Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3

Article Abstract:

Spinal muscular atrophy (SMA) is actually a group of inherited degenerative diseases affecting the alpha motor neurons in the spinal cord. These diseases are the leading cause of genetically caused infant mortality and are second only to cystic fibrosis as the most common autosomal recessive Mendelian disorder. It is often the case with genetic disorders that a variety of independently arising mutations all cause a similar clinical picture. Since SMA is a clinically heterogeneous group of disorders, it might be expected to be genetically heterogeneous as well, making it difficult to analyze. However, a genetic linkage analysis of 13 families with SMA has demonstrated that at least some forms of SMA can be found to have their genetic origin on chromosome 5. Spinal muscular atrophy cases are characterized by symmetric weakness, deterioration of limb muscles, and degeneration of anterior horn cells. Conduction times of nerve signals appear to be normal. Type I SMA, also known as Werdnig-Hoffmann, infantile, or severe SMA, is an acute, clinically homogeneous form in which the patients deteriorate rapidly, often dying in the first year of life and usually by age four. Types II and III, sometimes called intermediate and mild, are much more heterogeneous. It is worth noting that the childhood-onset SMAs are invariably transmitted in a recessive form, but the adult-onset form may be a dominant gene. In an investigation of six families with type I SMA and seven with type II or III, the gene was mapped to chromosome 5; the precise position was found to be 5q11.2-13.3. Although the confidence interval for the chromosomal mapping of type I (acute) SMA was too broad to assign it precisely, the evidence suggests that it, too, is on chromosome 5, and may be about 15 centiMorgans towards the distal end away from the locus of the chronic SMA. (A centiMorgan is a unit of crossover frequency used as an operational definition for distance along a chromosome.) The enzyme hexosaminidase B is located in the same region of chromosome 5, and deficiencies in this enzyme have been observed in cases of chronic SMA. It will be interesting to determine if cases of adult-onset, and Mendelian dominant, SMA also map to this region of chromosome 5. (Consumer Summary produced by Reliance Medical Information, Inc.)

Central nervous system diseases

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Genetic homogeneity between acute and chronic forms of spinal muscular atrophy

Article Abstract:

Many muscle cells are controlled by neurons in the anterior horn of the spinal cord. In some individuals, these motor neurons begin to degenerate due to an inherited disorder, and if the motor neurons die, muscle atrophy occurs. Spinal muscular atrophy (SMA) is a genetic disorder that is actually a set of disorders with significant differences in clinical effects and mode of inheritance. Acute SMA, also called Type I SMA, Werdnig-Hoffmann SMA, severe SMA, and infantile SMA, is the most common heritable killer of infants, and is second only to cystic fibrosis as a common genetic disorder. Affected infants generally die between eight months and four years of age. Acute SMA is inherited as an autosomal recessive gene; other forms of SMA that are termed chronic are generally milder, with a greater age of onset, and express either a recessive or dominant mode of inheritance. Previous research has shown that the gene for chronic SMA is located on chromosome 5; specifically, at the 5q11.2-13.3 position. While previous studies could not define the gene location (locus) for the acute form to the same degree of precision, the analysis of four additional inbred families has permitted the assignment of the gene to the same locus (5q11.2-13.3) on chromosome 5. This means that the mutations which result in the acute and chronic forms of the disease occur within the same gene. However, two families were identified, one carrying acute SMA and one carrying chronic SMA, in which the SMA gene did not map to 5q at all. It is not known whether this represents a significant variant of spinal muscular atrophy or a distinct neurological disease which may have been misdiagnosed. (Consumer Summary produced by Reliance Medical Information, Inc.)

Research, Chromosome mapping, Muscle diseases, Muscular diseases

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Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

Article Abstract:

The X chromosome is one of the two sex chromosomes and is present in both men, who have an XY complement, and women, who have an XX complement. X-linked spinal and bulbar muscular atrophy, also known as Kennedy's disease, is an inherited disease in which there is degeneration of motor neurons (nerve cells sending impulses to the muscles or glands). The disease results in muscle weakness and atrophy (wasting). It develops in adults and can occur in both sexes. Affected males may be infertile and may have enlarged breasts. Research has shown that these patients have reduced functional levels of the receptors for androgens (hormones that cause male characteristics). Androgens affect nerve cell growth and development in the spinal cord. Analyses of the chromosomes (structures in cells on which genes are located) of 35 unrelated patients from diverse ethnic backgrounds who had X-linked spinal and bulbar muscular atrophy showed that genetic mutations (changes) are present in the gene encoding for the androgen receptor. The genetic changes are in the form of repetitions of a small stretch of nucleotides (the chemical units comprising the genes). These repeats were not found in normal individuals. Therefore, the repeated nucleotides in the gene for the androgen receptor are probably the cause of X-linked spinal and bulbar muscular atrophy. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abnormalities, Causes of, Cell receptors, Sex chromosome abnormalities

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