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Neurogenetic Disorders


Neurogenetic Disorders
A large number of genetic disorders involve the nervous system, and some of these have pathology confined solely to this system. Recent advances in molecular genetics have meant that many dis- eases of the nervous system are being redefined by their underlying genetic defect.

Three major new developments have revolutionized the role of genetic factors in the evolution of neurological disease. First, genes encoded in the maternally inherited mitochondrial genome can cause neurological disorder; Second, a number of inherited neurological disorders have as their basis an expanded trinucleotide repeat (triplet repeat disorders); Third, the ability to use sophisticated genotyping of individual cases (exome sequencing) to find novel mutations is starting to yield new insights into diseases of the nervous system.

Neurogenetic Disorders

Disorders with gene deletions
Many different disorders within the nervous system result from the loss of a single gene or part thereof. For example, hereditary neuropathy with a liability to pressure palsies, in which the patient has a tendency to develop recurrent focal entrapment neuropathies in association with a large deletion on chromosome 17, which includes the gene coding for the peripheral myelin protein 22 (PMP 22).

Disorders with gene duplications
The duplication of a gene can, under some circumstances, cause disease. An example of this is in certain types of hereditary motor and sensory neuropathy, where the patient develops distal weakness, wasting and sensory loss in the first decades of life. In some of these cases there is duplication of part of chromosome 17, including the gene coding for PMP 22.

Disorders with gene mutations
This is the most common form of genetic defect and in these diseases there is a mutation in the gene coding for a specific enzyme or protein which results in that product failing to work normally. An example of such a situation is found in some familial forms of motor neurone disease (see Chapter 60) and muscular dystrophies (see Chapter 21) as well as myotonic syndromes (see Chapter 14).

Disorders showing genetic imprinting
Genetic imprinting is the differential expression of autosomal genes depending upon their parental origin. Thus, disruption of the maternal gene(s) on a certain part of chromosome 15 (15q11- q13) causes Prader–Willi syndrome (mental retardation with obesity, hypogenitalism and short stature) while disruption of the same genes from the father causes Angelman’s syndrome (a condition of severe mental retardation, cerebellar ataxia, epilepsy and craniofacial abnormalities).

Mitochondrial disorders
Mitochondria contain their own DNA and synthesize a number of the proteins in the respiratory chain responsible for oxidative phosphorylation (see Chapter 60), although the vast majority of mitochondrial proteins are encoded by nuclear DNA.
Thus, mitochondrial disorders (deletions, duplication or point mutations) can result from defects in:
·       these nuclear-coded genes;
·       the mitochondria genome.
However, mitochondrial DNA mutates more than 10 times as frequently as nuclear DNA and has no introns (non-coding parts of the genome), so that a random mutation will usually strike a coding DNA sequence. As mitochondria are inherited from the fertilized oocyte, disorders with point mutations in the mitochondrially coded DNA show maternal inheritance (always inherited from the mother). However, within each cell there are many mitochondria and so a given cell can contain both normal and mutant mitochondrial DNA, a situation known as heteroplasmy, and it is only when a given threshold of mutant mitochondria is reached does the disease result.
The clinical disorders associated with different defects in the mitochondrial genome are legion, and the reason why some areas are targeted in some conditions and not others is not clear.

Trinucleotide repeat disorders
A number of different disorders have now been identified that have as their major genetic defect an expanded triplet repeat, i.e. there is a large and abnormal expansion of three bases in the genome. In normal individuals triplet repeat sequences are not uncommon but once the number of repeats exceeds a certain number the disease will definitely appear.
This pathological triplet (or trinucleotide) repeat either occurs in the coding part of a gene (e.g. Huntington’s disease; see Chapter 42) or in a non-coding part of the genome (e.g. Friedreich’s ataxia). The resulting expansion either causes a loss of function (e.g. frataxin in Friedreich’s ataxia) or a new gain of function in that gene product (e.g. huntingtin in Huntington’s disease). This latter aspect is of interest as the new protein appears to have a function that is unique to it and which is critical to the evolution of the neurodegenerative process. However, the mechanism by which this protein produces selective neuronal death in specific CNS sites is not known as many of the mutant gene products are widely expressed throughout the brain and body.
The consequence of a large unstable DNA sequence as occurs in these disorders is that the triplet repeat can increase during mitosis and meiosis, resulting in longer triplet repeat sequences (dynamic mutations). This means that the most likely time for triplet expansion is during spermatogenesis and subsequent fertilization/embryogenesis, and has two major implications. First, longer repeats tend to occur in the offspring of affected men and, second, longer repeats tend to occur in subsequent generations. This results in patients of subsequent generations presenting with earlier onset and more severe forms of the disorder a phenomenon known as genetic anticipation as longer repeat sequences are associated with younger onset and more severe forms of the disease.

Genome-wide association studies
In recent years the ability to look across the whole genome in populations of patients with diseases of a complex genetic basis has proved possible both technically and financially. The use of a large number of markers to cover the whole genome has identified a number of regions conveying risk in disorders of the central nervous system (CNS), such as Parkinson’s and Alzheimer’s disease. This is turn will yield new insights into the common sporadic forms of the disease, as hitherto the genetics of these disorders has largely been in the domain of rare mendelian forms of the disease.

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