Genetically Determined Errors of Metabolism

B. Genetically Determined Errors of Metabolism

1. Introduction

These disorders are generally associated with specific enzyme deficiencies and result in blockage of amino acid, carbohydrate or lipid metabolism, with reduction of some substances and accumulation of others. Functional and/or morphologic changes may occur and in some instances (phenylketonuria, galactosemia, Refsum's disease) may be ameliorated by therapy. In many disorders the carrier state can be identified to permit genetic counseling. By the testing of amniotic fluid before birth or appropriate screening at birth, these metabolic disorders can be detected. Since these disorders seldom occur, the in utero testing can usually assure parents that their child will be normal.

Clinical Expression: The neurological complications of these disorders range from specific focal abnormalities to mental retardation. The precise reason for the mental retardation is not clear. There is marked variation in the age of onset, rate of progression and organ and skeletal involvement among disorders and among variants of each disorder. This is due to factors such as the different isoenyzmes involved, solubility of accumulated products for excretion and the specific biochemical reactions occurring in various organs.

Inheritance Pattern: Almost all of these disorders are characterized by autosomal recessive transmission. The chromosome on which the defective gene is located has been determined for many of the disorders. Research is in progress to characterize the enzyme defect and develop possible therapeutic approaches to correct the defect.

Mechanisms of Damage: Functional and pathological damage may be produced by loss of end product of a reaction due to enzyme deficiency, accumulation of substances prior to the metabolic block, or production of toxic metabolites. Almost certainly, indirect effects are also exerted on other metabolic pathways or functional elements.

Specific Enzyme Deficiencies: Examples from this class of disorders are discussed below. These were selected because they are amenable to therapy or are representative of a class of enzyme deficiency diseases.

1. General Principles

The Toxic-Metabolic-Nutritional Diseases discussed here result in neurological disorders in which biochemical lesions most clearly produce specific morphological changes. In some cases, although functional derangements may be quite severe and may be related to known or presumed biochemical defects, specific morphological changes have not been described. A case in point is delirium tremens, a clinical disorder following alcohol withdrawal. While the effects of withdrawal seem to be specifically related to abnormal limbic system function, there are no morphological changes specific for this condition. Similarly, water intoxication and hypocalcemia profoundly affect the function of the nervous system, but morphological changes are non-specific.

2. Phenylketonuria (disorder of amino acid metabolism)

a) Biochemical defect: deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine; increased blood levels of phenylalanine and increased urinary excretion of phenylpyruvic acid.

b) Clinical expression: symptoms in infancy or early childhood; mental retardation, seizure and hyperactivity

c) Detection: practically all newborns are screened (Guthrie test-serum analysis).

d) Therapy: low phenylalanine diet supplemented with tyrosine.

e) Pathological Characteristics:

- hypomyelination; gliosis; microcephaly; no lysosomal storage in neurons

3. Galactosemia (disorder of carbohydrate metabolism)

a) Biochemical defect: deficiency of galactose-1-phosphate uridyl transferase; accumulation of galactose-1-phosphate; galactosuria and presumed hypergalactosemia

b) Clinical expression: mental retardation

c) Therapy: galactose-free diet

d) Pathological Characteristics: no lysosomal storage in neurons; non-specific changes with neuronal loss and gliosis

4. Refsum's Disease (disorder of lipid metabolism)

a) Biochemical defect: deficiency of phytanic oxidase; increased phytanic acid in plasma.

b) Clinical expression: peripheral neuropathy signs, sometimes cerebellar signs.

c) Therapy: low phytol diet (phytol is a component of foods derived from some plants).

d) Pathological Characteristics: hypertrophic interstitial neuropathy; sometimes associated with cerebellar degeneration.

5. Sphingolipidoses (disorders of sphingolipid metabolism)

a) Biochemical defect: deficiency of acid hydrolases which degrade specific lipids in lysosomes

b) Clinical expression: variable when infants and children are affected, progressive mental and motor deterioration and death is the usual pattern. There are many variants, some of which have a milder form with adult onset.

c) Two categories:

Storage Disease-Type Sphingolipidoses

---characterized primarily by storage of uncleaved substrate in neurons and other cell types.

---category includes Tay-Sachs, and Niemann-Pick diseases

Leukodystrophy-Type Sphingolipidoses

---characterized by impairment of a biochemical process necessary for myelin development or maintenance.

---category includes Krabbe's disease and metachromatic leukodystrophy.

This image shows part of a coronal section; the ventricle is seen at the bottom. Pale areas in the white matter (compared to normally dark staining of myelin) indicate areas of demyclination in Krabbe's disease)