Molecular basis of different forms of metachromatic leukodystrophy
Article Abstract:
Metachromatic leukodystrophy is an inherited disorder that results in progressive demyelination and the loss of white matter in the nervous system. (Demyelination involves the loss of the myelin sheath of nerve tissue.) This condition may lead to weakness, ataxia (poor muscle coordination), and dementia (loss of intellectual functioning). There are three major forms of metachromatic leukodystrophy: a late-infantile form that is fatal within a few years of life, a juvenile form that attacks between the ages of 3 and 16 years, and an adult form. Genetic analysis of patients with metachromatic leukodystrophy has shown that all three forms of the disease can result from different combinations of two genetic alleles. The genetic defect involved in metachromatic leukodystrophy results in deficiencies in arylsulfatase A, a lysosomal enzyme that breaks down cerebroside sulfate, an important glycolipid in the structure of myelin. Researchers have identified several genetic defects that affect arylsulfatase A. One allele, termed I, fails to produce functional arylsulfatase A. Another allele, termed A, produces an enzyme molecule that is functional, but unstable and falls apart rapidly. An individual with two I alleles has virtually no arylsulfatase A, and develops the late-infantile form of the disorder. Individuals with one I allele and one A allele are less severely affected and develop the juvenile form of the disease. Patients with two copies of the A allele develop the more protracted adult form. In the course of their research, the researchers also identified what they term a pseudodeficiency allele. This allele is defective in the signal for the translation of the enzyme molecule from mRNA. This results in a perfectly normal enzyme that is present in reduced amounts. An individual with one copy of the I allele and one copy of the pseudodeficiency allele has about 10 percent of the normal level of arylsulfatase activity. Two adult patients with such a genotype have not yet developed any signs of metachromatic leukodystrophy, suggesting that 10 percent activity, although low, is still adequate to prevent the accumulation of cerebroside sulfate and the development of disease symptoms. (Consumer Summary produced by Reliance Medical Information, Inc.)
Publication Name: The New England Journal of Medicine
Subject: Health
ISSN: 0028-4793
Year: 1991
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Molecular basis of phenotypic heterogeneity in phenylketonuria
Article Abstract:
Phenylketonuria (PKU) is a genetic disorder that results from an inherited deficiency of the liver enzyme phenylalanine hydroxylase. Without this enzyme, phenylalanine accumulates in the blood; metabolic products of the excess phenylalanine damage the developing brain in the child born with PKU. The resulting mental retardation may be reduced somewhat by restricting the dietary intake of phenylalanine so that an excess can not accumulate. It is clear, however, that not all patients with PKU are equally affected. With the advent of the techniques of molecular biology, it has become possible to investigate the variation among PKU patients and to attempt to determine how the phenotype of the disease (that is, the characteristics that can be directly observed) correlates with the different genes responsible for the disorder. Researchers investigated 258 patients with phenylketonuria. A total of 64 percent of the mutant enzyme genes could be accounted for by 8 known mutations. Using the techniques of molecular biology, the investigators inserted the mutant genes into tissue culture cells which then used the gene to manufacture copies of the enzyme. The biochemical activity of the enzyme could then be easily measured. The researchers found that the level of severity of the phenylketonuria correlated closely with the levels of enzyme activity. This correlation is important since it rules out several genetic possibilities, including the theory that the severity of PKU might depend on some other enzyme in addition to phenylalanine hydroxylase. Another possibility is that two different PKU mutations, when inherited by one individual, might ''complement'' one another in an unpredictable fashion. However, the strong correlation between the measured levels of phenylalanine hydroxylase activity and clinical features of the disease strongly suggests that such mechanisms are not at work and that, for the most part, the features of the disease result directly from a deficiency of one single enzyme. (Consumer Summary produced by Reliance Medical Information, Inc.)
Publication Name: The New England Journal of Medicine
Subject: Health
ISSN: 0028-4793
Year: 1991
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Brief report: the molecular basis of steroid 5alpha-reductase deficiency in a large Dominican kindred
Article Abstract:
A mutation in the gene for 5alpha-reductase may cause a form of pseudohermaphroditism that is often characterized by the presence of female genitalia in boys. 5alpha-reductase is an enzyme that is involved in the metabolism of male sex hormones. A study examined the occurrence of 5alpha-reductase deficiency in a family from the Dominican Republic. 5alpha-reductase deficiency was found throughout seven generations of the family. Forty-seven male family members from 29 families were identified as having the deficiency, and they could all be traced to a female ancestor who carried the gene for 5alpha-reductase deficiency. Genetic analysis found that 5alpha-reductase deficiency was caused by the same type of mutation in all of the affected family members. This mutation produced a form of 5alpha-reductase that did not function properly under normal conditions in the body.
Publication Name: The New England Journal of Medicine
Subject: Health
ISSN: 0028-4793
Year: 1992
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