Huntington disease (HD)

HD is a progressive fatal neurodegenerative disease. Like
FRAX–A, HD is caused by a triplet repeat expansion. The HD
expansion involves a CAG triplet in exon 1 of the IT15 gene on
chromosome 4. The expansion is translated into a
polyglutamine tract in the huntingtin protein gene product
that is believed to cause a dominant gain of function leading to
neuronal loss.
In normal individuals, the CAG unit in exon 1 has between
9 and 35 repeats. Affected individuals have repeats of 36 units
or greater, with over 90% of affected subjects having 40–55
repeats. In general, the greater the number of repeats an
individual has, the earlier the age of onset will be, although this
relationship is stronger for higher repeat numbers.

CAG

Since the CAG repeat expansion is the sole mutation
responsible for all HD cases, molecular genetic analysis
concentrates on this single region. Small CAG expansions can
be detected using PCR amplification of the repeat region.
The PCR products are then sized using polyacrylamide gel
electrophoresis. Samples with known repeat sizes may be used
as controls to determine the size of the expansion. Larger
expansions cannot be detected by PCR and the time-consuming
Southern blotting method must be used in cases where two
normal sized repeat alleles are not detected by PCR.

Charcot–Marie–Tooth disease (CMT)

CMT disease (or hereditary motor and sensory neuropathy,
HMSN) is clinically and genetically heterogeneous, but is
generally characterised by wasting and weakness of the distal
limb muscles with or without distal sensory loss. CMT may be
inherited in an autosomal dominant, autosomal recessive or
X linked manner. Clinically, the condition is divided into the
demyelinating CMT1 (with reduced nerve conduction
velocities) and axonal CMT2 (with nerve conduction velocites
largely preserved). Rarer clinical forms exist, including the
severe Dejerine–Sottas syndrome and hereditary neuropathy
with increased reflexes. The related condition HNPP
(hereditary neuropathy with liability to pressure palsies) creates
a milder phenotype characterised by recurrent, usually
transient sensorimotor neuropathies.

genes involved in CMT

Many of the genes involved in CMT have now been cloned
and sequenced, allowing a genetic classification to be made
depending on the mutation or gene locus identified. Mutations
in over five genes have been reported in CMT, including
PMP22 (peripheral myelin protein on chromosome 17),
MPZ (myelin protein zero on chromosome 1), Connexin-32
(X chromosome), EGR2 and NEFL. The commonest mutational
event is the duplication of the entire PMP22 gene resulting in
clinical CMT type 1a. A deletion of the same gene gives rise to
the milder HNPP phenotype. Phenotypes of varying severity
can also be produced by point mutations (often base
substitutions) in any of the five genes mentioned above.
Prediction of disease severity in presymptomatic patients is
difficult as there is varying severity even within families.

duplication or deletion of the PMP22 gene

Detection of the duplication or deletion of the PMP22 gene
is achieved using fluorescent dosage PCR analysis to determine
the number of gene copies present. Following initial PCR
amplification with fluorescently-labelled primers, the products
are analysed by automated laser-induced fluorescence. Point
mutations in all five CMT genes are detected by a variety of
methods depending on local practices, including SSCP, DGGE
and DNA sequencing. Requests for prenatal testing in the UK
are rare.

Spinal muscular atrophy (SMA)

SMA encompasses a clinically and genetically heterogeneous
group of disorders characterised by degeneration and loss of
the anterior horn cells in the spinal cord and sometimes in the
brainstem nuclei, resulting in muscle weakness and atrophy.
Most cases are inherited in an autosomal recessive fashion,
although some affected families show dominant inheritance.
Childhood onset SMA is the second most common, lethal
autosomal recessive disorder in white populations, with an
overall incidence of 1 in 10 000 live births and a carrier
frequency of approximately 1 in 50. It is estimated to be the
second most frequent disease seen in paediatric neuromuscular
clinics after Duchenne muscular dystrophy.

Childhood onset SMA

Childhood onset SMA can be classified into three types,
distinguished on the basis of clinical severity and age of onset.
In type I (Werdnig–Hoffman disease), onset occurs within the
first six months of life and children usually die within two years.
In type II (intermediate type Dubowitz disease) onset is before
18 months with death occuring after two years. In type III
(Kugelberg–Welander disease), the disease has a later onset
and milder, chronic cause with affected children achieving
ambulation.