Lipid Storage Diseases Lipidoses

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If tissues lack a key breakdown enzyme, lipids accumulate. The resulting pathologies are usually fatal. However, enzyme replacement therapies can be effective.

Several inborn errors of metabolism exist in which the missing enzyme is one that is involved in the breakdown of a specific lipid molecule. Since the biosynthesis of these lipids is not impaired, the result of the enzyme deficiency is the gradual accumulation of lipids in the tissues. Most of the important diseases of this type are ones that involve structural lipids, frequently glycosphingolipids, of the central nervous system and they are summarized in Table 7.10. The diseases are rare and frequently fatal, which serves to indicate how important it is that the amounts and types of lipids in membranes are strictly controlled to preserve biological function. Many of the lipids involved in these disorders are readily synthesized in the body, so that dietary treatment is ineffective. There is one lipid storage disease, Refsum's disease, however, that can be controlled by strict exclusion of a fatty acid from the diet. This disease is due to failure to break down by a-oxidation, the branched-chain fatty acid, phytanic acid (Section 2.3.2), which is formed from phytol, a universal constituent of green plants (Fig. 7.24). In patients, there is a characteristic build-up of phytanic acid in the blood

Table 7.10 Enzyme deficiencies and accumulating lipids in the main sphingolipidoses

Disease Signs and symptoms Major lipid accumulation Enzyme defect

Table 7.10 Enzyme deficiencies and accumulating lipids in the main sphingolipidoses

Disease Signs and symptoms Major lipid accumulation Enzyme defect

Ceramide lactoside; lipidosis

Slowly progressing brain damage.

Ceramide lactoside

Neutral P-galactosidase

Fabry's disease

Reddish-purple skin rash, kidney failure, pain in lower extremities.

Gal-Gal-Glu-ceramide

a-Galactosidase

Farber's disease

Hoarseness, dermatitis, skeletal deformation, mental retardation.

Ceramide

Ceramidase

Gaucher's disease

Spleen and liver enlargement, erosion of long bones and pelvis, mental retardation only in infantile form.

Glucocerebroside

Glucocerebrosidase

Generalized gangliosidosis (GMj gangliosidosis)

Mental retardation, liver enlargement, skeletal deformities, about 50% with red spot in retina.

Ganglioside GMi

P-Galactosidase

Krabbe's disease (globoid leukodystrophy)

Mental retardation, almost total absence of myelin, globoid bodies in white matter of brain.

Galactocerebroside

Galactocerebroside P-galactosidase

Metachromatic leukodystrophy (two forms)

Mental retardation, psychological disturbance in adult form, nerves stain yellow-brown with cresyl violet dye.

Sulphatide

Aryl sulphatase A (sulphatide activator/ saposin inactivator-deficient form)

Niemann-Pick disease

Liver and spleen enlargement, mental retardation, about 30% with red spot in retina.

Sphingomyelin

Sphingomyelinase

Tay-Sachs disease

Mental retardation, red spot in retina, blindness, muscular weakness.

Ganglioside GM2

Hexosaminidase A

Tay-Sachs variant

Same as Tay-Sachs disease, but progressing more rapidly.

Globoside (and ganglioside GM2)

Hexosaminidase A and B

Reproduced with kind permission from Annual Review of Biochemistry, 47 (1978), 687 by Annual Reviews Inc.; modified with reference to Neufeld (1991).

Reproduced with kind permission from Annual Review of Biochemistry, 47 (1978), 687 by Annual Reviews Inc.; modified with reference to Neufeld (1991).

where it may represent 30% of the total fatty acids. A condition of ataxic neuropathy develops and the disease is normally fatal. To survive, the patients must have a low phytol diet.

Since an important consequence of the accumu lation of sphingolipids in the central nervous system is to produce mental retardation, it is important to be able to detect the defect as early as possible. It is now possible to detect the enzyme deficiency responsible for some of the lipid storage diseases in

Phytol

,ch2oh

CH3 CH3

HCO-CoA

(formyl-CoA) CH3 CH3

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