This ongoing study has been active for many years, seeking to discover the biochemical and biophysical defects responsible for myotonic dystrophy DM) and other muscle and genetic diseases. Patients known or suspected of having myotonic dystrophy (or other genetic diseases) are admitted to Rankin Ward for diagnostic history and physical examinations. Specific blood tests, urinalysis, and specific endocrine examinations are performed and blood samples obtained for research laboratory investigation. At this time, chest x-rays may be obtained and muscle biopsies may be performed in the operating room. The muscle tissue is sent for pathological examination and biochemical evaluation in our laboratories. The test results are used for research family linkage and genetic analysis. These studies aid in diagnosing at-risk individuals who may have minimal manifestations of the genetic disease. Research progress has primarily focused on myotonic dystrophy (DM) research during the past year. DM is the first autosomal dominant disease to be transmitted by the inheritance of a dynamic mutation. In Kennedy's disease and Fragile X syndrome the deleterious effect of the variable insert is on a gene that is present as a single copy in males. Abnormal or absent transcription is easier to understand. In DM the presence of one interrupted gene and one normal gene complicates the hypotheses for disease expression. The dynamic mutation locus is inherited as a highly polymorphic, but stable, polymorphism in normal individuals. Normal individuals usually have less than 30 trinucleotide repeats while in mildly affected individuals there are more than 50 repeats interrupting the 3' untranslated region of a previously undescribed protein kinase gene. The remarkable number of repeats (up to several thousand) that are present in more severely manifesting DM patients occurs with the co-inheritance of one normal allele. (There is little doubt that homozygous affected individuals will soon be diagnosed in inbred families, and that they may be very mildly affected if two minimally increased repeats are inherited.) How does a large insert interrupting the 3' untranslated region of a protein kinase gene cause specific, variable expression of the disease phenotype in multiple tissues at different rates? Is disease expression a function of an abnormal protein kinase activity coded from one allele in the presence of a normal form of the enzyme? Could the expression of genes and the expression of disease phenotype be due to more complicated mechanisms? These questions are currently under investigation and remain unanswered.
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