Inborn Errors of CNS Metabolism

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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 Hunter's syndrome.

• 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 disease.

• 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 peripheral nerves

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 chromosome 22.

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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Revised: 09-01-1428.