| dc.description.abstract | Neuromuscular disorders can be subdivided into anterior horn cell disorders, neuropathies, myasthenic disorders and myopathies. Some multisystem disorders, such as myotonic dystrophy and mitochondrial encephalomyopathies, are traditionally also included. The frequency in childhood of these disorders in general and of mitochondrial encephalomyopathies in particular is not well known. The purpose of this study was to perform an epidemiologic survey of neuromuscular disorders in children < 16 years of age from western Sweden. Cases were ascertained from different registers and medical records, investigations and diagnoses were reviewed in order to determine prevalence and incidence figures. A population-based study was conducted to describe the preschool incidence, point prevalence, mortality and the clinical spectrum of mitochondrial encephalomyopathies in childhood. In addition, a large family with a new type of congenital myopathy was investigated to characterize the clinical, muscle morphologic and genetic features of the disorder. In children of school age (6-15 years) the point prevalence was 79.8 x 10-5 for all neuromuscular disorders, 66.5 x 10-5 for hereditary neuromuscular disorders and 19.9 x 10-5 for hereditary motor and sensory neuropathies. The incidences of Duchenne muscular dystrophy, spinal muscular atrophy type I, spinal muscular atrophy type II, congenital myopathy and congenital myotonic dystrophy were estimated to be 21.5 x 10-5, 4.1 x 10-5, 1.0 x 10-5, 5.8 x 10-5 and 5.2 x 10-5 respectively. The incidence of mitochondrial encephalomyopathies in preschool children (< 6 years of age) was 8.9 x 10-5, while the point prevalence in children < 16 years of age was 4.7 x 10-5. The median survival among cases with infantile onset was up to 12 years of age. The most common disorders were Leigh syndrome, Alpers syndrome and infantile mitochondrial myopathy with cytochrome C-oxidase deficiency. The investigated congenital myopathy showed autosomal dominant heredity with full penetrance. Characteristic clinical features were congenital joint contractures which normalized during early childhood, external ophthalmoplegia and proximal muscle weakness. The course was frequently progressive in adulthood. The major histopathologic changes in skeletal muscle in childhood were focal disorganization of myofilaments and type 2A-fiber hypoplasia. In adults with progressive muscle weakness, the muscle biopsies showed rimmed vacuoles with inclusions of 15-21 nm filaments. Linkage analysis, haplotype/recombination analysis and radiation hybrid mapping showed that the locus is located in 17p13 and that a myosin heavy-chain (MyHC) gene cluster colocalizes to the same region. DNA sequencing and mutation screening of the MyHC IIa gene identified a missense mutation, Glu706Lys, in a highly conserved region of the motor domain. Conclusions: Neuromuscular disorders appear to be more common in childhood than has been reported in previous studies. Our findings in a population-based study indicate that mitochondrial encephalomyopathies are relatively common neurometabolic disorders in childhood. There was a predominance of infantile and encephalopathic disorders with high mortality. A new congenital myopathy, which may be regarded as a variant of hereditary inclusion-body myopathy (h-IBM) was characterized. This is the first identification of a genetic defect in an h-IBM and also the first human myopathy associated with a mutation in a fast MyHC gene. | en |
