Tay-Sachs disease

(1)

Tay-Sachs Disease

Tay-Sachs disease is a hereditary neurodegenerative disor- der resulting from excess storage of G

_M2

ganglioside within the lysosomes of cells. The incidence of the disease is estimated to be 1 in 3600 in Ashkenazi Jews with carrier frequency of 1 in 30 and 1 in 360,000 in other population with carrier frequency of 1 in 300. Tay-Sachs disease is the most frequently occurring sphingolipidoses.

GENETICS/BASIC DEFECTS

1. Inheritance: autosomal recessive

2. Biochemical defect: deficiency of the isoenzyme β- hexosaminidase A (Hex A)

3. Genetic basis

a. Mutations in the HEXA gene (on chromosome 15q23-q24) that codes for the subunit of the β-hex- osaminidases results in the deficiency of Hex A ( αβ) that results in Tay-Sachs disease

b. Over 100 different mutations have been identified in the HEXA gene to date

c. Presence of a small number of common mutations in populations where the carrier frequency is high

i. Ashkenazi Jews

a) Two common mutations associated with Tay- Sachs disease [a four base-pair insertion into exon 11 of the HEXA gene (1278insTATC) accounting for 75–80% of all mutations in this population; a splice site mutation in intron 12 (1421 +1G→C) accounting for 15%

of mutations]

b) One mutation associated with a late onset form of the disease (G269S in 3% of carriers) c) Pseudodeficiency polymorphism (R247W in

2% of carriers) ii. Pennsylvania Dutch

a) An intron 9 splice site mutation (1073 +1G

→A)

b) Pseudodeficiency allele (R247W) iii. Cajuns in Southern Louisiana

a) An intron 9 splice site mutations (1073 +1G

→A)

b) 4 base-pair insertion in exon 11 (1278ins TATC)

iv. French Canadians in Eastern Quebec

a) A large (7.6 kb) deletion at the 5 ′ end of the gene

b) A splice site mutation in intron 7 (805 +1G →A) c) Common 4 base-pair insertion in exon 11

seen in Ashkenazi Jews (1278insTATC)

CLINICAL FEATURES

1. Natural history

a. Appear normal at birth

b. Normal motor development in the first few months of life

c. Progressive weakness and loss of motor skills begin- ning around 2–6 months of life

d. Followed by decreased social interaction, increased sensitivity to noise (hyperacusis), and an increased startle response to noise

e. Progressive neurodegeneration

f. Uniformly fatal: death from pneumonia usually occurring between 2–5 years of age

2. Clinical features

a. Delayed development b. Poor feeding

c. Lethargy d. Hypotonia e. Hyperreflexia

f. Opisthotonos g. Hyperacusis

h. A cherry red spot on the fovea centralis of the macula, representing loss of ganglion cells in the foveal area with the remaining ones filled with the ganglioside i. Progressive neurodegeneration

i. Developmental regression

ii. Macrocephaly secondary to accumulation of stor- age material within the brain after about 15 months of age. There is no evidence of hepatosplenomegaly or other peripheral evidence of storage disease iii. Myoclonic seizures, most during the first year of life

iv. Progressive macular degeneration leading to blindness, usually by 1 year of age

v. Deafness vi. Spasticity

vii. Complete disability

DIAGNOSTIC INVESTIGATIONS

1. Diagnosis and carrier testing a. Indications for carrier testing

i. Fully or partially Jewish ii. Pennsylvania Dutch

iii. Cajuns of Southern Louisiana iv. French Canadians of Eastern Quebec b. Preconceptional counseling for at-risk couples c. Enzyme assay

i. Using fluorimetric study measuring activity of both Hex A and Hex B in either serum or leukocytes ii. Decreased activity of Hex A with normal or

increased activity of Hex B in carriers iii. Limitations of serum assay

a) Overlapping of the values between carriers and noncarriers

b) Unreliable in pregnant women and in women taking oral contraceptives

943

(2)

944 TAY-SACHS DISEASE

c) Inability to distinguish carriers of pseudode- ficiency alleles from carriers of disease- causing mutations

iv. Clarification of abnormal or inconclusive results of enzyme assay by:

a) Enzyme assay on leukocytes

b) DNA mutation analysis for common muta- tions and pseudodeficiency alleles

2. CT scan of the brain: areas of low density in the basal ganglia and cerebral white matter

3. MRI of the brain: an increased signal in the basal ganglia and cerebral white matter on T

₂

-weighted images 4. Characteristic neuropathological findings

a. Pathologic changes are restricted to the nervous system b. Ballooning of neurons with massive intralysosomal

accumulation of lipophilic membranous bodies c. Nature and structure of the stored intraneuronal mate-

rial: GM

₂

ganglioside

d. Abnormal cytoplasmic inclusion bodies identified in fetal spinal cord at 12 weeks and retina and spinal ganglia during 19th–22nd week of gestation

e. Cisternae of the endoplasmic reticulum: the primary site of lipid accumulation in neurons during the fetal stage of Tay-Sachs disease

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib: 25%

b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis

a. Enzyme analysis (absence of hexosaminidase A) on cultured amniocytes or chorionic villus cells

b. DNA analysis when one of the common mutations had been identified in the family

i. Preferred method of prenatal diagnosis ii. Less prone to error

3. Management

a. No effective treatment to alter the natural history b. Primarily supportive

i. Provide adequate nutrition and hydration ii. Manage infections

iii. Protect airway iv. Control seizures

v. Bowel management

c. Enzyme replacement therapy and bone marrow trans- plantation: not yet successful

d. Options to modify 25% risk of having an affected child with each pregnancy if both partners are found to be carriers

i. Prenatal diagnosis by amniocentesis or chorionic villus sampling

ii. Egg or sperm donation

iii. Preimplantation genetic diagnosis iv. Adoption

REFERENCES

Adachi M, Schneck L, Volk BW: Ultrastructural studies of eight cases of fetal Tay-Sachs disease. Lab Invest 30:102–112, 1974.

Adachi M, Torii J, Schneck L, et al.: The fine structure of fetal Tay-Sachs dis- ease. Arch Pathol 91:48–54, 1971.

Akerman BR, Natowicz MR, Kaback MM, et al.: Novel mutations and DNA- based screening in non-Jewish carriers of Tay-Sachs disease. Am J Hum Genet 60:1099–1106, 1997.

Akli S, Boue J, Sandhoff K, et al.: Collaborative study of the molecular epidemi- ology of Tay-Sachs disease in Europe. Eur J Hum Genet 1:229–238, 1993.

Ambani LM, Bhatia RS, Shah SB, et al.: Prenatal diagnosis of Tay-Sachs dis- ease. Indian Pediatr 26:1052–1053, 1989.

Argov Z, Navon R: Clinical and genetic variations in the syndrome of adult GM2 gangliosidosis resulting from hexosaminidase A deficiency. Ann Neurol 16:14–20, 1984.

Brett EM, Ellis RB, Haas L, et al.: Late onset GM2-gangliosidosis. Clinical, pathological, and biochemical studies on 8 patients. Arch Dis Child 48:775–785, 1973.

Brady RO: Tay-Sachs disease: the search for the enzymatic defect. Adv Genet 44:51–60, 2001.

Callahan JW, Archibald A, Skomorowski MA, et al.: First trimester prenatal diagnosis of Tay-Sachs disease using the sulfated synthetic substrate for hexosaminidase A. Clin Biochem 23:533–536, 1990.

Chamoles NA, Blanco M, Gaggioli D, et al.: Tay-Sachs and Sandhoff dis- eases: enzymatic diagnosis in dried blood spots on filter paper: retro- spective diagnoses in newborn-screening cards. Clin Chim Acta 318:133–137, 2002.

Childs B, Gordis L, Kaback MM, et al.: Tay-Sachs screening: social and psy- chological impact. Am J Hum Genet 28:550–558, 1976.

Cotlier E: Tay-Sachs’ disease and Fabry’s disease: clinical and chemical diagnosis of two metabolic eye diseases. Bull N Y Acad Med 50:777–787, 1974.

Cutz E, Lowden JA, Conen PE: Ultrastructural demonstration of neuronal stor- age in fetal Tay-Sachs disease. J Neurol Sci 21:197–202, 1974.

Desnick RJ, Goldberg JD: Tay-Sachs disease: prospects for therapeutic inter- vention. Prog Clin Biol Res 18:129–141, 1977.

Desnick RJ, Kaback MM: Future perspectives for Tay-Sachs disease. Adv Genet 44:349–356, 2001.

Eeg-Olofsson L, Kristensson K, Sourander P, et al.: Tay-Sachs disease. A gen- eralized metabolic disorder. Acta Paediatr Scand 55:546–562, 1966.

Grabowski GA, Kruse JR, Goldberg JD, et al.: First-trimester prenatal diagnosis of Tay-Sachs disease. Am J Hum Genet 36:1369–1378, 1984.

Gravel RA, Triggs-Raine BL, Mahuran DJ: Biochemistry and genetics of Tay- Sachs disease. Can J Neurol Sci 18:419–423, 1991.

Grebner EE, Jackson LG: Prenatal diagnosis for Tay-Sachs disease using chori- onic villus sampling. Prenat Diagn 5:313–320, 1985.

Hansis C, Grifo J: Tay-Sachs disease and preimplantation genetic diagnosis.

Adv Genet 44:311–315, 2001.

Kaback M, Lim-Steele J, Dabholkar D, et al.: Tay-Sachs disease—carrier screening, prenatal diagnosis, and the molecular era. An international per- spective, 1970 to 1993. The International TSD Data Collection Network.

JAMA 270:2307–2315, 1993.

Kaback MM: Tay-Sachs disease: from clinical description to prospective con- trol. Prog Clin Biol Res 18:1–7, 1977.

Kaback MM: Screening for reproductive counseling: social, ethical, and medicolegal issues in the Tay-Sachs disease experience. Prog Clin Biol Res 103 Pt B:447–459, 1982.

Kaback MM: Population-based genetic screening for reproductive counseling:

the Tay-Sachs disease model. Eur J Pediatr 159 Suppl 3:S192–S195, 2000.

Kaback MM: Screening and prevention in Tay-Sachs disease: origins, update, and impact. Adv Genet 44:253–265, 2001.

Kaback MM, Desnick RJ: Tay-Sachs disease: from clinical description to molecular defect. Adv Genet 44:1–9, 2001.

Kaback MM, Nathan TJ, Greenwald S: Tay-Sachs disease: heterozygote screening and prenatal diagnosis—U.S. experience and world perspec- tive. Prog Clin Biol Res 18:13–36, 1977.

Kaback MM, Zeiger RS, Reynolds LW, et al.: Approaches to the control and prevention of Tay-Sachs disease. Prog Med Genet 10:103–134, 1974.

Kivlin JD, Sanborn GE, Myers GG: The cherry-red spot in Tay-Sachs and other storage diseases. Ann Neurol 17:356–360, 1985.

MacQueen GM, Rosebush PI, Mazurek MF: Neuropsychiatric aspects of the adult variant of Tay-Sachs disease. J Neuropsychiatry Clin Neurosci 10:10–19, 1998.

Mahuran DJ, Triggs-Raine BL, Feigenbaum AJ, et al.: The molecular basis of Tay-Sachs disease: mutation identification and diagnosis. Clin Biochem 23:409–415, 1990.

O’Brien JS, Okada S, Fillerup DL, et al.: Tay-Sachs disease: prenatal diagnosis.

Science 172:61–64, 1971.

(3)

TAY-SACHS DISEASE 945

Rattazzi MC, Dobrenis K: Treatment of GM2 gangliosidosis: past experiences, implications, and future prospects. Adv Genet 44:317–339, 2001.

Risch N: Molecular epidemiology of Tay-Sachs disease. Adv Genet 44:233–252, 2001.

Rodriguez-Torres R, Schneck L, Kleinberg W: Electrocardiographic and biochemi- cal abnormalities in Tay-Sachs disease. Bull N Y Acad Med 47:717–730, 1971.

Schneck L, Adachi M, Volk BW: The fetal aspects of Tay-Sachs disease.

Pediatrics 49:342–351, 1972.

Schweitzer-Miller L: Tay-Sachs disease: psychologic care of carriers and affected families. Adv Genet 44:341–347, 2001.

Streifler J, Golomb M, Gadoth N: Psychiatric features of adult GM2 gangliosi- dosis. Br J Psychiatry 155:410–413, 1989.

Streifler JY, Gornish M, Hadar H, et al.: Brain imaging in late-onset GM2 gan- gliosidosis. Neurology 43:2055–2058, 1993.

Sutton VR: Tay-Sachs disease screening and counseling families at risk for metabolic disease. Obstet Gynecol Clin North Am 29:287–296, 2002.

Suzuki K: Saul R. Korey Lecture. Molecular genetics of Tay-Sachs and related disorders: a personal account. J Neuropathol Exp Neurol 53:344–350, 1994.

Thurmon TF: Tay-Sachs genes in Acadians. Am J Hum Genet 53:781–

783, 1993.

Volk BW: Understanding Tay-Sachs disease. Recent advances. Clin Pediatr (Phila) 5:653–654, 1966.

Wilkins RH, Brody IA: Tay-Sachs’ disease. Arch Neurol 20:103–111, 1969.

(4)

946 TAY-SACHS DISEASE

Fig. 1. A cherry red spot on the fovea centralis of the macula from the fundus of an infant with Tay-Sachs disease.

Fig. 2. Myenteric plexus of the rectum (H & E, ×400) showing many enlarged ganglion cells with abundant foamy cytoplasm due to gan- glioside storage. Rectal biopsy can be a good source of neurons in confirming neuronal storage disease. In this patient, Tay-Sachs disease was confirmed by electron microscopic examination of ganglion cells.