lysosomes are membrane-bound organelles containing an array of hydrolytic enzymes involved in the degradation of a variety of biologic macromolecules. Pathogenic variants in these hydrolases are unique because they lead to the accumulation of their substrates inside the lysosome, where the substrates remain trapped because their large size prevents their egress from the organelle. Their accumulation and sometimes toxicity interferes with normal cell function, eventually causing cell death. Moreover, the substrate accumulation underlies one uniform clinical feature of these diseases – their unrelenting progression. In most of these conditions, substrate storage increases the mass of the affected tissues and organs. When the brain is affected, the picture is one of neurodegeneration. The clinical phenotypes are very distinct and often make the diagnosis of a storage disease straightforward. More than 50 lysosomal hydrolase or lysosomal membrane transport deficiencies, almost all inherited as autosomal recessive conditions, have been described. Historically these diseases were untreatable. However, bone marrow transplantation and enzyme replacement therapy have dramatically improved the prognosis of these conditions.

Tay-Sachs Disease

 Tay-Sachs disease is one of a group of heterogeneous lysosomal storage diseases, the GM2 gangliosidoses, that result from the inability to degrade a sphingolipid, GM2 ganglioside (Fig. 1). The bio chemical lesion is a marked deficiency of hexosaminidase A (hex A). Although the enzyme is ubiquitous, the disease has its clinical impact almost solely on the brain, the predominant site of GM2 ganglioside synthesis. Catalytically active hex A is the product of a three-gene system (see Fig. 1). These genes encode the α and β subunits of the enzyme (the HEXA and HEXB genes, respectively) and an activator protein that must associate with the substrate and the enzyme before the enzyme can cleave the terminal N-acetyl-β-galactosamine residue from the ganglioside.

Fig1. The three-gene system required for hexosaminidase A activity and the diseases that result from defects in each of the genes. The function of the activator protein is to bind the ganglioside substrate and present it to the enzyme. Hex A, Hexosaminidase A; Hex B, hexosaminidase B; NANA, N-acetyl neuraminic acid. (Modified from Sandhoff K, Conzelmann E, Neufeld EF, et al: The GM2 gangliosidoses. In Scriver CR, Beaudet Al, Sly WS, et al, editors: The metabolic bases of inherited disease, ed 6, New York, 1989, McGraw-Hill, pp 1807–1839.)

The clinical manifestations of defects in the three genes are indistinguishable, but they can be differentiated by enzymatic analysis. Pathogenic variants in the HEXA gene affect the α subunit and disrupt hex A activity to cause Tay-Sachs disease (or less severe variants of hex A deficiency). Defects in the HEXB gene or in the gene encoding the activator protein impair the activity of both hex A and hex B (see Fig. 1) to produce Sandhoff disease or activator protein deficiency (which is very rare), respectively.

The clinical course of Tay-Sachs disease is tragic. Affected infants appear normal until ~3 to 6 months of age but then gradually undergo progressive neurologic deterioration until death at 2 to 4 years. The effects of neuronal death can be seen directly in the form of the cherry-red spot in the retina (Case 43). In contrast, HEXA alleles associated with some residual activity lead to later-onset forms of neurologic disease, with manifestations including lower motor neuron dysfunction and ataxia due to spinocerebellar degeneration. In contrast to the infantile disease, vision and intelligence usually remain normal, although psychosis develops in one-third of these patients. Finally, pseudodeficiency alleles (discussed next) cause no disease.

Hex A Pseudodeficiency Alleles and Their Clinical Significance. An unexpected consequence of screening for Tay-Sachs carriers in the Ashkenazi Jewish population was the discovery of a unique class of hex A alleles, the pseudodeficiency alleles. Although the two pseudodeficiency alleles are clinically benign, individuals identified as pseudodeficient in screening tests are genetic compounds with a pseudodeficiency allele on one chromosome and a common Tay-Sachs vari ant on the other chromosome. These individuals have a low level of hex A activity (~20% of controls) that is adequate to prevent GM2 ganglioside accumulation in the brain. The importance of hex A pseudodeficiency alleles is twofold. First, they complicate prenatal diagnosis because a pseudodeficient fetus could be incorrectly diagnosed as affected. More generally, the recognition of the hex A pseudodeficiency alleles indicates that screening programs for other genetic dis eases must recognize that comparable alleles may exist at other loci and may confound the correct characterization of individuals in screening or diagnostic tests.

Population Genetics. In many monogenic diseases, some alleles are found at higher frequency in some populations than in others. This situation is illustrated by Tay-Sachs disease, in which three alleles account for 99% of the variants found in Ashkenazi Jewish patients, the most common of which accounts for 80% of cases (Fig. 2). Approximately 1 in 27 Ashkenazi Jews is a carrier of a Tay-Sachs allele, and the incidence of affected infants was 100 times higher than in other populations, prior to screening. A founder effect or heterozygote advantage is the most likely explanation for this high frequency. Because most Ashkenazi Jewish carriers will have one of the three common alleles, a practical benefit of the molecular characterization of the disease in this population is the degree to which carrier screening has been simplified.

Fig2. Four-base insertion (TATC) in the hexosaminidase A (hex A) gene in Tay-Sachs disease, leading to a frameshift. This variant is the major cause of Tay-Sachs disease in Ashkenazi Jews. No detectable hex A protein is made, accounting for the complete enzyme deficiency observed in these infantile-onset patients.

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مواضيع ذات صلة

Aminoacidopathies

Diseases due to pathogenic variants in different classes of proteins

Renal cysts and diabetes (HNF1B MODY)

Maternally inherited diabetes and deafness

Genetic testing in neonatal diabetes

Human Hemoglobin and Associated Diseases

The Relationship Between Genotype and Phenotype in Genetic Disease

Effect of Pathogenic Variants on Protein Function

HNF1A and HNF4A (Transcription factor MODY)

Categories of Epigenetic disorders

Epigenetics in Development

Mosaicism