[Show abstract][Hide abstract] ABSTRACT: The delayed relaxation or sustained contraction of skeletal muscle-myotonia-is frequently seen in myotonic dystrophy and sodium channelopathies (hyperkalemic periodic paralysis, paramyotonia congenita). Many cases of congenital myotonia without other clinical symptoms have been associated with mutations in the muscle chloride channel gene. Most cases reported to date show a recessive inheritance pattern, with loss of function of the corresponding protein. Six families have been reported with dominantly inherited myotonia and mutations of the chloride channel gene. Here we report clinical and molecular data on 38 family members from four new families with dominantly inherited myotonia congenita. Three families show a previously characterized G230E mutation, and we show that these three share a common affected ancestor despite living in different regions of the United States (linkage disequilibrium). One Italian family is shown to have a novel dominant mutation-I290M. This is the sixth mutation identified in Thomsen's myotonia. Genotype/phenotype correlations in these four families showed that both of the dominant mutations resulted in a mild clinical picture in 90% of the patients, and no symptoms in 10% of mutation-positive patients. The EMG was the clinical feature that most closely correlated with mutation data; however, 3 of 16 (19%) mutation-positive patients tested negative by electromyography at least once, and 1 (6%) tested negative despite multiple tests. Only about half (55%) of the mutation-positive patients tested positive for percussion myotonia. Most of the clinically symptomatic individuals stated that cold temperatures and stress substantially worsened their myotonia. Our data show that dominantly inherited Thomsen's myotonia is most often a very mild disorder that shows considerable clinical heterogeneity.
[Show abstract][Hide abstract] ABSTRACT: We studied a group of 14 patients from Northern Italy with myophosphorylase deficiency. The disease presented considerable clinical and biochemical heterogeneity, which was reflected at the molecular level. The clinical presentation was typical in 3 patients, mild in 7 (exercise intolerance), and severe in 4 (fixed weakness). Enzyme activity was undetectable in 10 patients, below 3% of control in 3, and 13% of control in one. Enzymatic protein was detectable immunologically only in 1 patient. Myophosphorylase mRNA was present in 8 patients, but in 7 of them it was reduced in amount. Two patients were homozygous for the common nonsense R49X mutation, 5 were heterozygous. Two missense mutations not previously observed were identified in this group of patients. The frequency of alleles with the R49X mutation was significantly lower in this group of patients than in previously reported series. Myophosphorylase deficiency is genetically heterogeneous even among patients living in a small region and with a common ethnic background.
Journal of the Neurological Sciences 05/1996; 137(1):14-9. DOI:10.1016/0022-510X(95)00298-G · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In 132 DMD muscle biopsies we investigated the presence of dystrophin-positive fibers and the relationship of dystrophin immunohistochemical pattern to the clinical severity of the disease. Reverted fibers were detected in 37% of patients; their prevalence increased significantly in each biopsy with age of patients. We suggest that reversion occurs in satellite cells, when muscle differentiation is completed. The longitudinal extent of dystrophin-positive domain spans a maximum length of 900 microns. No correlation was found between the presence of reverted fibers and the clinical severity of DMD, whereas a milder form of Duchenne dystrophy was observed in patients showing a faint reaction in all fibers. The occurrence of reverted fibers is independent of the type of gene mutation; however, a higher proportion of cases with reverted fibers was found among patients with gene duplications.
[Show abstract][Hide abstract] ABSTRACT: We studied 19 symptomatic female carriers of the Duchenne muscular dystrophy (DMD) gene. Most of these dystrophinopathy patients had had an erroneous or ambiguous diagnosis prior to dystrophin immunofluorescence testing. We assessed clinical severity by a standardized protocol, measured X-chromosome inactivation patterns in blood and muscle DNA, and quantitated the dystrophin protein content of muscle. We found that patients could be separated into two groups: those showing equal numbers of normal and mutant dystrophin genes in peripheral blood DNA ("random" X-inactivation), and those showing preferential use of the mutant dystrophin gene ("skewed" X-inactivation). In the random X-inactivation carriers, the clinical phenotype ranged from asymptomatic to mild disability, the dystrophin content of muscle was > 60% of normal, and there were only minor histopathologic changes. In the skewed X-inactivation patients, clinical manifestations ranged from mild to severe, but the patients with mild disease were young (5 to 10 years old). The low levels of dystrophin (< 30% on average) and the severe symptoms of the older patients suggested a poor prognosis for those with skewed X-inactivation, and they all showed morphologic changes of dystrophy. The random inactivation patients showed evidence of biochemical "normalization," with higher dystrophin content in muscle than predicted by the number of normal dystrophin genes. Seventy-nine percent of skewed X-inactivation patients (11/14) showed genetic "normalization," with proportionally more dystrophin-positive nuclei in muscle than in blood. In 65% of the skewed X-inactivation patients, dystrophin was not produced by dystrophin-positive nuclei; an average of 20% of myofiber nuclei were genetically dystrophin-positive but did not produce stable dystrophin. Biochemical normalization seems to be the main mechanism for rescue of fibers from dystrophin deficiency in the random X-inactivation patients. In the skewed X-inactivation patients, genetic normalization is active, but production failure of dystrophin by dystrophin-normal nuclei may counteract any effect of biochemical normalization. In the skewed X-inactivation patients, the remodeling of the muscle through cycles of degeneration and regeneration led to threefold increase in the number of dystrophin-competent nuclei in muscle myofibers (3.3 +/- 4.6), while dystrophin content was on the average 1.5-fold less then expected (-1.54 +/- 3.38). Our results permit more accurate prognistic assessment of isolated female dystrophinopathy patients and provide important data with which to estimate the potential effect of gene delivery (gene therapy) in DMD.
[Show abstract][Hide abstract] ABSTRACT: A multidisciplinary study was conducted in order to assess dystrophin expression in a large series of mild X-linked muscular dystrophy patients, with well-defined clinical phenotype. Patients (104) were divided in 4 clinical groups, according to clinical severity: asymptomatic (sub-clinical), benign, moderate and severe, Cardiopathy was also assessed, and dilated cardiomyopathy was found in 47% of sub-clinical and benign cases. Myoglobinuria, cramps and myalgia were also associated with a sub-clinical or benign clinical status. Dystrophin immunohistochemical pattern of labelling and dystrophin amount decreased gradually across clinical groups. Our study showed a significative correlation between: (1) dystrophin amount and immunohistochemical score (p < 0.05); (2) dystrophin amount and clinical score (p < 0.05). Therefore, the combined use of these different techniques for prognosis of mild X-linked muscular dystrophy patients is useful. Our study assesses the prevalence of the various disease courses in a large cohort of mild X-linked muscular dystrophy patients. From our series, up to 30% of patients may be either asymptomatic or have sub-clinical changes.