Inherited and Metabolic Disease of the CNS

=Objectives=

Describe 3 ways how metabolic deficiencies lead to CNS disease

 * Enzymes require trace materials for normal synthesis
 * ex: B12 deficiency leads to ascending and descending corticospinal demyelination. B12-dependent enzymes are involved in myelin synthesis


 * Deficiency in metabolic synthesis leads to generation of toxic metabolites
 * ex1. phenylketonuria. Phenylalanine hydroxylase catalyzes the conversion of phenylalanine to tyrosine.  In the absence of the enzyme, the metabolites phenylpyruvate and phenylacetate are generated.  These metabolites are neurotoxic.
 * ex2. Krabbe disease, an inherited leukodystrophy due to deficiency of galactocerebroside B-galactosidase. With enzyme deficiency, galactocerbroside builds up.  This molecule is not toxic, but the subsequent generation of galactosylsphingosine is directly toxic.


 * Neuronal storage disease results in cellular dysfunction
 * ex. The lysosomal storage disease like Tay-Sachs, Niemann-Pick, lead to accumulation of gangliosides. The cells begin to swell and are unable to perform normal cellular functions.
 * ex2. Gaucher's disease (type 2 for the neuropathic effect). Defect in glucocerebrosidase --> accumulation of glucocerebroside


 * Disruption of energy metabolism
 * ex: Leigh Syndrome, a mitochondria encephalomyopathy characterized by lactic acidemia, feeding problems, seizures, extraocular palsies. An autosomal recessive disorder with decreased activity of cytochrome c oxidase.

Explain the significance of a Cherry Red Spot

 * Cherry red spots occur in the macula of lysosomal neuronal storage diseases. Ganglion cells of the retina swell with intracellular sphingolipids and become pale white.  The pale white zone is contrasted with the foveola which remains bright red because there aren't ganglion cells directly over the foveola.

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