most PLS were observed in deep layers of the cortex and subcortical white matter, and were accompanied by small vessels. They were intimately associated with the small-vessel walls and astrocytes. They were composed of two types of fibres. The first type comprised straight and loosely interwoven fibres about 25–30 nm in diameter, while the other type evoked tangles. These authors mention that these PLS have not been found in other neurodegenerative diseases, including Alzheimer's disease (AD) (Terada et al. 2001). However, Tanabe et al. (2000) reported that the NFT in DNTC are ultrastructurally identical to paired helical filaments observed in AD. Furthermore they showed on immunoblotting that tau from DNTC brains appears as three major bands of 60, 64, and 68 kDa with a minor band at 72 kDa, which is the same as that in AD. Alpha-synuclein-positive structures have been described. (Hishikawa et al. 2003). Tsuchiya et al. (2002) examined the basal ganglia pathology in detail. Obvious neuronal loss in the substantia nigra with the presence of Lewy bodies was noticed in four out of five cases examined. The amygdala bore the brunt, with moderate to severe neuronal loss more prominent in the basolateral part than in the corticomedial area, unlike the pattern seen in the amygdala in AD. The caudate nucleus had moderate and the putamen and pallidum had mild neuronal loss. The authors concluded that in DNTC, the degree and distribution of the basal ganglia lesions (except for nigral lesions) was analogous to those found in Pick's disease with Pick bodies. Later, the authors (Tsuchiya et al. 2005) postulated a more widespread distribution of cerebral cortical lesions in DNTC when they found lesions in the temporal lobes and insular gyri of all four studied cases, which could topographically explain the unusual clinical signs of DNTC, including parietal signs such as apraxia and agnosia observed in some.

Thus, although it is clear that DNTC is also a taupathy its exact noslogy with regard to other taupathies remains uncertain. In this regard it is interesting to note that with the exception of the autopsy case of Langley et al. (1995), virtually all patients reported with this disorder have been Japanese (Kosaka 1994; Terada et al. 2001; Narita et al., 2002). However, basal ganglia calcification has been described in two cases from Europe with clinical diagnosis of corticobasal degeneration (CBD) (Warren et al. 2002) and progressive supranuclear palsy (PSP) (Saver et al. 1994) respectively, both disorders being taupathies like DNTC. The case reported by Warren et al. (2002) had left-sided rigidity and apraxia with imaging showing bilateral basal ganglia, as well as centrum semiovale, dentate, and cerebellar white matter calcification. The 63-year-old man reported by Saver et al. (1994) had striatopallidodentate calcifications and exhibited a marked supranuclear defect of eye movement in addition to an extrapyramidal movement disturbance and dementia. Unfortunately neither of these cases had pathological examination and it is feasible that these two cases may well have DNTC as basal ganglia and dentate calcification is not generally seen in either CBD or PSP.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. The condition usually manifests in stages (Kluenemann et al. 2005). Following a normal development and early adulthood, the first symptoms appear during the osseous phase in the third decade of life. Patients experience pain in the ankles and feet usually following strain or a minor accident. Fractures, typically of the wrists or ankles, start to occur after minor trauma from the late 20s. Polycystic osseous lesions and loss of bone trabeculae can be demonstrated radiologically. Insidious onset of neurological symptoms is in the fourth decade as a frontal lobe syndrome with progressive loss of judgement, euphoria, lack of social inhibitions (including Witzelsucht), disturbance of concentration, and lack of insight and libido. Memory disturbance is less prominent initially, but is progressive. Upper motor neuron features, gait disturbance, primitive reflexes, and in some cases choreo-athetotic movements, myoclonic twitches, and epileptic seizures develop. In the late neurologic stage the patients progress to a profound dementia, a vegetative state, and death by age 50 years (Kluenemann et al. 2005). Mutations in TREM2 and DAP12 have recently been associated with this disorder and cause a similar clinical phenotype with respect to the neurologic and skeletal abnormalities (Kluenemann et al. 2005). The genes encode subunits of a cell membrane-associated receptor complex.

Idiopathic bilateral striatopallido-dentate calcification, of unknown cause, inherited as an autosomal dominant trait, has been described in a number of families (Foley 1951; Moskowitz et al. 1971; Boller et al. 1977; Ravindran 1979; Aiello et al. 1981; Ellie et al. 1989; Manyam et al. 1992; Kobari et al., 1997) (see also Chapter 41). Other families have been reported, but, for reasons described earlier, investigation was inadequate to exclude metabolic causes now known to cause this condition. It continues erroneously to be referred to as Fahr's disease in the literature.

Manyam et al. (1992) provided a review of 31 patients with such calcification, drawn from the seven families described by the authors referred to above. There were 13 males and 18 females. Eighteen of the 31 cases were asymptomatic at the time of the reports. The age of onset in the 13 cases with symptoms was between 21 and 62 years (median 43). Dementia was reported in five cases, cerebellar ataxia in eight, parkinsonism in four, chorea (or choreoathetosis) in three, dysarthria in seven, a gait disorder in five, seizures in three, incontinence in two, and pyramidal signs in four. The condition is progressive. CT evidence of calcification may precede symptoms by many years. Once symptoms appear they generally get worse.

Manyam et al. (2001a) detailed the clinical features of 38 cases (five autosomal dominant families and eight sporadic cases) recruited through a registry combined with 61 cases from the literature that were included following strict criteria. The mean age of the registry patients was 43 years (+/– 21) and that of the literature was 38 (+/– 17). In the combined dataset (n = 99), 67 were symptomatic and 32 were asymptomatic. Of the symptomatic, the incidence among men was higher compared with women (45:22). Movement disorders accounted for 55% of the total symptomatic patients. Of the movement disorders, parkinsonism accounted for 57%, chorea for 19%, tremor for 8%, dystonia for 8%, athetosis for 5%, and orofacial dyskinesia for 3%. Other neurologic manifestations included: cognitive impairment, cerebellar signs, speech disorder, pyramidal signs, psychiatric features, gait disorders, sensory changes, and pain. A significantly greater amount of calcification by volume was found in symptomatic patients compared to asymptomatic patients. The study concluded that movement disorders were the most common manifestations of this condition and parkinsonism was most frequent.

CT scan, when undertaken, often showed calcification not only in the basal ganglia (striatum and globus pallidus), but also in the dentate nucleus, cerebellar white matter, thalamus, and cerebral white matter (Fig. 14.4). Biochemical indices of calcium metabolism are, by definition, normal. CSF examination and peripheral nerve conduction studies have been reported normal (Manyam et al. 1992). MRI of the brain merely confirms calcification as hypodensities, but is less sensitive than CT (Manyam et al. 1992). On magnetic resonance images the calcifications exhibit different signal intensities. The differences in signal intensity are thought to be related to the stage of the disease, differences in calcium metabolism, and the volume of the calcium deposit (Ogi et al. 2002). Surrounding hyperdensities on MRI probably are attributable to gliosis or demyelination (Ellie et al. 1989a). The moderate reduction of cerebral blood flow in bilateral thalami was also identified using brain SPECT (Ogi et al. 2002). Positron emission tomography with ¹⁸F-dopa in two cases was unremarkable (Manyam et al. 1992), suggesting a normal nigrostriatal dopamine system. This is compatible with the usual failure of levodopa treatment to improve parkinsonian symptoms, although there are rare exceptions. Manyam et al. (2001b) reported that one patient from an autosomal dominant family with parkinsonism and bilateral basal ganglia calcification responded to levodopa. On pathology this patient had Lewy bodies in substantia nigra neurons apart from the characteristic changes consistent with basal ganglia calcification, idiopathic 1 (BSPDC). Interestingly, another patient from the same family also with clinical evidence of parkinsonism and radiological and neuropathological evidence of BSPDC did not show Lewy bodies and had no response to levodopa.

The cause of this condition is unknown. Manyam et al. (1992) found a two-fold increase of homocarnosine in the CSF of two of three cases, with no alteration in the levels of histidine or γ-aminobutyric acid. Homocarnosine (γ-aminobutyrl-l-histidine) is a dipeptide of γ-aminobutyric acid and histidine. It is an endogenous antioxidant in the brain. Basal ganglia calcification is not reported to occur in inherited homocarnosinosis (Gjessing et al. 1974). Low levels of serum 25-OH vitamin D₃ in the presence of normal 1,25(OH)2 vitamin D₃ and calcium metabolism have been described in one family (Martinelli et al. 1993), but the relationship of this to the group as a whole is uncertain.

As mentioned above the familial form of idiopathic basal ganglia calcification (IBGC) is usually inherited as an autosomal dominant disorder [except for the family of Smits et al. (1983) which was autosomal recessive]. Geschwind et al. (1999), in a multigenerational family with dominantly inherited IBGC, performed a whole-genome scan in 24 members of this family using polymorphic microsatellite markers and identified the first genetic locus for this disorder (IBGC1) on chromosome 14q. It is not yet clear whether other families also link to the same site and the discovery of the gene will help in indicating whether this disorder is genetically heterogeneous or not. Meanwhile, it is interesting to note that in an autosomal dominant family with IBGC on CT scanning but without any neurological, cognitive, and psychiatric abnormalities, except in two siblings who were the index cases presenting with a bipolar disorder and parkinsonism, the condition was not found to be linked to chromosome 14q IBGC1 locus (Brodaty et al. 2002). Similarly, linkage to IBGC1 was excluded in other families with autosomal dominant IBGC, including a family reported by Boller et al. (1977) where the phenotype consisted of palilalia, accompanied by chorea and dementia in some, beginning in the third or fourth decade.

Aicardi–Goutières syndrome is an autosomal recessive encephalopathy due to mutations in the TREX1 gene or the RNASEH2 genes which causes developmental arrest, intracerebral calcification, and white matter disease in the presence of chronic CSF lymphocytosis, and a raised level of CSF interferon-alpha (IFN-alpha). Diagnosis requires the presence of progressive encephalopathy with onset shortly after birth, and characteristic clinical neurological and neuroimaging signs together with chronic CSF lymphocytosis. The syndrome has superficial resemblance to the neurological sequelae of congenital infection; thus a rigorous search for microbiological and serological evidence of embryopathic infections (ToRCH)should be carried out in each case (Aicardi and Goutières 1984; Tolmie et al. 1995).

Goutières et al. (1998) presented a review of 27 patients. In 19 children, the onset was within the first 4 months of life. Most patients had normal head circumference at birth, but 21 developed microcephaly between 3 and 12 months. Neuroimaging showed severe and progressive brain atrophy in all patients. The extent and intensity of the calcification was variable even in the same sibship. CSF lymphocytosis persisted beyond 12 months of age in seven children. High levels of interferon-alpha were found in serum and CSF in 14 patients but they were higher in the CSF, suggesting intrathecal synthesis. Tubuloreticular inclusions related to the presence of interferon were found in four additional children. The authors had no explanation for the high level of interferon-alpha but felt it could play a role in the pathogenesis of the disorder. The syndrome presented with individual variations in severity, rapidity of evolution, and imaging features. Neuropathological examination in two patients failed to detect significant inflammatory lesions and showed only foci of necrosis and widespread demyelination.

The variabilty in clinical presentation even within the same family is being increasingly recognized. McEntagart et al. (1998) reported two brothers of consanguineous parents who presented in the first year with developmental delay. The first boy was normocephalic with spastic diplegia and normal intelligence. Tests in the second year of life showed punctate calcification of the basal ganglia and subcortical white matter and CSF pleocytosis. At 9 years clinical and imaging features were unchanged and CSF, including IFN alpha levels, was normal. However, the second boy at 21 months had dystonic cerebral palsy, fall-off in head growth, and cognitive delay. Imaging abnormalities were more marked than those in the brother and CSF examination revealed pleocytosis and marked increase in IFN alpha.

Crow et al. (2000) studied 23 children from 13 families with a clinical diagnosis of Aicardi–Goutières syndrome and, by means of genome-wide linkage analysis, found significant linkage to chromosome 3p21 in a proportion of families, which pointed to locus heterogeneity and to the existence of at least one additional disease locus. The condition was subsequently found to be due to mutations in the TREX1 gene, when Crow et al. (2006) identified five different mutations in affected members of ten unrelated families. The gene encodes an exonuclease involved in the excision of nucleotides from DNA 3-prime termini and thus plays a role in the processes of DNA replication, repair, and recombination. TREX1 null mutations are common, and among Europeans a specific mutation (Arg-114-to-His) was identified in multiple pedigrees (Rice et al. 2007). Mutations, almost all missense, in RNASEH2A, RNASEH2B, and RNASEH2C have also been identified in Aicardi–Goutières patients (Rice et al. 2007). The authors defined genotype–phenotype correlations and pointed out that the early-onset neonatal form, highly reminiscent of congenital infection, was seen particularly with TREX1 mutations, whereas later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, was most frequently due to RNASEH2B mutations.