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March 1976, Vol 33, No. 3 >
Article | March 1976

Biochemical Genetics in Neurology

Roscoe O. Brady, MD
[+] Author Affiliations

Accepted for publication June 17, 1975.

Reprint requests to National Institutes of Health, Building 10, Room 3D03, Bethesda, MD 20014 (Dr Brady).


Arch Neurol. 1976;33(3):145-151. doi:10.1001/archneur.1976.00500030001001
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Article
References
Comments

Remarkable advances in the past five years now permit the control of an important segment of hereditary disorders of metabolism that cause central nervous system (CNS) damage. The application of this knowledge has provided immense relief of human suffering and distress. It is therefore exigent that neurologists be aware of these developments and how they may be applied to patients. This article describes briefly how we learned the causes of ten inherited lipid storage diseases and indicates how this information is used to control the incidence of these disorders. It also provides a précis of the current status of research in mucopolysaccharide storage diseases, and concludes with a demonstration of a new concept in hereditary neurologic diseases caused by a defect in the synthesis of critical brain components.

LIPID STORAGE DISEASES 

Clinical Descriptions  Physicians have been aware of clinical manifestations of several of the lipidoses for nearly a century.

REFERENCES

1 +
Brady RO:  Inborn errors of lipid metabolism , in Meister A (ed): Advances in Enzymology . New York, John Wiley & Sons Inc, 1973;, vol 38, pp 293-315.
2 +
Aghion A: La Maladie de Gaucher dans l'enfance, thesis, University of Paris, 1934.
3 +
Klenk E:  Über die Natur der Phosphatide und anderer Lipoide des Gehirns und der Leber bei der Niemann-Pickschen Krankheit . Hoppe-Seylers Z Physiol Chem 235:24-36, 1935;.
4 +
Dawson G, Stein AO:  Lactosylceramidosis: Catabolic defect of glycosphingolipid metabolism . Science 170:556-558, 1970;.
5 +
Wenger DA, Sattler M, Clark C, et al:  Lactosylceramidosis: Normal activity for two lactosylceramide β galactosidases . Science 188:1310-1312, 1975;.
6 +
Trams EG, Brady RO:  Cerebroside synthesis in Gaucher's disease . J Clin Invest 39:1546-1550, 1960;.
7 +
Brady RO, Kanfer JN, Shapiro D:  The metabolism of glucocerebrosides: I. Purification and properties of a glucocerebroside-cleaving enzyme from spleen tissue . J Biol Chem 240:39-43, 1965;.
8 +
Brady RO, Kanfer JN, Shapiro D:  Metabolism of glucocerebrosides: II. Evidence of an enzymatic deficiency in Gaucher's disease . Biochem Biophys Res Commun 18:221-225, 1965;.
9 +
Brady RO, Kanfer JN, Bradley RM, et al:  Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease . J Clin Invest 45:1112-1115, 1966;.
10 +
Kattlove HE, Williams JC, Gaynor E, et al:  Gaucher cells in chronic myelocytic leukemia: An acquired abnormality . Blood 33:379-390, 1969;.
11 +
Brady RO, Kanfer JN, Mock MB, et al:  The metabolism of sphingomyelin: II. Evidence of an enzymatic deficiency in Niemann-Pick disease . Proc Natl Acad Sci USA 55:366-369, 1966;.
12 +
Brady RO:  The sphingolipidoses . N Engl J Med 275:312-318, 1966;.
13 +
Suzuki K, Suzuki Y:  Globoid cell leukodystrophy: Deficiency of galactocerebroside beta-galactosidase . Proc Natl Acad Sci USA 66:302-309, 1970;.
14 +
Mehl E, Jatzkewitz H:  Evidence for a genetic block in metachromatic leukodystrophy (ML) . Biochem Biophys Res Commun 19:407-411, 1965;.
15 +
Brady RO, Gal AE, Bradley RM, et al:  Enzymatic defect in Fabry's disease: Ceramidetrihexosidase deficiency . N Engl J Med 276:1163x-1167, 1967;.
16 +
Kolodny EH, Brady RO, Volk BW:  Demonstration of an alteration of ganglioside metabolism in Tay-Sachs disease . Biochem Biophys Res Commun 37:526-531, 1969;.
17 +
Tallman JF, Johnson WG, Brady RO:  The matabolism of Tay-Sachs ganglioside: Catabolic studies with lysosomal enzymes from normal and Tay-Sachs tissue . J Clin Invest 51:2339-2345, 1972;.
18 +
Sandhoff K, Andreae U, Jatzkewitz H:  Deficient hexosaminidase activity in an exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral organs . Life Sci 7:283-288, 1968;.
19 +
Okada S, O'Brien JS:  Generalized gangliosidosis: Beta-galactosidase deficiency . Science 160:1002-1004, 1968;.
20 +
Van Hoof F, Hers HG:  Mucopolysaccharidosis by absence of α-flucosidase . Lancet 1:1198, 1968;.
21 +
Dawson G, Spranger JW:  Fucosidosis: A glycosphingolipidosis . N Engl J Med 285:122, 1971;.
22 +
Sugita M, Dulaney JT, Moser HW:  Ceramidase deficiency in Farber's disease (lipogranulomatosis) . Science 178:1100, 1972;.
23 +
Kampine JP, Brady RO, Kafner JN, et al:  Diagnosis of Gaucher's disease and Niemann-Pick disease with small samples of venous blood . Science 155:86-88, 1967;.
24 +
Suzuki Y, Suzuki K:  Krabbe's globoid leukodystrophy: Deficiency of galactocerebrosidase in serum, leukocytes, and fibroblasts . Science 171:73-75, 1971;.
25 +
Percy AK, Brady RO:  Metachromatic leukodystrophy: Diagnosis with samples of venous blood . Science 161:594-595, 1968;.
26 +
Kint JA, Fabry's disease:  Alpha-galactosidase deficiency . Science 167:1268-1269, 1970;.
27 +
O'Brien JS, Okada S, Chen A, et al:  Tay-Sachs disease: Detection of heterozygotes and homozygotes by serum hexosaminidase assay . N Engl J Med 283:15-20, 1970;.
28 +
Wolfe LS, Callahan J, Fawcett JS, et al:  GM1-gangliosidosis without chondrodystrophy or visceromegaly: β-galactosidase deficiency with gangliosidosis and the excessive excretion of keratan sulfate . Neurology 20:23-44, 1970;.
29 +
Van Hoof F:  Fucosidosis , in Hers HG, Van Hoof F (eds): Lysosomes and Storage Diseases . New York, Academic Press Inc, 1973;, p 286.
30 +
Gal AE, Brady RO, Hibbert SR, et al:  A practical chromogenic procedure for the detection of homozygotes and heterozygous carriers of Niemann-Pick disease . N Engl J Med 293:632-636, 1975;.
31 +
Radin NS, Hof L, Bradley RM, et al:  Lactosylceramide galactosidase: Comparison with other sphingolipid hydrolases in developing rat brain . Brain Res 14:497-505, 1969;.
32 +
Ho MW, Seck J, Schmidt D, et al:  Adult Gaucher's disease: Kindred studies and demonstration of a deficiency of acid glucosidase in cultured fibroblasts . Am J Hum Genet 24:37-45, 1972;.
33 +
Brady RO, Johnson WG, Unhlendorf BW:  Identification of heterozygous carriers of lipid storage diseases . Am J Med 51:423-431, 1971;.
34 +
Brady RO:  Prenatal diagnosis of lipid storage diseases . Clin Chem 16:811-815, 1970;.
35 +
Brady RO:  Enzyme defects in the lipidoses and their prenatal detection , in Curtius HC, Roth M (eds): Clinical Biochemistry: Principles and Methods . New York, Walter de Gruyter, 1974;, pp 1277-1291.
36 +
Brady RO:  Hereditary fat-metabolism diseases . Sci Am 229:88-97, 1973;.
37 +
Brady RO, Tallman JF, Johnson WG, et al:  Replacement therapy for inherited enzyme deficiency: Use of purified ceramidetrihexosidase in Fabry's disease . N Engl J Med 289:9-14, 1973;.
38 +
Brady RO, Pentchev PG, Gal AE:  Investigations in enzyme replacement therapy in lipid storage diseases . Fed Proc 34:1310-1315, 1975;.
39 +
Brady RO, Pentchev PG, Gal AE, et al:  Replacement therapy for inherited enzyme deficiency: Use of purified glucocerebrosidase in Gaucher's disease . N Engl J Med 291:989-993, 1974;.
40 +
Johnson WG, Desnick RJ, Long DM, et al:  Intravenous injection of purified hexosaminidase into a patient with Tay-Sachs disease , in Desnick RJ, Bernlohr RW, Krivit W (eds): Enzyme Therapy in Genetic Diseases . New York, The National Foundation, 1973;, pp 120-124.
41 +
Dorfman A, Matalon R:  The mucopolysaccharidoses , in Stanbury JB, Wyngaarden JB, Fredrickson DS (eds): The Metabolic Basis of Inherited Disease , ed 3. New York, McGraw-Hill Book Co Inc, 1972;, pp 1218-1272.
42 +
Neufeld EF, Lim TW, Shapiro LJ:  Inherited disorders of lysosomal metabolism . Ann Rev Biochem 44:357-376, 1975;.
43 +
Constantopoulos G, Dekaban AS:  Acid mucopolysaccharides in cerebrospinal fluid of patients with Hunter-Hurler's syndrome . J Neurochem 17:117-120, 1970;.
44 +
Neufeld EF, Cantz M:  The mucopolysaccharidoses studied in cell culture , in Hers HG, Van Hoof F (eds): Lysosomes and Storage Diseases . New York, Academic Press Inc, 1973;, pp 261-275.
45 +
Fratantoni JC, Neufeld EF, Uhlendorf BW, et al:  Intrauterine diagnosis of the Hurler and Hunter syndromes . N Engl J Med 280:686-688, 1969;.
46 +
DiFerrante N, Neufeld EF, Uhlendorf BW, et al:  Induced degradation of glycosaminoglycans in Hurler's and Hunter's syndromes by plasma infusion . Proc Natl Acad Sci USA 68:303-307, 1971;.
47 +
Knudson AG Jr, DiFerrante N, Curtis JE:  Effect of leukocyte transfusion in a child with type II mucopolysaccharidosis . Proc Natl Acad Sci USA 68:1738-1741, 1971;.
48 +
Dekaban AS, Holden KR, Constantopoulos G:  Effects of fresh plasma or whole blood transfusion in patients with various types of mucopolysaccharidosis . Pediatrics 50:688-692, 1972;.
49 +
Maclaren NK, Max SR, Cornblath M, et al:  GM3 gangliosidosis: A novel human sphingolipodystrophy . Pediatrics , to be published.
50 +
Tanaka J, Garcia JH, Max SR, et al:  Cerebral sponginess and GM3 gangliosidosis: Ultrastructure and probable pathogenesis . J Neuropathol Exp Neurol 34:249-262, 1975;.
51 +
Max SR, Maclaren MK, Brady RO, et al:  GM3 (hematoside) sphingolipodystrophy . N Engl J Med 291:929-931, 1974;.
52 +
Fishman PH, Max SR, Tallman JF, et al:  Deficient ganglioside biosynthesis: A novel human sphingolipidosis . Science 187:68-70, 1975;.

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1 +
Brady RO:  Inborn errors of lipid metabolism , in Meister A (ed): Advances in Enzymology . New York, John Wiley & Sons Inc, 1973;, vol 38, pp 293-315.
2 +
Aghion A: La Maladie de Gaucher dans l'enfance, thesis, University of Paris, 1934.
3 +
Klenk E:  Über die Natur der Phosphatide und anderer Lipoide des Gehirns und der Leber bei der Niemann-Pickschen Krankheit . Hoppe-Seylers Z Physiol Chem 235:24-36, 1935;.
4 +
Dawson G, Stein AO:  Lactosylceramidosis: Catabolic defect of glycosphingolipid metabolism . Science 170:556-558, 1970;.
5 +
Wenger DA, Sattler M, Clark C, et al:  Lactosylceramidosis: Normal activity for two lactosylceramide β galactosidases . Science 188:1310-1312, 1975;.
6 +
Trams EG, Brady RO:  Cerebroside synthesis in Gaucher's disease . J Clin Invest 39:1546-1550, 1960;.
7 +
Brady RO, Kanfer JN, Shapiro D:  The metabolism of glucocerebrosides: I. Purification and properties of a glucocerebroside-cleaving enzyme from spleen tissue . J Biol Chem 240:39-43, 1965;.
8 +
Brady RO, Kanfer JN, Shapiro D:  Metabolism of glucocerebrosides: II. Evidence of an enzymatic deficiency in Gaucher's disease . Biochem Biophys Res Commun 18:221-225, 1965;.
9 +
Brady RO, Kanfer JN, Bradley RM, et al:  Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease . J Clin Invest 45:1112-1115, 1966;.
10 +
Kattlove HE, Williams JC, Gaynor E, et al:  Gaucher cells in chronic myelocytic leukemia: An acquired abnormality . Blood 33:379-390, 1969;.
11 +
Brady RO, Kanfer JN, Mock MB, et al:  The metabolism of sphingomyelin: II. Evidence of an enzymatic deficiency in Niemann-Pick disease . Proc Natl Acad Sci USA 55:366-369, 1966;.
12 +
Brady RO:  The sphingolipidoses . N Engl J Med 275:312-318, 1966;.
13 +
Suzuki K, Suzuki Y:  Globoid cell leukodystrophy: Deficiency of galactocerebroside beta-galactosidase . Proc Natl Acad Sci USA 66:302-309, 1970;.
14 +
Mehl E, Jatzkewitz H:  Evidence for a genetic block in metachromatic leukodystrophy (ML) . Biochem Biophys Res Commun 19:407-411, 1965;.
15 +
Brady RO, Gal AE, Bradley RM, et al:  Enzymatic defect in Fabry's disease: Ceramidetrihexosidase deficiency . N Engl J Med 276:1163x-1167, 1967;.
16 +
Kolodny EH, Brady RO, Volk BW:  Demonstration of an alteration of ganglioside metabolism in Tay-Sachs disease . Biochem Biophys Res Commun 37:526-531, 1969;.
17 +
Tallman JF, Johnson WG, Brady RO:  The matabolism of Tay-Sachs ganglioside: Catabolic studies with lysosomal enzymes from normal and Tay-Sachs tissue . J Clin Invest 51:2339-2345, 1972;.
18 +
Sandhoff K, Andreae U, Jatzkewitz H:  Deficient hexosaminidase activity in an exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral organs . Life Sci 7:283-288, 1968;.
19 +
Okada S, O'Brien JS:  Generalized gangliosidosis: Beta-galactosidase deficiency . Science 160:1002-1004, 1968;.
20 +
Van Hoof F, Hers HG:  Mucopolysaccharidosis by absence of α-flucosidase . Lancet 1:1198, 1968;.
21 +
Dawson G, Spranger JW:  Fucosidosis: A glycosphingolipidosis . N Engl J Med 285:122, 1971;.
22 +
Sugita M, Dulaney JT, Moser HW:  Ceramidase deficiency in Farber's disease (lipogranulomatosis) . Science 178:1100, 1972;.
23 +
Kampine JP, Brady RO, Kafner JN, et al:  Diagnosis of Gaucher's disease and Niemann-Pick disease with small samples of venous blood . Science 155:86-88, 1967;.
24 +
Suzuki Y, Suzuki K:  Krabbe's globoid leukodystrophy: Deficiency of galactocerebrosidase in serum, leukocytes, and fibroblasts . Science 171:73-75, 1971;.
25 +
Percy AK, Brady RO:  Metachromatic leukodystrophy: Diagnosis with samples of venous blood . Science 161:594-595, 1968;.
26 +
Kint JA, Fabry's disease:  Alpha-galactosidase deficiency . Science 167:1268-1269, 1970;.
27 +
O'Brien JS, Okada S, Chen A, et al:  Tay-Sachs disease: Detection of heterozygotes and homozygotes by serum hexosaminidase assay . N Engl J Med 283:15-20, 1970;.
28 +
Wolfe LS, Callahan J, Fawcett JS, et al:  GM1-gangliosidosis without chondrodystrophy or visceromegaly: β-galactosidase deficiency with gangliosidosis and the excessive excretion of keratan sulfate . Neurology 20:23-44, 1970;.
29 +
Van Hoof F:  Fucosidosis , in Hers HG, Van Hoof F (eds): Lysosomes and Storage Diseases . New York, Academic Press Inc, 1973;, p 286.
30 +
Gal AE, Brady RO, Hibbert SR, et al:  A practical chromogenic procedure for the detection of homozygotes and heterozygous carriers of Niemann-Pick disease . N Engl J Med 293:632-636, 1975;.
31 +
Radin NS, Hof L, Bradley RM, et al:  Lactosylceramide galactosidase: Comparison with other sphingolipid hydrolases in developing rat brain . Brain Res 14:497-505, 1969;.
32 +
Ho MW, Seck J, Schmidt D, et al:  Adult Gaucher's disease: Kindred studies and demonstration of a deficiency of acid glucosidase in cultured fibroblasts . Am J Hum Genet 24:37-45, 1972;.
33 +
Brady RO, Johnson WG, Unhlendorf BW:  Identification of heterozygous carriers of lipid storage diseases . Am J Med 51:423-431, 1971;.
34 +
Brady RO:  Prenatal diagnosis of lipid storage diseases . Clin Chem 16:811-815, 1970;.
35 +
Brady RO:  Enzyme defects in the lipidoses and their prenatal detection , in Curtius HC, Roth M (eds): Clinical Biochemistry: Principles and Methods . New York, Walter de Gruyter, 1974;, pp 1277-1291.
36 +
Brady RO:  Hereditary fat-metabolism diseases . Sci Am 229:88-97, 1973;.
37 +
Brady RO, Tallman JF, Johnson WG, et al:  Replacement therapy for inherited enzyme deficiency: Use of purified ceramidetrihexosidase in Fabry's disease . N Engl J Med 289:9-14, 1973;.
38 +
Brady RO, Pentchev PG, Gal AE:  Investigations in enzyme replacement therapy in lipid storage diseases . Fed Proc 34:1310-1315, 1975;.
39 +
Brady RO, Pentchev PG, Gal AE, et al:  Replacement therapy for inherited enzyme deficiency: Use of purified glucocerebrosidase in Gaucher's disease . N Engl J Med 291:989-993, 1974;.
40 +
Johnson WG, Desnick RJ, Long DM, et al:  Intravenous injection of purified hexosaminidase into a patient with Tay-Sachs disease , in Desnick RJ, Bernlohr RW, Krivit W (eds): Enzyme Therapy in Genetic Diseases . New York, The National Foundation, 1973;, pp 120-124.
41 +
Dorfman A, Matalon R:  The mucopolysaccharidoses , in Stanbury JB, Wyngaarden JB, Fredrickson DS (eds): The Metabolic Basis of Inherited Disease , ed 3. New York, McGraw-Hill Book Co Inc, 1972;, pp 1218-1272.
42 +
Neufeld EF, Lim TW, Shapiro LJ:  Inherited disorders of lysosomal metabolism . Ann Rev Biochem 44:357-376, 1975;.
43 +
Constantopoulos G, Dekaban AS:  Acid mucopolysaccharides in cerebrospinal fluid of patients with Hunter-Hurler's syndrome . J Neurochem 17:117-120, 1970;.
44 +
Neufeld EF, Cantz M:  The mucopolysaccharidoses studied in cell culture , in Hers HG, Van Hoof F (eds): Lysosomes and Storage Diseases . New York, Academic Press Inc, 1973;, pp 261-275.
45 +
Fratantoni JC, Neufeld EF, Uhlendorf BW, et al:  Intrauterine diagnosis of the Hurler and Hunter syndromes . N Engl J Med 280:686-688, 1969;.
46 +
DiFerrante N, Neufeld EF, Uhlendorf BW, et al:  Induced degradation of glycosaminoglycans in Hurler's and Hunter's syndromes by plasma infusion . Proc Natl Acad Sci USA 68:303-307, 1971;.
47 +
Knudson AG Jr, DiFerrante N, Curtis JE:  Effect of leukocyte transfusion in a child with type II mucopolysaccharidosis . Proc Natl Acad Sci USA 68:1738-1741, 1971;.
48 +
Dekaban AS, Holden KR, Constantopoulos G:  Effects of fresh plasma or whole blood transfusion in patients with various types of mucopolysaccharidosis . Pediatrics 50:688-692, 1972;.
49 +
Maclaren NK, Max SR, Cornblath M, et al:  GM3 gangliosidosis: A novel human sphingolipodystrophy . Pediatrics , to be published.
50 +
Tanaka J, Garcia JH, Max SR, et al:  Cerebral sponginess and GM3 gangliosidosis: Ultrastructure and probable pathogenesis . J Neuropathol Exp Neurol 34:249-262, 1975;.
51 +
Max SR, Maclaren MK, Brady RO, et al:  GM3 (hematoside) sphingolipodystrophy . N Engl J Med 291:929-931, 1974;.
52 +
Fishman PH, Max SR, Tallman JF, et al:  Deficient ganglioside biosynthesis: A novel human sphingolipidosis . Science 187:68-70, 1975;.

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