Oxford Handbook of Genetics
Annotate
Cite
Introduction 180
Atopy 181
Autoimmune disease 182
Ankylosing spondylitis (AS) 183
Coeliac disease 184
Deafness of congenital or childhood onset 186
Deafness of adult onset 188
Dementia 190
Epilepsy 198
Family history of a possible genetic disorder 202
Glaucoma 204
Hyperlipidaemia 206
Osteoporosis 210
Parkinson disease 212
Psychiatric disorders 214
Sensitivity to anaesthetic agents 216
Thrombophilia 226
Introduction
One of the main discoveries of recent genetic research is the emerging importance of genetic factors in common disorders. Technological developments such as genome-wide scans are enabling large-scale research studies to identify specific regions of the genome that appear to have a role in susceptibility to certain common disorders.
In the long-term, it is hoped that this will enable a clearer biological understanding of the genetic factors and the gene–environment interactions underlying common disorders. Armed with this knowledge, it may then become possible to define genetic subtypes and tailor advice and therapies accordingly. At the present time this is very rarely possible and, despite media hype, current clinical practice is yet to reap significant benefits from these promising developments.
Atopy
Asthma, eczema, and allergic rhinitis are allergic or atopic disorders with a complex genetic aetiology but well-recognized environmental triggers. The genetic background of an individual influences the response to allergens. The prevalence in the adult population is 5–8%.
PCPs are aware that atopy clearly clusters in families. Most atopic families do not just present with asthma or eczema but an increased risk for all allergic disorders.
These conditions were poorly documented prior to the Industrial Revolution which has led to the hypothesis that both 21st century ‘cleanliness’ in the home and pollution may be implicated in the increasing prevalence of allergy.
Genetics
Research studies of atopic families have identified gene loci that may either increase the risk or have a protective effect. It is hoped that research into identifying the genetic cause may offer therapeutic benefits as we begin to understand the way in which the genes interact with the environmental trigger.
Genetic predictive testing is not yet possible within families.
Promotion of breastfeeding.
Stop smoking.
Advice on avoidance of obvious environmental triggers.
Appropriate medical management of atopic disorder.
Autoimmune disease
Autoimmune disorders are diseases caused by the body producing an immune response (antibodies) against its own tissues, which then leads to tissue and organ damage.
These conditions show familial clustering but do not follow a regular Mendelian pattern of inheritance.
Large-scale research projects looking at affected sib-pairs, or families with a high incidence of autoimmune disorders, recently showed that certain chromosomal loci and SNPs had associations with different autoimmune disorders.
In addition, studies have looked at gene expression in selected tissues from patients with autoimmune disorders. These have shown the activation of specific pathways in these diseases. In the future, combining this gene and protein expression together with SNP data should help our understanding of the pathogenesis of autoimmunity.
There have always been interesting differences in the sex ratios of affected individuals. For example, females more frequently develop rheumatoid arthritis and scleroderma, whereas males more commonly develop ankylosing spondylitis (AS). It has been thought that this could be explained partially by the presence of fetal cells in mothers or conversely the mother’s cells persisting in the affected individual, triggering the immune response.
Autoimmune disorders fall into two general types: those that damage many organs (‘systemic’), and those where only a single organ or tissue is directly damaged by the autoimmune process (‘localized’).
Major histocompatability complex (MHC)
These are a series of genes that are subdivided into three groups, of which the Class I and II make up the human leucocyte antigen (HLA) genes, which encode for cell surface proteins designed to produce an immune response when they bind to an antigenic protein. Such a reaction is appropriate when that antigen is foreign, e.g. invading pneumococci, but, clearly, destructive if the antigen recognized is an individual’s own tissue.
There are clear disease associations with the MHC, such as AS and other joint diseases, e.g. psoriatic arthritis. The complex also contains the tumour necrosis factor (TNF) gene, which produces a protein product that is the target of the new anti-TNF drugs being used for rheumatoid arthritis.
Transplantation of human organs necessitates elimination of antigenic dissimilarity between donor and recipient, which explains why the risk of rejection is least when the two have identical HLA genes—they are histocompatible.
Ankylosing spondylitis (AS)
This condition is well known as a cause of sacro-iliitis and progressive spinal damage and has an incidence of ~1:1000. It is best known as one of the first diseases to have a link to a cluster of genes on chromosome 6, known as the major histocompatability complex (MHC).
Genetics
Genetic factors contribute ~90% of an individual’s susceptibility to AS, with about half of that being from HLA-B27 and other major histocompatability genes and some non-major histocompatability genes, e.g. interleukin-1 (IL-1), with other links to chromosomes 3, 10, 16, and 19.
Although a positive HLA-B27 may predict more severe disease and systemic involvement in an individual, the test needs to be used carefully.
90+% of individuals with AS are HLA-B27 positive, but so are 10% of the general population. Given the incidence above, in a population of 1000, 1 will have AS but 100 (10% of 1000) will be HLA-B27 positive. This is therefore a test of minimal predictive value which may cause unnecessary concern in the 99% of the HLA-B27+ population who will never develop AS. However, it may be a useful investigation in those with a probable clinical diagnosis of AS.
Coeliac disease
Introduction
Coeliac disease (CD) is a complex, inflammatory disorder of the small intestine induced by gluten. The clinical presentation can be very variable from severe ‘failure to thrive’ as a baby to mild abdominal symptoms or unexplained anaemia as an adult.
It is common and has a prevalence of approximately 1:200 in Western populations, with a sibling relative risk of 30. Monozygotic twin studies have shown a concordance of 70%. The highest prevalence is in the west of Ireland.
Genetics
Coeliac disease has a strong genetic component, higher than for many other common complex diseases. Possession of the HLA-DQ2 variant is required for presentation of disease-causing dietary antigens to T cells, although this is also common in the healthy population.
However, the genetic contribution of this region is limited to approximately 40%, so non-HLA genes must also be involved in the disease aetiology.
Genetic studies have so far identified multiple loci that may potentially be involved in disease aetiology, although the majority of these loci are expected to point to genes with a small effect.
A major CD locus on chromosome 19 was recently identified in the Dutch population.
There is some marked overlap when comparing genetic linkage studies conducted in different autoimmune disorders, suggesting that common pathways contribute to these diseases.
Coeliac disease is more prevalent among patients with type 1 (insulin-dependent) diabetes mellitus, and coeliac disease-related antibodies have been reported to increase in frequency in their first-degree relatives.
It is very useful for the PCP to be aware of a family history of coeliac disease, leading to a high index of suspicion for checking endomysial antibodies (EMA) on a first-degree relative who becomes symptomatic.
Routine screening of first-degree relatives of a patient with coeliac disease should be discussed by the gastroenterology clinic that made the diagnosis.
Patients with coeliac disease are at risk of osteoporosis. This is often forgotten by the gastroenterologists and can be discussed in primary care.
The increased prevalence of coeliac disease (CD) among children with type 1 diabetes mellitus (T1D) implies that there is more than a simple association. A link between the gut immune system and T1D has been suggested, both in animal models and in humans. GPs should be aware of this.
Prevalence of coeliac disease among siblings of children with type 1 diabetes appears to be correlated with the prevalence of coeliac disease associated HLA-DQB1 alleles. However, routine screening for coeliac disease among all first-degree relatives of patients with type 1 diabetes is not warranted.
The two major complications of coeliac disease are T-cell lymphoma and ulcerative jejunoileitis. Any previously well coeliac who presents with abdominal pain, diarrhoea, weight loss, and anaemia needs urgent referral.
Support groups
Coeliac UK: 
01494 437 278; 01494 474 349
Deafness of congenital or childhood onset
Severe or profound deafness affects approx 1/1000 infants at birth or during early childhood (pre-lingual phase). Acquisition of speech is a major difficulty for these children, and some may be considered for cochlear implantation. A further 2–3/1000 children have moderate/progressive deafness requiring aids. In developed countries, deafness has an important genetic origin and at least 60% of cases are inherited. The pattern of inheritance can be AD, AR, XLR or mitochondrial. The most common genetic cause of severe to profound deafness in infants is recessive mutations of GJB2 (connexin 26).
Mutations in connexin 26 Cx26 (GJB2) may account for up to 50% of all cases of pre-lingual AR non-syndromic hearing loss and 10–40% of sporadic cases.
Genetics—
refer to Clinical Genetics
If the child is the only affected individual and no environmental or genetic diagnosis can be made, recurrence risk for future pregnancies is 10% (empiric figure; in reality some families will have 25% recurrence risk, and others much lower risks, but it is not possible to discriminate without a more precise diagnosis of the cause).
If two affected sibs or consanguinity, the cause will be assumed to be AR with a 25% risk in future pregnancies.
If affected parent and child, the cause will be assumed to be AD with a 50% risk in future pregnancies.
If one parent has severe congenital hearing loss, and environmental and genetic forms have been excluded as far as possible, empiric risk to offspring is 5%.
If both parents have severe congenital hearing loss (neither with environmental or genetic form) and there is no consanguinity or likelihood of consanguinity, empiric risk to offspring is 10%.
PCPs should be aware that some deaf couples would not wish to pursue genetic testing and may have a preference for a deaf child.
Carrier detection
Audiograms will be done in all parents, with sibling audiograms if there is any clinical suspicion of hearing loss.
For connexin 26 deafness and other types where the mutations are defined, it is possible to offer accurate carrier detection to family members.
Neonatal screening
In the UK there is a national newborn hearing screening programme (NHSP) to detect bilateral hearing loss of greater than 40dB (
http://hearing.screening.nhs.uk/surveillance).
Best practice guidelines have been produced and babies who are detected with hearing loss have a wide range of investigations both to understand the aetiology and to plan management. These are performed in secondary care by the paediatrician and audiologist.
PCPs may be the first to detect hearing problems at the neonate’s 8-week check, if the child has missed the neonatal screening.
Natural history and further management (preventative measures)
Hearing aids. Skilled assessment by an audiologist is required to ensure good results. In young children the ear moulds need to be changed periodically as the ear canal grows.
Cochlear implants. These represent an exciting advance in the management of very young children with profound hearing loss. They are best suited to children in the pre-school years who, with optimal hearing aid correction, still have a loss >65dB.
Education. Provision needs to be carefully matched to the child’s level of hearing loss.
Support groups
Deafness of adult onset
As in childhood, the aetiology is an interplay of genetic and environmental factors. Environmental influences include
Noise
Infections
Drugs such as aminoglycosides.
Deafness of adult onset is usually progressive. Although all patterns of inheritance can be found, recessive and syndromic causes are less likely, AD is the most likely mode of inheritance. The family history may suggest AD inheritance with incomplete penetrance. The pattern of hearing loss combined with knowledge of the rate of loss is documented.
Adults who have hearing loss may present for counselling and it is possible to follow a similar investigation protocol to that used to assess infants.
Initial investigations in secondary care may include:
Hearing assessment of first-degree relatives.
Ophthalmology referral for syndromic associations.
CT/MRI of temporal bone.
Renal USS.
Urine dipstick.
ECG (
see Long QT, Sudden cardiac death: cardiac channelopathies, p. 224).
Connexin 26 and 30 (GJB6) mutation analysis.
Maternal family history of hearing loss, or hearing loss following exposure to aminoglycosides, will indicate the need to test for A1555G mitochondrial DNA (mtDNA) mutation.
Chromosome analysis if developmental delay or dysmorphic features.
These give additional information that may help delineate both the cause and probable inheritance.
Clinical implications for primary care
Developmental delay (mild delay in motor milestones is common in deaf children who are otherwise neurologically normal, probably due to involvement of the vestibular system).
Vestibular symptoms may coexist.
Referral to Audiology for investigation.
Referral to Clinical Genetics for:
children and adults with syndromic forms of deafness;
families with defined mutations (including carriers of GJB2);
families in whom no definitive cause for severe deafness has been established.
Support group
Dementia
The Royal College of Physicians Committee on Geriatrics (1981) defined dementia as ‘The global impairment of higher cortical functions including learned perceptuomotor skills, the correct use of social skills, and the control of emotional reactions in the absence of gross clouding of consciousness. The condition is often irreversible and progressive.’
Clinically, dementia affects memory, speech, perception, and mood. The risk of developing dementia increases with age. Alzheimer disease is the most common neurodegenerative condition affecting older people.
Alzheimer disease has a prevalence of 1–2% among those aged 65–69yrs increasing to 40–50% among persons 95yrs of age and over.
Dementia is a feature of many progressive disorders affecting the central nervous system (CNS) but the most common dementia over the age of 40yrs is Alzheimer disease. Other common causes include vascular dementia, Lewy body dementia, frontotemporal dementia, and Parkinson disease.
Pathologically, Alzheimer disease and many other neurodegenerative disorders are characterized by neuronal loss and intracellular and/or extracellular aggregates of proteinaceous fibrils. In Alzheimer disease these are intracytoplasmic neurofibrillary tangles (hyperphosphorylated forms of the microtubular protein tau) and extracellular amyloid or senile plaques.
Early-onset Alzheimer disease can be defined as onset at age <65yrs. A prevalence study based on the population of Rouen, using a very strict definition of early-onset Alzheimer disease with age of onset <61yrs, found a prevalence of early-onset Alzheimer disease of ~40/100 000 persons at risk.
Causes of dementia
Alzheimer disease ( see p. 191).
AD frontotemporal dementia with parkinsonism (including Pick disease). The second most common pre-senile dementia after Alzheimer disease.
Lewy body dementia. Clinical presentation is typically with fluctuating cognitive impairment, visuo-spatial dysfunction, marked attentional deficits, psychiatric symptoms (especially complex visual hallucinations), and mild extrapyramidal features.
CADASIL Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.
Prion diseases (Gerstmann–Straussler–Shencker syndrome and Creutzfeldt–Jakob disease (CJD)). AD, and caused by mutations in the PRNP gene on 20p. Prion diseases may also be sporadic or have infectious aetiologies (e.g. new-variant CJD).
Late-onset metabolic disorders.
Other (non-genetic) causes
AIDS-related: the most prevalent dementing disease in the USA among those aged <40yrs
Treatable conditions such as drug toxicity in the elderly, nutritional deficiency, hypothyroidism
Alcohol-related
Tumour
Vasculitis
Head injury
Transmitted CJD
Genetic advice—Alzheimer disease
Alzheimer disease may be caused by monogenic, high-penetrance mutations, but Alzheimer disease risk can also be influenced by complex predisposition alleles, e.g. apolipoprotein E (APOE).
There is no clinical or pathological way of distinguishing genetic from sporadic Alzheimer disease in an individual. Family history and age of onset are used initially to determine the likelihood of an inherited form of Alzheimer disease.
Three genes have been identified, β-amyloid precursor protein on chromosome 21, presenilin 1 and presenilin 2, that cause early-onset Alzheimer disease and show AD inheritance.
The inheritance of different APOE genotypes affects the age of onset and apparent risk of Alzheimer disease. The usefulness of APOE testing is controversial—50% of those with a pathological diagnosis of Alzheimer made at post-mortem do not carry an APOE′4 allele. APOE testing is generally not indicated in a clinical setting, e.g. for clinical diagnosis/prediction. However, it may be useful in research contexts.
Inheritance and recurrence risk
Early-onset dementia. For families with a known mutation, or clearly dominant family history, autosomal dominant risks may be used.
Later-onset dementia. For most families empiric risks are all that can be given. Risks are higher when both parents have had dementia and when there is a younger age of onset. There is a three- to fourfold risk of developing Alzheimer disease in the first-degree relatives of individuals with Alzheimer disease compared to controls (19% against 5%). Risks for second-degree relatives are about twice that for controls (i.e. about 10%).
Predictive testing— refer to Clinical Genetics
This is possible in families with known Alzheimer disease mutations using a protocol similar to that used in HD.
Natural history and management
Individuals affected by early-onset dementia should be referred to a neurologist or psychiatrist with special expertise in dementia for comprehensive evaluation, investigation, and care. Cholinesterase inhibitors, e.g. Donepezil, may be of limited benefit. Drug therapy for vascular dementia is under development.
Potential long-term complications
Progressive loss of higher mental functions with loss of independence.
Surveillance
At-risk individuals are advised to avoid deleterious environmental factors such as alcohol excess. Folic acid supplementation may have some protective value.
Affected individuals need a full systems interview, examination, including Mini-Mental State Examination (MMSE), and diagnostic evaluation by an appropriate specialist (e.g. neurologist or old-age psychiatrist) in order to identify potentially treatable causes of cognitive impairment or dementia.
There are no clinical differences between sporadic Alzheimer disease and early-onset AD types, other than the age of onset.
A depression questionnaire may aid diagnosis of depression vs. dementia.
Onward referral to appropriate local screening resource (Integrated Team for Older People, old-age psychiatrist, Clinical Psychology, Neurology) for diagnosis and assessment.
Discuss Social Service input re. personal services, day care, etc.
Elderly Care community psychiatric nurse (CPN).
DSS benefits.
Code patient’s notes.
May need to discuss driving/DVLA contact.
Manage relatives with sensitivity with respect to possible familial disease.
Refer to Genetics under advice from, or in conjunction with, specialist if genetic disease suspected.
Consider DNA storage on affected individuals when a genetic aetiology is possible, after obtaining appropriate consent.
Support group
Diabetes mellitus
Diabetes mellitus is a common and rapidly increasing medical problem arising from a combination of environmental and genetic risk factors. The condition is divided into two types:
Type 1 diabetes mellitus (T1D) formerly known as insulin-dependent diabetes mellitus (IDDM).
Type 2 diabetes (T2D) formerly known as non-insulin-dependent diabetes mellitus (NIDDM), although 750% of T2D subjects require insulin within 6yrs of diagnosis. This condition becomes more common as a population ages and obesity levels rise.
Individuals with all types of diabetes require regular medical and nursing supervision to ensure accurate control of the disease in order to help prevent long-term complications. Assessment of cardiovascular risk is probably the most important part of management of T2D in terms of prognosis, due to the constellation of associated metabolic risk factors for atherosclerosis.
See Chapter 11 in Oxford Handbook of Endocrinology and Diabetes for a full description of the management and surveillance of diabetes. If investigating/seeing an ‘at-risk’ family member, consider:
A fasting blood glucose >7mmol/L on two occasions = diabetes mellitus (American Diabetic Association diagnostic criteria); a fasting blood glucose 5.6–6.9mmol/L = impaired fasting glucose (i.e. needs follow-up by GP/physician).
NB. Individuals with mutations in glucokinase (see Maturity-onset diabetes of the young, below) have stable hyperglycaemia throughout life.
PCPs will be well aware of diabetes as the greatest exemplar of multidisciplinary team (MDT) working: primary care doctors/nurses, specialist diabetic nurses, consultant physicians, dieticians, medical photographers, chiropodists, etc.
Diabetic research, including genetics, is very active across the UK. Since much care is shared with hospital departments, they will usually identify the small proportion of patients for whom genetic mutation testing is both appropriate and possible.
Code patient’s notes.
May need to discuss driving/DVLA contact.
For paediatric patients liaison with school nurses is important.
Manage patient and relatives with sensitivity at the time of diagnosis, as, for many, the spectre of previous generations’ problems associated with diabetes (e.g. persistent ulcers, amputations) may immediately appear.
Type 1 diabetes
Affects about 0.3% of Caucasians, with the highest rates in northern Europe. Treatment of T1D is insulin replacement therapy by percutaneous injection.
The HLA (human leucocyte antigen) or MHC (major histocompatability complex) region ( see Autoimmune disease, p. 182) and the insulin gene region are thought to contain the main susceptibility genes for IDDM, although at least 20 regions have been linked to IDDM.
Most studies have been on European and US families and there may be ethnic differences. Risks follow a multifactorial mode. Genetic factors can be seen in the difference in concordance between monozygous twins and siblings.
The aetiology is complex and the condition arises from the action of many genes and environmental factors. There is rarely evidence for monogenic inheritance.
Genetic advice
Inheritance and recurrence risk
30–50% concordance in monozygous twins.
Sibling risk 6%, with HLA identical sibs having a greatly increased risk of developing T1D.
Offspring risks show some differences between affected fathers and mothers; a greater proportion of fathers (approximately 4%) than mothers (approximately 2%) of children with IDDM have the disease themselves.
Predictive testing
HLA testing of sibs has been used but half of HLA-compatible sibs will never develop the condition. There is currently no pre-symptomatic treatment to alter the disease process. Consideration must be given to the ethical position and issues of informed consent. Autoantibodies (anti-islet cell, anti-glutamic acid decarboxylase (GAD), etc.) have been used predictively to assess risk in sibs in research, but not in routine clinical practice.
Other family members
Individuals who are at high genetic risk should know the symptoms of diabetes mellitus and attend for prompt assessment if they develop these features.
Type 2 diabetes
Type 2 diabetes is becoming more common as the population becomes older and fatter. It is estimated that 1 in 10 European and US individuals will develop T2D.
T2D is pathologically heterogeneous, but is most commonly the result of defects in the action of insulin (insulin resistance) with a secondary failure of the β-cells to compensate with increased insulin production.
Treatment is by dietary and lifestyle manipulation and oral hypoglycaemic medication in the early stages, with many progressing to insulin therapy within a few years.
Although the environmental factors are more apparent than in T1D, there has been more success in identifying monogenic forms of T2D.
Maturity-onset diabetes of the young (MODY)
MODY is a form of T2D with autosomal dominant (AD) inheritance, non-obese body habitus, and an age of onset before 25yrs. It accounts for 1–2% of people with diabetes. Five genes account for 87% of UK MODY.
Asymptomatic family members at high genetic risk require biochemical investigation for diabetes.
Predictive testing— refer to Clinical Genetics
Possible in those with a known familial mutation. Mutation testing is recommended for other affected family members in order to confirm the aetiology of their diabetes. Consider predictive testing for MODY in children of affected parents, together with appropriate dietary and lifestyle advice.
Other types of diabetes
Mitochondrial disorders. The most common symptom, other than the diabetes, is deafness and this usually precedes the diabetes.
Insulin receptor mutation. AD inheritance of a single dominant-negative mutation may cause type A insulin resistance ± diabetes mellitus.
Support group
Epilepsy
Introduction
Epilepsy is a disorder of the brain. It may occur as part of an acute or acquired process affecting the central nervous system (CNS). Genetic factors and genetically determined syndromes contribute in many patients. Epilepsy and seizures are common medical problems—in the general population the cumulative incidence for developing epilepsy to the age of 40yrs is just under 2%.
One epidemiological survey of >10 000 patients with epilepsy found that the prevalence of epilepsy in first-degree relatives of patients with idiopathic generalized epilepsies was 5.3%. Probands with idiopathic generalized epilepsies were highly concordant with respect to their relative’s type of epilepsy. Risks to relatives were higher when the epilepsy in the proband began at <14yrs of age. Concordance has been found to be higher in monozygotic (MZ) twin pairs than in dizygotic (DZ) twin pairs. In 94% of concordant MZ pairs and 71% of concordant DZ pairs, both twins had the same major epilepsy syndrome. This strongly suggests the presence of syndrome-specific genetic determinants rather than a broad genetic predisposition to seizures.
Most genetic epilepsies have a complex mode of inheritance and genes identified so far account only for a minority of families and sporadic cases. Many of the genes associated with idiopathic generalized epilepsy are within the ion-channel family and show autosomal dominant inheritance. Other genes are implicated in AD lateral temporal lobe epilepsy, malformations of cortical development and X-linked mental retardation syndromes in which seizures are a component.
The following definitions may be helpful:
Epileptic seizure. A transient episode of abnormal cortical neuronal activity. This may manifest as a motor, sensory, cognitive, or psychic disturbance.
Epilepsy. A disorder of the brain characterized by recurrent (two or more) unprovoked seizures.
Other diagnoses/conditions to consider
Long QT syndromes, see Sudden cardiac death: cardiac channelopathies, p. 224.
Non-epileptic causes, e.g. syncope, pseudoseizures, Mönchausen syndrome (by proxy in children). These diagnoses should be evaluated by a neurologist.
Genetic advice ( see Table 6.1)
Idiopathic epilepsy
In practice, genetic testing is rarely available but there are some specific forms of epilepsy that have a known genetic cause that can be identified by the patient’s neurologist.
Inheritance and recurrence risk
For isolated/idiopathic epilepsy with no clear familial inheritance, multifactorial inheritance is assumed and empiric risk figures used. The offspring risk for epilepsy is between 1.5% and 7.5%.
| Individual affected | Cumulative risk of clinical epilepsy to age 20yrs (%)* |
|---|---|
Monozygotic twins | ~60 |
Dizygotic twins | ~10 |
Sibling with onset <10 yr | 6 |
Sibling with onset >25 yrs | 1–2 |
Overall sibling risk | 2.5 |
Parent | 4 (1.5–7.5) |
Parent and sibling | ~10 |
Both parents | ~15 |
General population | ~1 |
| Individual affected | Cumulative risk of clinical epilepsy to age 20yrs (%)* |
|---|---|
Monozygotic twins | ~60 |
Dizygotic twins | ~10 |
Sibling with onset <10 yr | 6 |
Sibling with onset >25 yrs | 1–2 |
Overall sibling risk | 2.5 |
Parent | 4 (1.5–7.5) |
Parent and sibling | ~10 |
Both parents | ~15 |
General population | ~1 |
Excluding febrile convulsions.
Variability and penetrance
Most of the familial epilepsy syndromes show intra- and interfamilial variability.
Prenatal diagnosis
Only available in conditions with a known mutation or cytogenetic abnormality.
Approximately 0.4% of pregnant women take anticonvulsant medication. Overall, there is a fairly solid consensus that treatment with anticonvulsants in pregnancy, for whatever reason, i.e. epilepsy or mood disorder, is associated with an overall two- to threefold increased risk of congenital malformation, compared to the risk in the general population ( see Chapter 9, Drugs in Pregnancy, p. 336).
Potential long-term complications
Fetal anti-epileptic drug effects and increased risk of neural tube defects. Possible neurodevelopmental consequences for fetus of frequent maternal tonic–clonic seizures in pregnancy.
Increased risk of sudden death in patients with epilepsy (mainly attributable to the underlying disease, accidents, or suicide), especially in certain groups (e.g. young people and those with frequent generalized seizures and mental retardation).
Restrictions on driving; possible discrimination; long-term effects of the epilepsy, seizures, and medication.
Surveillance
By a neurologist, unless fit-free and stable, in which case PCPs can manage.
Refer back to secondary care if nature, or frequency, of fits change, or for prenatal counselling.
Seek neurology advice if a patient wishes to stop medication.
Refer to neurologist if a first fit occurs, or on suspicion that the patient may have had an epileptic event.
ECG if hint of cardiac problems (e.g. long QT).
Contact Neurology if there is a change in nature/frequency of fits.
Liaison with school re. care of epileptic fits and general effects on education.
Discuss fears and anxieties.
Patient to notify diagnosis (when confirmed) to DVLA.
Code patient’s notes and add to epilepsy register.
Annual epilepsy check (fit frequency, medication review, etc.) as in Quality and outcomes Framework (QoF).
Support groups
Family history of a possible genetic disorder
One of the most frequent referrals from PCPs to Clinical Genetics is of the patient who is worried about the implications of a medical problem within a family.
The most common times for individuals to present are immediately after a diagnosis has been made, in early pregnancy, at the time a child leaves home/school, at the start of a serious relationship, or after the death/funeral of the affected individual. These are all times of heightened emotion and the added input of a potentially serious genetic problem means that the PCP often has to deal with a very anxious and apparently demanding patient/family.
Even if the diagnosis has been apparent for some time, this second event brings it to attention and the family suddenly want answers.
Draw the family tree, highlighting affected individuals. This may show the likely pattern of inheritance.
Assess urgency of need for referral. Pregnancies require urgent referral and assessment.
Find out more about the diagnosis: the family may be able to provide a death certificate or have copies of hospital letters and discharge summaries.
See appropriate section of this handbook for more clinical information.
Families may get support from relevant patient support groups for the familial condition.
Support groups
Glaucoma
Introduction
Glaucoma is an optic neuropathy with characteristic field loss that may or may not be associated with increased intraocular pressure. It is classified, according to the mechanism causing the glaucoma, into the following:
Primary open-angle glaucoma (POAG) is due to an intrinsic disorder of the trabecular meshwork.
Closed-angle glaucoma (acute and chronic).
Secondary glaucomas arise as a consequence of disease or abnormality, either elsewhere in the eye or in other systems, e.g. Marfan syndrome, ectopia lentis, and homocystinuria, where acute glaucoma secondary to lens dislocation may develop.
Most adult-onset glaucoma is a complex disease showing multifactorial inheritance, and family history is an important risk factor.
Glaucoma in infancy and childhood may form part of a wider condition. Primary congenital glaucoma is rare and is also known as buphthalmos.
Glaucoma is usually a purely ocular condition but associated non-ocular features may suggest a syndrome diagnosis.
Potential long-term complications
Untreated glaucoma can lead to irreversible constriction of the visual fields and, eventually, blindness.
Surveillance
Ensure ophthalmological surveillance for affected individuals and arrange ophthalmological follow-up for ‘at-risk’ family members.
Genetic advice
Inheritance and recurrence risk
Juvenile and adult primary glaucoma. If inherited, it is mainly AD but most adult glaucoma is a complex (multifactorial) disease.
Other family members
First-degree relatives need screening, the age at which to begin screening depending on the family history, but screening is free for those >40yrs of age with a positive family history. Seek guidance from your ophthalmological colleagues if there is an unusual history.
Identify first-degree relatives who require ophthalmological screening.
For affected individuals:
Onward referral, enclosing GOS18 form from optician (UK) to ophthalmologist.
Regular repeat prescriptions for ophthalmologist-recommended eye drops.
Code patient’s notes.
Recommend local services for those with low visual acuity.
Support group
Hyperlipidaemia
Introduction
The level of serum cholesterol increases in an individual with advancing age, and is the result of the interplay between a number of genetic and environmental factors; hypercholesterolaemia in the population has a multifactorial basis. Hydroxymethylglutaryl coenzyme (HMG-CoA) reductase inhibitors (‘statins’) have revolutionized the treatment of hypercholesterolaemia.
The most common genetic cause of hyperlipidaemia is familial hypercholesterolaemia (FH).
There are other rare causes of hyperlipaemia that may be diagnosed by the lipid clinic.
Familial hypercholesterolaemia (FH)
Approximately 1/500 of the population in Europe and North America are heterozygous for mutations in the low-density lipoprotein (LDL) receptor (LDLR). There is a much higher incidence of FH in certain populations, such as the Afrikaaners (1/80), Christian Lebanese, Finns, and French-Canadians, due to founder effects.
Guidelines for a diagnosis of FH (Scientific Steering Committee on behalf of the Simon Broome Register Group 1999) are a serum cholesterol >6.7mmol/L in children <16yrs, or >7.5mmol/L in adults plus tendon xanthomata in the patient or in a first- or second-degree relative of the patient.
Homozygotes and compound heterozygotes have very severe hypercholesterolaemia, and develop xanthomata in childhood over tendons, the skin of the popliteal and antecubital fossae, buttocks, and in the webs between the fingers. Most die by the age of 20yrs due to supravalvular aortic stenosis and coronary heart disease.
Heterozygotes develop xanthomata over tendons, especially the Achilles tendons and the tendons overlying the knuckles of the hand. Corneal arcus and xanthelasma also tend to develop at a younger age than in the general population.
Heterozygotes are at high risk of coronary heart disease, and without treatment the elevated serum cholesterol concentrations lead to a more than 50% risk of fatal or non-fatal coronary heart disease by age 50yrs in men and of at least 30% in women aged 60yrs.
The clinical diagnosis of FH is based on a family history of hypercholesterolaemia and premature coronary atherosclerosis, the lipid profile, and the presence of xanthomata.
Treatment is with statins, which are usually started in the late teens in men and later, perhaps after completion of childbearing, in women. Lifestyle modifications such as a healthy diet, and especially avoidance of smoking, are important adjuncts to drug therapy.
The prognosis for patients with heterozygous FH has improved with the introduction of more effective treatment, with recent studies showing a decline in the relative risk of coronary mortality in patients aged 20–59yrs from an eightfold risk prior to 1992 and the introduction of statin therapy to 3.7-fold thereafter.
Genetic advice—FH
Mutations are currently only detected in 30–50% of patients with a clinical diagnosis of FH. Some families with FH are more susceptible to coronary heart disease than others and, in a few, coronary heart disease occurs at a strikingly young age, e.g. affecting men in their 20s.
Prenatal diagnosis
May be considered for the homozygous form of FH, but is not generally indicated for the heterozygous form for which treatment is available.
Predictive testing
This is possible by analysis of lipid profiles or, more definitively, by molecular genetic analysis if the familial mutation has been defined.
Cascade screening of family members is indicated, but in FH, since treatment is not usually initiated until the late teens, it may be appropriate to defer genetic testing until individuals are in their mid-teens and able to participate in the testing process.
Three-generation family tree, with enquiry about relatives with hypercholesterolaemia, heart attacks (document age), angina (document age of onset), and cause of death (document age).
History of Achilles ‘tenosynovitis’.
Examine carefully for tendon xanthomata over the Achilles tendons (often there is fibrous swelling overlying cholesterol accumulation deep within the tendon, so the xanthoma may feel hard) and over the tendons overlying the knuckles with the fingers outstretched.
Check blood pressure (BP).
Fasting lipid profile including triglycerides.
LFTs.
Affected patients should either be under the care of a lipid clinic, or, with clear surveillance guidelines, primary care.
Referral to appropriate secondary care expert (e.g. biochemist with an expertise in lipid management).
Prescribe initial statins (where advised) and manage long term with advice about side-effects and drugs, etc. to avoid (e.g. macrolides, grapefruit, etc.), yearly monitoring of lipid profile, LFTs.
Advice on healthy lifestyle (smoking cessation, exercise).
Code patient’s notes.
Support group
Osteoporosis
Introduction
Osteoporosis is a skeletal disorder of compromised bone strength leading to an increased risk of bone fracture. It affects postmenopausal women, if they live long enough (virtually all >85yrs) and 1 in 12 men.
A fragility fracture (sustained as the result of a fall from standing height or less) is the clinically apparent and relevant outcome of osteoporosis. In the absence of fracture, osteoporosis is asymptomatic and often remains undiagnosed. Indeed, women may develop a ‘dowager’s hump’ from asymptomatic osteoporotic vertebral fractures without presenting to their GPs at all. Osteoporotic fragility fractures occur most commonly in the vertebrae, hip, and wrist, and are associated with substantial disability, pain, and reduced quality of life.
Osteoporosis is defined by the World Health Organization (WHO) as a T-score of –2.5 standard deviations (SD) or lower on dual-energy X-ray absorptiometry (DXA) scanning.
‘Case finding’ indicators of a low bone mineral density are:
A low body mass index (BMI < 22kg/m2).
Medical conditions such as ankylosing spondylitis and rheumatoid arthritis.
Any malabsorption (Crohn’s disease, ulcerative colitis, coeliac disease, pancreatic insufficiency).
Conditions that result in prolonged immobility (stroke, paralysis).
Untreated premature menopause (<45yrs old).
Oral glucocorticoid usage is a special risk factor.
A first-degree relative with a fractured hip.
Smoking.
High (>3units/day) alcohol consumption.
Chronic obstructive airways disease has a very high risk as these patients often smoke, are relatively immobile, often thin, and have intermittent courses of oral glucocorticoids.
Women on anastrozole for breast cancer are at increased risk for osteoporosis and local guidelines for DXA scans and management should be followed.
Thyroid disease.
The diagnosis may be assumed in women aged 75yrs or older sustaining a fragility fracture, if the responsible clinician considers a DXA scan to be clinically inappropriate or unfeasible (NICE guidelines).
Treatment
Standard pharmacological therapy for the prevention and/or treatment of osteoporosis includes bisphosphonates (alendronic acid 70 mg once weekly), selective oestrogen receptor modulators (SERMS), or second-line alternative regulators of bone turnover, such as calcitonin, strontium ranelate, and teriparatide: all with appropriate supplementation with adequate levels of calcium and vitamin D. (See NICE guidelines.)
Genetic advice
Inheritance and recurrence risk
There is an increased risk if a first-degree relative has osteoporosis (RR 2.3) but the disease is so multifactorial that general bone health advice should be given to all (see National Osteoporosis Society (NOS) website)
RR of other indicators of low bone mineral density are:
glucocorticoids, 2.3
alcohol excess, 1.7
smoking, 1.6
previous fracture, 1.6
low BMI, 1.4.
History to determine any indicators of a low bone mineral density.
Height (how much shrinkage?), weight, BMI.
Referral for DXA scan.
Referral, if locally available, to specific osteoporosis classes/physio.
Encourage smoking cessation, increased physical activity.
Refer for alcohol counselling if appropriate.
Use WHO Fracture Risk Assessment tool (see Medical resources, below)
Code patient’s notes.
At present surveillance is controversial, with some clinical services offering follow-up DXA scans at intervals which vary from 1 to 3yrs. Other bone metabolic units follow up patients with bone markers such as P1NP on a blood test, which gives some idea of bone turnover.
Refer patient to osteoporosis specialist if further advice is required, or if male.
Medical resources
Support group
Parkinson disease
Introduction
Parkinson disease is a neurodegenerative disease characterized by tremor, slowness of movement and difficulty initiating movement, rigidity, and poor postural reflexes. This disturbance of motor function is due to the loss of neurons in the substantia nigra and elsewhere, in association with the presence of Lewy bodies (cytoplasmic protein deposits containing aggregates of A-synuclein) and thread-like proteinaceous inclusions within neurites, also containing A-synuclein (Lewy neurites).
It is the second most common neurodegenerative condition after Alzheimer disease, with a prevalence of 0.5–1% at age 65–69yrs and 1–3% amongst persons of 80yrs and older.
Most cases are sporadic, but there are occasional families with dominant or recessive inheritance. There are few patients with clear Mendelian inheritance compared with the number of sporadic cases.
Monozygotic (MZ) twins with early-onset disease have a very high rate of concordance (much higher than for dizygotic (DZ) twins) suggesting a significant genetic component, at least in early-onset disease.
Other similar diagnoses/conditions
Parkinsonism may be post-encephalitic, drug-induced (antipsychotic agents) or arteriosclerotic, and these may all cause confusion with the idiopathic or familial forms of Parkinson disease.
Huntington disease in previous generations is not infrequently mistaken for PD.
AD Parkinson disease, see below.
Demetia variants, see Dementia, p. 190.
Benign essential tremor. A common disorder inherited as a late-onset -AD condition. May be mistaken for PD.
Genetic advice
Inheritance and recurrence risk
There are a few families with a clearly Mendelian pattern of inheritance (AR or AD) or a defined disease-causing mutation.
For the remainder, advice is based on empirical data. A threefold increase in risk for first-degree relatives of patients with classical Parkinson disease seems appropriate. Given the fairly low prevalence of Parkinson disease in the population, i.e. 0.5–1% at age 65–69yrs and 1–3% amongst persons of 80yrs and older, the absolute risks remain fairly low.
A 7.75-fold increase in risk may be appropriate in first-degree relatives of patients with onset of Parkinson disease before the age of 50yrs.
Storage of a DNA sample from an affected member of the family may be considered, although relevant mutations are rare—mutation analysis for parkin and A-synuclein being usually only available as part of a research programme.
Post-mortem reports are very helpful as the diagnosis is not always accurate in life.
Natural history and management
The early treatment of Parkinson disease involves education for the patient and family, access to support groups, regular exercise, and good nutrition. Dopamine agonists rather than levodopa should be the initial symptomatic therapy. There is active research into disease-modifying therapies that will provide neurorescue or neuroprotection.
Does the consultee have any symptoms of Parkinson disease (tremor, cogwheel rigidity, posture/balance problems)?
Are there neurological features in the affected individual or other family members?
Examine for clinical features of Parkinson disease.
Mini-Mental State examination (MMSE).
Depression questionnaire may aid diagnosis of depression vs. dementia.
Three-generation family tree with careful enquiry about who in the family is/was affected, the age at onset of symptoms, treatment given, and age and cause of death.
Referral to a neurologist for evaluation.
Liaise with available local services (e.g. specialist Parkinson nurse).
Consider DLA, invalidity benefit where appropriate.
Discussion on driving ( www.dvla.gov.uk).
Remain aware of an increased incidence of both depression and dementia.
Code patient’s notes.
Add patient to Carers’ register.
Add family carers to Carers’ register.
Support group
Psychiatric disorders
These are common and well represented in GP consultations.
There has long been debate about the relative contribution of nature and nurture in the aetiology of these conditions.
Family, twin, and adoption studies have shown a clear genetic contribution to schizophrenia and bipolar disorders but only recently has research begun to tease out the underlying genetic mechanisms.
Schizophrenia
Schizophrenia is has a population prevalence of about 1%. The condition is diagnosed by the presence of hallucinations, delusions, and other cognitive abnormalities.
Twin studies have shown a high concordance between identical twins and the risk of schizophrenia, in the children of parent(s) with the condition, is not reduced if they are adopted, and heritability has been estimated at 70–90%.
For many years genetic studies looking for susceptibility genes have given inconsistent results, but recent work looking at rare variants and small chromosome deletions and duplications has shown these changes to be more frequent in patients with schizoprenia.
Geneticists are most commonly asked to advise about genetic risks by the normal siblings of affected individuals, or by adoption agencies that are placing children born to affected parents. Despite new promising research, at present empirical risk data are still used.
The cumulative risk of schizophrenia in the offspring of an affected individual is 10–15%. The risk to nephews and nieces is much lower at about 3.5%.
Major affective disorder (bipolar disease, manic depression)
1–2% prevalence.
Like schizophrenia, there are strong genetic risk factors with concordance in monozygotic and dizygotic twins, respectively, of 40–70% and about 10%. There have been many genes reported as possible candidates for increasing susceptibility, but none are currently of use clinically to help predict at-risk individuals in the population.
Clinical geneticists still use empirical data if family members wish to be informed of their genetic risk. A first-degree relative has a lifetime risk of 5–10%.
Depression
Depression is very common, with lifetime prevalence for major depressive disorder in the community estimated at 15–17% (DSM4 1994). It occurs twice as frequently in women as in men. Depression can begin at any age, but usually has its onset in the mid-20s. Genetic factors have an important role in the aetiology of depression. Heritability has been estimated from twin studies as 31–42%.
Consider genetic advice if children of parents with a major psychiatric problem are to be adopted.
Support the family appropriately through liaison with community psychiatric services.
Support group
http://www.rcpsych.ac.uk/mentalhealthinformation.aspx
Sensitivity to anaesthetic agents
Introduction
Suxamethonium sensitivity
Pseudocholinesterase deficiency, butyrylcholinesterase deficiency.
Suxamethonium (succinylcholine) is a drug used in general anaesthesia to induce neuromuscular blockade to facilitate tracheal intubation. It is metabolized in the plasma by the non-specific esterase pseudocholinesterase. Normally this happens quickly and the neuromuscular blockade lasts less than 5 min. Patients who are homozygous or compound heterozygotes for some pseudocholinesterase (BChE) variants produce pseudocholinesterase of abnormal affinity and reduced amount and metabolize the suxamethonium only slowly, resulting in markedly prolonged neuromuscular blockade and paralysis. Artificial ventilation is used to support the patient until the neuromuscular blockade wears off (usually ~90 min after succinylcholine and ~5h after mivacurium). Apnoea after suxamethonium can last for up to 3 days in a highly sensitive individual.
Affected individuals are otherwise entirely asymptomatic (although they may be sensitive to cocaine).
The gene encoding pseudocholinesterase is CHE1 on 3q26.1. ‘Silent’ alleles are also found, due to nonsense mutations/deletions in the CHE1 gene.
Using biochemical assays, the patient’s phenotype can be defined. It is often not possible to ascribe a definitive genotype without performing family studies and therefore usually only the phenotype is reported. Molecular genetic studies may be available in some centres.
The frequency of the atypical variant (A) is 0.017 in Caucasians, giving a homozygous frequency of ~1/3500.
Cholinesterase levels can also be reduced in pregnancy, liver disease, and by other drugs. However, any clinical prolongation of effect is small.
Malignant hyperthermia (MH)
MH is a dangerous hypermetabolic state after anaesthesia with suxamethonium and/or volatile halogenated anaesthetic agents such as halothane and methoxyflurane. It affects ~1/20 000 anaesthetized patients. MH may also be triggered in susceptible individuals by severe exercise in hot conditions, infections, neuroleptic drugs, and overheating in infants, and the overall prevalence is estimated at 1/10 000. The body temperature rises acutely to 40 or 41°C with muscle stiffness, tachycardia, sweating, cyanosis, and tachypnoea. Hyperkalaemia, acidosis, and hypercapnia, as well as the fever, alert the anaesthetist. Dantrolene, which decreases the amount of calcium released from the sarcoplasmic reticulum, is an effective treatment that has reduced case fatality from 70% to 5%.
The inherited abnormalities in MH-susceptible individuals lie in the regulation of myoplasmic calcium (Ca).
Genetic advice
Inheritance and recurrence risk
Suxamethonium sensitivity. The condition follows autosomal recessive (AR) inheritance and therefore siblings are at 1 in 4 risk.
MH is inherited in an autosomal dominant (AD) manner, giving a 50% risk to offspring of an affected individual.
Other family members
Suxamethonium sensitivity. All siblings should be tested biochemically (and molecularly if available). Parents should also be tested, both to help define the phenotypes and also because the relatively high carrier rate in Caucasians means there is a small chance that they, too, could be affected.
MH. Parents and offspring should be offered in vitro muscle testing if an RYR1 mutation that would enable predictive genetic testing is not identified within a short time.
Three-generation family tree with specific enquiry about anaesthesia.
Detailed history from the proband regarding experience following anaesthesia.
For MH, enquire specifically about muscle pains after exercise or episodes of rhabdomyolysis (myoglobinuria).
Most cases will have received, or begun, the appropriate investigation pathway after a general anaesthetic in hospital.
Code patient’s notes.
Refer to the condition when making any referral to secondary care.
May be asked to take relevant bloods on other family members.
Reinforce the advice that patients with suxamethonium sensitivity or susceptibility to MH should carry a laminated warning card and consider wearing a Medic-Alert bracelet.
Sudden cardiac death (SCD)
The major risk factor for sudden cardiac death in adults is the presence of ischaemic
heart disease. The sudden death of a young adult aged <35yrs from coronary artery disease may be a presentation of Familial hypercholesterolaemia ( see Hyperlipidaemia, p. 206).
Inherited cardiomyopathies and channelopathies are of particular importance in sudden cardiac death in young adults.
In children undiagnosed congenital cardiac anomalies may be detected at post-mortem.
Structural cardiac abnormalities evident at autopsy may include hypertrophic and dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy.
Cardiac channelopathies may account for one-third of autopsy-negative sudden unexplained deaths (SUDs) during childhood and adolescence. They are a heterogeneous group of conditions and include: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome and short QT syndrome. Sometimes sudden death due to one of these conditions is misdiagnosed as death due to epilepsy.
It is important to try to store a DNA sample (with consent) following the sudden cardiac death of a young person. This can be from blood (~5mls in an EDTA tube) within a short time of death or from a skin biopsy (placed into tissue culture medium up to 48hrs after death).
Because of the diagnostic difficulties even after a full post-mortem, genetic testing (which may be at a later date) can clarify the diagnosis and DNA should be stored. This post-mortem genetic analysis is sometimes called a molecular autopsy.
Management of these families requires specialist cardiac and genetic input and most regional centres will have an inherited cardiac conditions (ICC) clinic.
Three-generation family history with specific enquiry about the following:
deaths attributed to heart problems
sudden unexplained deaths
shortness of breath, chest pain/discomfort, palpitation, light-headedness, and black-outs
history of fainting, ‘epilepsy’, sudden death, and congenital deafness.
12-lead electrocardiogram (ECG) looking for LVH, rhythm disturbance, long QT.
Try to obtain death certificate/post-mortem report/copy of echocardiogram report to verify diagnosis in an affected family member.
At-risk family members should be reviewed by a specialist cardiologist who will refer where appropriate to genetics or preferably be seen in an ICC clinic.
Code patient’s notes.
Support groups
SCD: ischaemic heart disease
Ischaemic heart disease (IHD) remains the most significant cause of death in those living Western lifestyles and is characterized by angina (chest pain on exercise) or myocardial infarction, with possible adverse effects on cardiac rhythm, cardiac efficiency, etc.
Genetics
Single-gene defects account for a very small number of cases, and IHD is therefore a frequent expression of polygenic disease combined with environmental factors.
PCPs should manage the obvious, primary or secondary, preventative measures (lipid control, weight reduction, smoking cessation, aspirin, β-blockade, etc.) with which they are currently familiar.
It would be helpful to record a ‘family history of IHD’ in patients with such, using the relevant code, as the pace of genetic advancement may allow improved, effective screening and preventative measures in the future.
Clinical implications for primary care
( see p. 219)
Support group
SCD: structural cardiac abnormalities
Hypertrophic cardiomyopathy (HCM)
Previously hypertrophic obstructive cardiomyopathy (HOCM), this is a disease of the myocardium characterized by ventricular hypertrophy. Individuals with HCM are at risk for arrhythmia (which may cause sudden death), myocardial ischaemia, and heart failure. Cardiac hypertrophy can also be secondary to hypertension and valvular or supravalvular aortic stenosis. In the absence of a family history, these need to be excluded before a diagnosis of HCM is made. HCM can also occur in Noonan and LEOPARD syndrome ( see Chapter 5, Noonan syndrome, p. 160), Friedreich’s ataxia (FRDA), and some mitochondrial disorders.
Familial HCM affects up to 1/500 young adults. It follows an autosomal dominant (AD) mode of inheritance and many of the identified genes encode cardiac sarcomere proteins.
Overall, mutations are found in 60–70% of families with HCM.
Progression of symptoms due to left ventricular (LV) dysfunction is usually slow, but about 10% of patients develop a dilated end-stage cardiomyopathy. β-blockers, calcium-channel antagonists, and disopyramide may improve symptoms. Surgery or catheter intervention is an option for patients with obstruction that has not responded to medical therapy. LV outflow tract obstruction at rest is a predictor of progression to severe symptoms of heart failure and of death.
Potential long-term complications
Sudden death. Annual cardiovascular mortality is 0.7–1.4%. The greatest risk is in young patients with recurrent syncope or with a strong family history of sudden death. Intense physical exertion may trigger sudden death and should be avoided in high-risk patients. Amiodarone reduces risk of sudden death, and implantable cardioverter-defibrillators have a role in some high-risk patients.
Arrhythmia.
Subacute bacterial endocarditis (SBE). Patients with outflow obstruction and/or mitral regurgitation may need antibiotic prophylaxis, e.g. for dental work (see NICE guidelines).
Affected individuals will be under regular long-term surveillance by a cardiologist. Variable expression of disease is common even amongst family members carrying the same mutation. Where the familial mutation is known, definitive genetic testing may be possible to determine who needs surveillance.
Dilated cardiomyopathy and left ventricular non-compaction
This may be familial and follow a variety of patterns of inheritance. There are also many non-genetic causes.
Arrhythmogenic right ventricular dysplasia (ARVD) or cardiomyopathy (ARVC)
This is an AD heart muscle disorder that causes arrhythmia, heart failure, and sudden death. It is characterized by replacement of the right ventricular myocardium by adipose and fibrous tissue. This disorder may be as prevalent as 6 in 10 000. This disorder is difficult to diagnose and cardiac MRI rather than echocardiography may be needed for full evaluation.
Genetic advice—HCM
Inheritance and recurrence risk
AD with 50% risk to offspring of affected individuals.
Prenatal diagnosis
In a family with a known mutation this is technically possible. It is usually only considered by families with mutations carrying a high risk of sudden death.
Predictive testing
In a family with a known mutation this could be offered so that cardiac surveillance could be targeted more appropriately. Otherwise, screening of at-risk relatives should be offered ( see Chapter 1, Genetic testing of children, p. 24, for a discussion of the issues related to genetic testing in children).
Clinical implications for primary care
( See Sudden cardiac death, p. 219)
Support group
SCD: cardiac channelopathies
A number of genetic disorders can predispose to cardiac arrhythmia, these include: long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome.
Long QT syndromes
These are characterized by prolonged ventricular repolarization that predisposes carriers to life-threatening arrhythmia, most characteristically torsade de pointes, a type of ventricular tachycardia that causes syncope but may degenerate to ventricular fibrillation and cause cardiac arrest.
AD mutations in the potassium and sodium channel genes are the most common causes of long QT syndrome. A recessive type, Jervell–Lange–Nielsen syndrome, is distinguished by profound congenital deafness.
Birth incidence is unknown but has been estimated at 1/5000–1/7000.
Typically, syncope occurring during physical activity or emotional upset begins in pre-teen to teenage years and usually continues into the 20s, but may present at any age. First cardiac events are uncommon after 30–40yrs.
Importantly, it is estimated that in excess of 30–50% of carriers of mutations associated with this syndrome never have symptoms. Most others have one or many episodes of syncope but do not die suddenly. Sudden cardiac death occurs in only about 4% of affected individuals. Syncope typically occurs without warning, as distinct from vasovagal syncope, for example, in which patients feel dizzy or faint prior to collapse.
Long QT syndrome is often misdiagnosed as epilepsy, especially in children, and this needs careful attention.
Diagnosis of long QT syndrome
This is often a difficult diagnosis, relying on careful evaluation of the patient’s history, his/her non-invasive test results especially the 12-lead ECG, his/her family history, and, ideally, genetic analysis.
Known triggers for long QT-related arrhythmias include:
swimming, running
startle: alarm clock, loud horn, ringing phone
emotions: anger, crying, test taking, or other stressful situations.
NB. Sudden death may also occur during sleep.
Patients should be advised to avoid activities associated with intense physical activity and/or emotional stress, e.g. competitive sports, amusement park rides, scary movies, jumping into cold water, etc.
Long term β-blockers
The first-choice therapy in patients with long QT. Effective in ~70% of patients; cardiac events continue in the remaining 30%.
Implantable cardioverter defibrillator (ICD)
ICD may be necessary for those with symptoms despite β-blockade or for those with a history of cardiac arrest.
Annotate patient’s notes with (exhaustive) list of prescribable drugs that are contraindicated. See www.qtdrugs.org for list.
Clinical implications for primary care
( see p. 219)
Support groups
Thrombophilia
Introduction
Individuals with thrombophilia have blood that clots more easily than normal. In the normal state there is a balance between the natural clotting and anticoagulant systems. Both of these systems may be affected by either inherited or acquired (including both intrinsic and environmental) influences. The most common manifestation of thrombophilia is venous thrombosis. The incidence of venous thrombosis is about 1 per 1000 person-years. In the USA this leads to 50 000 deaths annually. Venous thromboembolism (VTE) is a multifactorial disorder, with well-characterized examples of gene–gene and gene–environment interactions underlying its pathogenesis. Genetic causes are present in approximately 25% of unselected venous thrombosis cases and up to 63% of familial cases.
Genetic causes
Genetic causes of inherited thrombophilias (hypercoagulabilities) include the following.
Factor V Leiden (R506Q mutation), causing activated protein C (APC) resistance is the most common genetic risk factor for venous thrombosis. 20% of individuals with an idiopathic first venous thrombosis have this mutation, and 60% of pregnant women with a venous thrombosis have this mutation. 4.4% of Europeans and white Americans carry the factor V Leiden mutation.
Prothrombin 20210A mutation (factor II Leiden) is carried by 1–2% of Europeans and white Americans.
Antithrombin III deficiency.
Deficiency of protein C. Purified human activated protein C selectively destroys factors Va and VIII:C in human plasma and thus has an important anticoagulant role.
Deficiency of protein S. Protein S is a vitamin K-dependent plasma protein that inhibits blood clotting by serving as a cofactor for APC.
Elevation of homocysteine is another potential risk factor in those found to be positive for factor V Leiden, as are anti-phospholipid antibodies which can cause APC resistance.
Acquired or environmental causes
Include the following.
Surgery. Only major surgery is associated with a risk, e.g. abdominal surgery under general anaesthetic or an orthopaedic operation.
Pregnancy (high factor VIII levels).
Oestrogens, e.g. oral contraceptives, hormone replacement therapy (HRT).
Malignancy.
Immobility, e.g. plaster casts, long-haul flights, stroke with limb weakness.
Patients with postoperative VTE have a very low risk of recurrence and a low incidence of thrombophilic defects. Patients with an unprecipitated VTE have a 20% cumulative recurrence rate at 2yrs; however, despite 27% of such patients having heritable thrombophilic defects, thrombophilia testing does not allow prediction of a high risk of recurrence.
Testing in patients from thrombosis-prone families may be warranted in order to identify individuals who might benefit from thromboprophylaxis during risk periods.
If a PCP is considering the need for such testing, they should consult with colleagues in Haematology.
The American College of Medical Genetics (ACMG) guidelines on testing for factor V Leiden currently suggest that testing should be performed in the following circumstance:
Age <50yrs, any venous thrombosis.
Venous thrombosis in unusual sites, e.g. mesenteric, hepatic, and cerebral veins.
Recurrent venous thrombosis.
Venous thrombosis and a strong family history of thrombotic disease.
Venous thrombosis in pregnant women or those taking the contraceptive pill.
Relatives of individuals who have had a venous thrombosis at <50yrs.
Myocardial infarction in female smokers <50yrs.
Random screening of the general population for Factor V Leiden is NOT recommended.
Potential long-term complications
Pregnancy. Heterozygosity for factor V Leiden has been linked to 2–3× increased risk of late pregnancy loss and has been associated with a higher risk of pre-eclampsia, abruption, intrauterine growth retardation (IUGR), and stillbirth. Individual assessment is required to assess whether the risk of thromboembolism, fetal loss, and pre-eclampsia is greater than the risks related to anticoagulation. Warfarin is a known teratogen with a recognizable embryopathy. Heparin prophylaxis is preferred for those at high risk.
Homozygotes for factor V Leiden have a higher overall risk of recurrence of VTE than heterozygotes. The thrombophilia team will make an assessment about treatment, balancing the risk of recurrence against the risk of major bleeding from oral anticoagulation therapy.
Genetic advice
Inheritance and recurrence risk
The genetic thrombophilias are usually inherited as an autosomal dominant (AD) trait. If both parents are carriers for the same disorder, then there is a 1 in 4 risk of a homozygous affected child.
Variability and penetrance
Although the relative risk of venous thrombosis is increased between four- and eightfold for factor V Leiden heterozygotes, the majority of heterozygous individuals never have a thrombotic event.
Predictive testing and testing of other family members
Routine testing of at-risk family members is not recommended for factor V Leiden or prothrombin 20210A as there is only a mildly increased risk for the individual and testing does not decrease morbidity or mortality.
As a general rule, young children should not be tested. Children have special defences against forming blood clots and it is not until they reach puberty that their risk of blood clots due to thrombophilia begins to increase.
Teenage daughters of patients with thrombophilia can be considered for testing if the results would influence decisions relating to contraceptive use.
For some individuals there is an indication to test, such as management of a pregnancy or avoidance of hormonal medication (oral contraceptive pill, HRT), and predictive testing can be offered to adults within families with known mutations after appropriate consent is obtained.
Patients on anticoagulants require regular surveillance of their INRs.
Advice should be given on ways to modify environmental risks and to report signs or symptoms of thrombosis.
Surgery, e.g. postoperative or associated with trauma. Minor surgery, such as dental surgery or biopsies under local anaesthetic, are not high-risk situations.
Pregnancy (high factor VIII levels).
Oestrogens. Consider alternative forms of contraception or progesterone-only preparations if oral contraceptive use is desired. HRT generally confers a two- to threefold increased risk for VTE. Early evidence suggests an interaction of HRT with thrombophilic states such as the factor V Leiden mutation, resulting in a synergistic increase in the risk of VTE.
Immobility, e.g. long-haul flights (ensure adequate hydration, relevant exercise, and the use of venous compression stockings).
Code patient’s notes.
