Inborn Errors of CNS
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Leukodystrophies are genetically determined
defects in myelin metabolism
Leukodystrophies generally present in childhood as cognitive or motor decline,
but can also be seen, although less commonly, in adult life. They are caused by
genetically determined metabolic abnormalities in the formation or metabolism of
myelin. Macroscopically, brains are small and there is loss of myelin with
gliosis. The main types of leukodystrophy are:
Adrenoleukodystrophy. X-linked recessive disease caused by deficiency of
peroxisomal enzymes involved in oxidation of long-chain fatty acids.
Metachromatic leukodystrophy. Autosomal recessive disease caused by lack of
activity of aryl sulphatase A.
Krabbe's disease (globoid-cell leukodystrophy). Autosomal recessive disease
caused by galactocerebroside ك-galactosidase deficiency.
The diagnosis of these metabolic defects in myelin formation is made by assay of
enzymes detectable in blood leukocytes or cultured fibroblasts.
Neurometabolic storage disorders are genetic diseases causing accumulation of
abnormal material in the brain.
Several of the inborn errors of metabolism are characterized by storage of
abnormal material in the nervous system. This type of disease most commonly
arises in childhood, when it presents as cognitive or motor decline. Among the
main types are:
Gangliosidoses, autosomal recessive disorders causing neuronal storage of
gangliosides, e.g. Tay-Sachs disease.
Mucopolysaccharidoses cause abnormal storage of mucopolysaccharides in brain
and other tissues, the main types being Hurler's syndrome (gargoylism) and
Gaucher's disease is caused by deficiency of ك-glucocerebrosidase resulting in
accumulation of glucocerebroside in brain and macrophages in other organs.
Ceroid lipofuscinoses are disorders in which there is neuronal storage of
lipofuscin-like lipids due to unknown enzyme defects. The main type is Batten's
Niemann-Pick disease is caused by deficient sphingomyelinase activity, only
some varieties having neurological involvement.
Diagnosis of neurometabolic storage diseases is made by showing the abnormal
enzyme activity in lymphocytes or cultured fibroblasts. As an enzyme defect has
not been characterized, Batten's disease is diagnosed by demonstration of
abnormal lipid material in the rectal ganglion cells on rectal biopsy.
NF1 is an autosomal dominant disease that causes multiple benign tumours of
NF1, formerly called 'von Recklinghausen's syndrome', is an autosomal dominant
disorder affecting 1 in 4000 individuals. The main clinical features are
development of benign tumours of peripheral nerves, termed neurofibromas, and
the presence of pigmented skin lesions called café au lait spots. Less prominent
are hamartomas of the iris, optic-nerve gliomas, and bone abnormalities.
Patients characteristically develop multiple polypoid skin nodules, which can
vary from 1 mm up to 5 cm in diameter. There is a risk of development of
malignant nerve tumours (neurofibrosarcomas). The gene defect in NF1 is located
on chromosome 17 .
NF2 is an autosomal dominant disease that causes tumours on the acoustic nerves
NF2 is an autosomal dominant disorder affecting 1 in 100,000 individuals. The
clinical features are development of bilateral benign tumours (also termed
schwannomas) of the VIIIth cranial nerve, which are also known as acoustic
neuromas, hence the alternative name of bilateral acoustic neurofibromatosis (BANF).
There is also a tendency to develop other brain tumours, meningiomas and gliomas.
Patients present with tinnitus, deafness, or signs of a mass lesion compressing
the lower cranial nerves and brain stem. The gene defect for NF2 is located on
Tuberous sclerosis is an autosomal dominant disease causing epilepsy and mental
retardation associated with hamartomas of the brain
Tuberous sclerosis is an autosomal dominant condition affecting 1 in 100,000
individuals. Affected patients develop epilepsy, mental retardation, skin
lesions called angiofibromas, and retinal hamartomas. A minority of patients
develop cardiac tumours termed benign rhabdomyomas, as well as renal tumours (angiomyolipomas).
As a result of incomplete genetic expression, formes frustes of tuberous
sclerosis are common.
The brain shows characteristic lesions termed tubers (after which the syndrome
is named), which appear as firm, white nodules, 1-3 cm in size, at the crest of
gyri. The tubers are hamartomatous overgrowths of neurons and astrocytes. A gene
for tuberous sclerosis is located on chromosome 16, and codes for a protein
termed tuberin, which has homology with a GTPase-activating protein, GAP-3.
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