ABSTRACT
We report on a three-year-old Kuwaiti boy with the aim of making pediatricians and geneticists aware of the clinical and biochemical findings of infantile Tay-Sachs disease [TSD] in Arab populations. It is essential that there is no delay in establishing the diagnosis in order to ensure appropriate genetic counseling. The boy was first evaluated when he was 17 months old with profound hypotonia and significant global developmental delay and he died at the ago of three years. The clinical and biochemical findings of this patient are compared with other reported Arab cases to illustrate that TSD exists amongst Arabs with an unknown incidence and probably is more common than thought previously. There isa need for additional research to delineate molecular phenotypes of this disorder in Arabs and to offer carrier detection especially in high-risk families
Subject(s)
Humans , Male , Arabs , Genetic Diseases, Inborn/ethnology , Chromosome Aberrations/ethnology , Hexosaminidase A , Gangliosidoses, GM2 , Genes, Recessive , PhenotypeABSTRACT
Sphingolipidoses are a subgroup of lysosomal storage disorders. They are characterized by relentless progressive storage in affected organs and concomitant functional impairments. No overall screening procedure for these disorders is available. Their course and appearance, however, are usually characteristic and, together with relevant technical procedures such as magnetic resonance imaging (MRI), clinical neurophysiology, ophthalmologic examination, etc., a provisional diagnosis can be made, after which enzymatic diagnosis can close the gap in the diagnostic process. Subgroups of sphingolipidoses are grouped together, such as disorders with prominent hepatosplenomegaly (Niemann-Pick A, B and Gaucher disease) and disorders with central and peripheral demyelination (metachromic leukodystrophy and Krabbe disease). Farber disease and Fabry disease are unique in themselves. The last decade has seen hopeful progress in therapeutic strategies, especially for Gaucher disease. Therefore, emphasis of this review has been placed on these new developments.
Subject(s)
Demyelinating Diseases , Diagnosis , Fabry Disease , Farber Lipogranulomatosis , Gangliosidoses, GM2 , Gangliosidosis, GM1 , Gaucher Disease , Hope , Leukodystrophy, Globoid Cell , Magnetic Resonance Imaging , Mass Screening , Neurophysiology , Niemann-Pick Diseases , SphingolipidosesABSTRACT
The deficiency of the A isoenzyme of á-hexosaminidase (Hex) produced by different mutations of the gene that codes for the alpha subunit (Tay-Sachs disease) has two variants with enzymological differences: the B variant consists of the absence of Hex A isoenzyme and the B1 variant produces an inactive Hex A isoenzyme for the hydrolysis of the GM2 ganglioside and synthetic substrates with negative charge. In contrast to the early childhood form of the B variant, the B1 variant appears at a later clinical stage (3 to 7 years of age) with neurodegenerative symptoms leading to the death of the patient in the second decade of life. The most frequent mutation responsible for the GM2 gangliosidosis B1 variant is R178H, which has a widespread geographic and ethnic distribution. The highest incidence has been described in Portugal, which has been suggested as the point of origin of this mutation. Biochemical characterization of this lysosomal disease is carried out using negatively charged synthetic alpha subunit-specific sulfated substrates, since Hex A isoenzyme heat-inactivation assays are not applicable. However, the determination of the apparent activation energy of Hex using the neutral substrate 3,3'-dichlorophenolsulfonphthaleinyl N-acetyl-á-D-glucosaminide, may offer a valid alternative. The presence of an alpha subunit in the alphaá heterodimer Hex A means that its activation energy (41.8 kJ/mol) is significantly lower than that of the áá homodimer Hex B (75.1 kJ/mol); however, as mutation inactivates the alpha subunit, the Hex A of the B1 variant presents an activation energy that is similar to that of the Hex B isoenzyme.
Subject(s)
Humans , Child, Preschool , Child , beta-N-Acetylhexosaminidases , Gangliosidoses, GM2 , Genetic Variation , Isoenzymes , Geography , Phenotype , Point MutationABSTRACT
We investigated the effect of age and sex on the serum activity of hexosaminidase (HEX) and á-glucuronidase (BGLU) in 275 normal term infants aged 12 h to 12 months. Up to six weeks of life, HEX was significantly higher in boys (P<=0.023). During the age period of 1-26 weeks, BGLU was also higher in boys, but differences were significant only at 2-6 and 7-15 weeks (P<=0.016). The developmental pattern of HEX and BGLU was sex dependent. HEX activity increased in both sexes from 4-7 days of life, reaching a maximum of 1.4-fold the birth value at 2-6 weeks of age in boys (P<0.001) and a maximum of 1.6-fold at 7-15 weeks in girls (P<0.001). HEX activity gradually decreased thereafter, reaching significantly lower levels at 27-53 weeks than during the first three days of life in boys (P = 0.002) and the same level of this age interval in girls. BGLU increased in both sexes from 4-7 days of age, showing a maximum increase at 7-15 weeks (3.3-fold in boys and 2.9-fold in girls, both P<0.001). Then BGLU decreased in boys to a value similar to that observed at 4-7 days of age. In girls, BGLU remained elevated until the end of the first year of life. These results indicate a variation of HEX and BGLU activities during the first year of life and a sex influence on their developmental pattern. This observation should be considered in the diagnosis of GM2 gangliosidosis and mucopolysaccharidosis type VII
Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , beta-Glucosidase , beta-N-Acetylhexosaminidases , Age Factors , Analysis of Variance , beta-Glucosidase , beta-N-Acetylhexosaminidases , Biomarkers , Gangliosidoses, GM2 , Mucopolysaccharidosis VII , Sex FactorsABSTRACT
<p><b>OBJECTIVE</b>To study the molecular mechanism of GM(2) gangliosidosis.</p><p><b>METHODS</b>The skin fibroblasts from 4 patients with GM(2) gangliosidosis were subjected to culture. Enzyme activities assay, Western blot and immunocytochemical analysis were performed using the cultured fibroblasts.</p><p><b>RESULTS</b>The hexosaminidase (Hex) activities of 4 patients with GM(2) gangliosidosis were significantly decreased. The activities were 12% 3% 15% and 6% of control values, respectively. Western blot analysis indicated that the amount of Hex mature alpha- and beta- subunits (alpha m, beta m) was decreased in cells from patients 2 and 3, but only decreased alpha m was found in patient 1 and both alpha m and beta m were normal in cells from patient 4. Immunocytochemical analysis revealed the accumulated GM(2) ganglioside in cells from patients 1-4.</p><p><b>CONCLUSION</b>The pathogenesis of GM(2) gangliosidosis was associated with deficiency of Hex alpha m and beta m and GM(2) activator caused by HEXA, HEXB and GM(2)A gene mutations.</p>
Subject(s)
Adult , Child, Preschool , Female , Humans , Infant , Male , Blotting, Western , Cells, Cultured , Gangliosidoses, GM2 , Pathology , Hexosaminidase A , Hexosaminidase B , Protein Subunits , Metabolism , beta-N-Acetylhexosaminidases , MetabolismABSTRACT
GM2 gangliosidosis II(Sandhoff disease) is a lysosomal storage disease due to deficiency of beta-hexosaminidase activity, transmitted by mode of autosomal recessive. Clinical features are so variable, ranging from infantile onset resulting death before 4 years, to subacute or chronic forms with more slowly progressive neurologic condition. We experienced a case of GM2 gangliosidosis II in a 14 months old male who had developmental deterioration and seizures, so we report and review the related literatures.