Objective: To determine the phenotype variability associated with the specific C-terminal M-line titin mutation known to cause autosomal dominant distal myo pathy, tibial muscular dystrophy (TMD; MIM 600334), and limb...Objective: To determine the phenotype variability associated with the specific C-terminal M-line titin mutation known to cause autosomal dominant distal myo pathy, tibial muscular dystrophy (TMD; MIM 600334), and limb girdle muscular dys trophy 2J (LGMD2J). Methods: Three hundred eighty-six individuals were genotype d for the Finnish founder mutation in titin (FINmaj) causing TMD/LGMD2J. Results : Two hundred seven patients were heterozygous for the mutation. Among these pat ients, 189 (91%) had a more common phenotype compatible with the classic descri ption of TMD. However, 18(9%) had unusual phenotypes such as proximal leg or po sterior lower leg muscle weakness and atrophy even at onset.Four patients were c onfirmed homozygotes representing the LGMD2J phenotype. These homozygotes were h alf of the eight LGMD patients previously described in the original large consan guineous kindred. Conclusions: Large variability of phenotypic expression caused by just one mutation, the Finnish FINmaj, suggests that no certain phenotype of myopathy/dystrophy can be excluded from being caused by mutated titin. Yet unkn own homozygous or compound heterozygous titin mutations without phenotype in the heterozygote carriers may be responsible for undetermined recessive MD and LGMD .展开更多
Background: Laing early onset distal myopathy (MPD1) is an autosomal dominant myopathy caused by mutations within the slow skeletal muscle fibre myosin heavy chain gene, MYH7. It is allelic with myosin storage myopath...Background: Laing early onset distal myopathy (MPD1) is an autosomal dominant myopathy caused by mutations within the slow skeletal muscle fibre myosin heavy chain gene, MYH7. It is allelic with myosin storage myopathy, with the commonest form of familial hypertrophic cardiomyopathy, and with one form of dilated cardiomyopathy. However, the clinical picture of MPD1 is distinct from these three conditions. Objective: To collate and discuss the histological features reported in the muscle biopsies of MPD1 patients and to outline the clinical features. Results: The phenotype of MPD1 was consistent, with initial weakness of great toe/ankle dorsiflexion, and later development of weakness of finger extension and neck flexion. Age of onset was the only variable, being from birth up to the 20s, but progression was always very slow. The pathological features were variable. In this retrospective series, there were no pathognomonic diagnostic features, although atrophic type I fibres were found in half the families. Rimmed vacuoles are consistently seen in all other distal myopathies with the exception of Myoshi distal myopathy. However, they were found in a minority of patients with MPD1, and were not prominent when present. Immunohistochemical staining for slow and f ast myosin showed co-expression of slow and fast myosin in some type I fibres, possibly indicating a switch to type II status. This may be a useful aid to diagnosis. Conclusions: The pathological findings in MPD1 are variable and appear to be affected by factors such as the specific muscle biopsied, the age of the patient at biopsy, and the duration of disease manifestations.展开更多
文摘Objective: To determine the phenotype variability associated with the specific C-terminal M-line titin mutation known to cause autosomal dominant distal myo pathy, tibial muscular dystrophy (TMD; MIM 600334), and limb girdle muscular dys trophy 2J (LGMD2J). Methods: Three hundred eighty-six individuals were genotype d for the Finnish founder mutation in titin (FINmaj) causing TMD/LGMD2J. Results : Two hundred seven patients were heterozygous for the mutation. Among these pat ients, 189 (91%) had a more common phenotype compatible with the classic descri ption of TMD. However, 18(9%) had unusual phenotypes such as proximal leg or po sterior lower leg muscle weakness and atrophy even at onset.Four patients were c onfirmed homozygotes representing the LGMD2J phenotype. These homozygotes were h alf of the eight LGMD patients previously described in the original large consan guineous kindred. Conclusions: Large variability of phenotypic expression caused by just one mutation, the Finnish FINmaj, suggests that no certain phenotype of myopathy/dystrophy can be excluded from being caused by mutated titin. Yet unkn own homozygous or compound heterozygous titin mutations without phenotype in the heterozygote carriers may be responsible for undetermined recessive MD and LGMD .
文摘Background: Laing early onset distal myopathy (MPD1) is an autosomal dominant myopathy caused by mutations within the slow skeletal muscle fibre myosin heavy chain gene, MYH7. It is allelic with myosin storage myopathy, with the commonest form of familial hypertrophic cardiomyopathy, and with one form of dilated cardiomyopathy. However, the clinical picture of MPD1 is distinct from these three conditions. Objective: To collate and discuss the histological features reported in the muscle biopsies of MPD1 patients and to outline the clinical features. Results: The phenotype of MPD1 was consistent, with initial weakness of great toe/ankle dorsiflexion, and later development of weakness of finger extension and neck flexion. Age of onset was the only variable, being from birth up to the 20s, but progression was always very slow. The pathological features were variable. In this retrospective series, there were no pathognomonic diagnostic features, although atrophic type I fibres were found in half the families. Rimmed vacuoles are consistently seen in all other distal myopathies with the exception of Myoshi distal myopathy. However, they were found in a minority of patients with MPD1, and were not prominent when present. Immunohistochemical staining for slow and f ast myosin showed co-expression of slow and fast myosin in some type I fibres, possibly indicating a switch to type II status. This may be a useful aid to diagnosis. Conclusions: The pathological findings in MPD1 are variable and appear to be affected by factors such as the specific muscle biopsied, the age of the patient at biopsy, and the duration of disease manifestations.
