Neurogenetics

Published on 10/04/2015 by admin

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Neurogenetics

Introduction

Individual genetic disorders are rare but there are many of them so that together their cumulative morbidity is significant. Some are particularly important as they are treatable. In recent years, new insights have been made into these diseases and this field is changing rapidly. This section will describe some aspects of clinical neurogenetics, and discuss the principal patterns of inheritance and some of the clinical problems posed by the more common neurological conditions.

Molecular genetic techniques have enabled identification of genes for inherited conditions, which allows:

identification of gene products, enhancing understanding of pathophysiology and potentially allowing the development of treatments

increased understanding of the relationships between phenotype and genotype

improved diagnosis for the affected patient and for patients at risk. This has improved both preconceptual and antenatal advice.

In this section we will explore the clinical approach to patients with genetic or suspected genetic disease and consider the ways in which the newer genetic tests are used.

Clues to diagnosis

Disease definition and genetic testing

The clinical definition of inherited diseases is crucial in the identification of their underlying defects. However, as genes underlying diseases are being identified, it is becoming apparent that the link between phenotype and genotype is less clear cut than had been anticipated. The phenotype of the same gene defect may be very different in different individuals, presumably because of other constitutional and environmental factors. This means that although a diagnosis can be made, it is sometimes difficult to give a prognosis, making it difficult to give clear advice. Equally the same clinical syndrome may be due to several gene defects, some unidentified, and a genetic diagnosis can only be made in a proportion of similarly affected individuals. For example, in Charcot–Marie–Tooth (hereditary sensory and motor neuropathy) type I disease, only 80% of patients have identified mutations. Thus a normal genetic test does not exclude the diagnosis. In any one family, however, the genetic defect should be in the same locus in all affected individuals.

Selected inherited diseases

Chromosomal abnormalities

Chromosomal abnormalities may cause disease if there is too much or too little genetic material: duplications or deletions. These large defects are often associated with severe mental retardation and epilepsy. Down’s syndrome (trisomy 21) is the most common and is due to replication of chromosome 21, resulting in three copies of the chromosome.

Single gene abnormalities

Autosomal dominant disorders

Males or females are equally affected, transmission is from mother or father and 50% of offspring are affected (Table 1; Fig. 1a).

Table 1 Some important autosomal dominant conditions

Condition	Clinical features	Genetic defect
Huntington’s disease	Progressive dementia with chorea	Huntington, chromosome 4
Myotonic dystrophy	Progressive myotonia and weakness, with multisystem disease (p. 112)	Myotonin protein kinase, chromosome 19
Torsion dystonia (some families)	Generalized dystonia (p. 92)	Chromosome 9
Dopa-responsive dystonia (rare but treatable)	Generalized dystonia, very responsive to levodopa	Defects of tyrosine hydroxylase and coenzymes
Charcot–Marie–Tooth disease type I	Progressive demyelinating neuropathy with pes cavus and champagne bottle legs	A: PMP 22 gene B: PO protein C: 20% unknown

Fig. 1 Common types of genetic inheritance.

Trinucleotide repeat expansions

In several neurological diseases the underlying mutation has been identified as consisting of repeat sequences of redundant trinucleotides. Normal individuals may have some repeats, and disease sufferers usually have increasing numbers. In general, the more repeats, the earlier the onset and the more severe the disease. Successive generations tend to have larger numbers of trinucleotide repeats and are affected earlier and more severely: the phenomenon of ‘anticipation’. Huntington’s disease and myotonic dystrophy are two common examples (dominant); other examples are fragile X syndrome, bulbospinal neuronopathy (Kennedy’s syndrome; X-linked), Friedreich’s ataxia (recessive) and other spinocerebellar degenerations.

Autosomal recessive disorders

Males and females are equally affected, often without a family history, as parents are asymptomatic carriers; 25% of offspring are affected (Fig. 1b). Autosomal recessive disorders are often due to single enzyme defects, raising the possibility of therapeutic metabolic manipulation (Table 2).

Table 2 Some rare but important treatable autosomal recessive disorders

Condition	Clinical features	Genetic defect
Wilson’s disease	Movement disorders and psychiatric illness. Liver disease in children (p. 92)	Copper-binding ATPase
Phenylketonuria	Developmental delay, retardation, hypopigmentation, emotional disturbance. Treated by diet. Routine screening at birth	Phenylalanine hydroxylase
Galactosaemia	Failure to thrive, retardation, liver and renal disease, hypoglycaemia. Treatment is avoidance of all milk products	Galactose-1-phosphate uridyl transferase
Vitamin E deficiency	Progressive ataxia, with myelopathy, ophthalmoplegia and neuropathy. Treatment is with vitamin E supplements	Abetalipoproteinaemia

These diseases almost exclusively affect males; females are carriers (Fig. 1c). The disease may appear to skip generations. Each son of a carrier is at 50% risk and each daughter is at 50% risk of being a carrier. Daughters of affected males may be carriers, but sons can never be affected. In the female, every cell contains only one active X chromosome: which one is inactivated varies between cells. If the abnormal chromosome is active in some cells important in the disease process (e.g. muscle cells in Duchenne muscular dystrophy), the female may suffer some disease symptoms. Duchenne (DMD) and Becker (BMD) muscular dystrophies are both due to abnormalities of the same gene, encoding the protein ‘dystrophin’ (p. 112). In DMD the protein may be absent, whereas in BMD it is deficient. Clinical features of muscular dystrophy are summarized on page 112. Fragile X syndrome (30% of female carriers affected) is a common cause of mental retardation and may cause late-onset ataxia.

Mitochondrial diseases

Many mitochondrial proteins are encoded in the nuclear DNA and their disorders are transmitted as autosomal traits. Some mitochondrial respiratory proteins are encoded in DNA within the mitochondrion itself. This DNA is passed from mother to child via mitochondria in the ovum; the sperm does not contribute any mitochondria. Consequently, defective DNA can only be passed from mother to child, although either sex may be affected: ‘maternal inheritance’. There are many mitochondria in the ovum, some of which may be normal.

The clinical pattern and the severity of the disease are very variable because they depend on the number of abnormal mitochondria, the nature of the chemical defect and where the abnormal mitochondria end up in the offspring. Several typical syndromes are recognized, for example Kearn–Sayres syndrome (progressive external ophthalmoplegia), Leber’s optic atrophy, mitochondrial encephalomyopathy and stroke-like episodes (MELAS), and myoclonic epilepsy and ragged red fibres (MERRF).

Common diseases

In some common conditions, relatives of sufferers are more frequently affected than the general population (Table 3). The increased risk is small and cannot be attributed to a simple gene defect. This may be because a combination of several genes and environmental factors are required for the disease, and having some of the abnormal genes puts the individual at increased risk. In other diseases, a minority of cases are inherited and these often have a younger onset than the sporadic, presumed polygenic forms. For example, familial Alzheimer’s disease is an autosomal dominant condition, with onset around 45–55 years, due to mutations of the presenilin or amyloid precursor protein genes.

Table 3 Risk associated with common inherited disorders

Condition	Risk in general population	Risk in first-degree relatives
Multiple sclerosis	0.2%	5–15%
Epilepsy	0.5%	5% (some types much higher)
Alzheimer’s disease	<1% at age 60 years (p. 54)	Three times age-matched controls
Parkinson’s disease	0.5% over age 70 years	1.5% (higher if younger onset)

Ethical issues of the new genetics

Being able to establish that an individual carries a gene defect raises ethical problems. These are highlighted by Huntington’s disease (autosomal dominant), which causes late-onset chorea with dementia (p. 93) with complete penetrance. Finding the gene in clinically normal people means that they will develop the disease and that their children are at 50% risk. This knowledge places a considerable burden, especially for those who have seen the decline of relatives affected with this devastating illness. Adults may not want to know their genetic status, but if their teenage child wishes to be tested and find they carry the gene, they know that their parent must also develop the disease. It is, therefore, important that patients understand fully the implications of any test they undergo, both for themselves and their families. Counselling should be undertaken by specialized clinical geneticists, and ideally should involve the whole family.

Neurogenetics