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 diseases 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.
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.
