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Duchenne muscular dystrophy is a progressive and lethal X-linked recessive neuromuscular disease caused by mutations in the dystrophin gene. It has a high rate of diagnostic delay; early diagnosis and treatment are often not possible due to delayed recognition of muscle weakness and lack of effective treatments. Current treatments based on genetic therapy can improve clinical results, but treatment must begin as early as possible before significant muscle damage. Therefore, early diagnosis and rehabilitation of Duchenne muscular dystrophy are needed before symptom aggravation. Creatine kinase is a diagnostic marker of neuromuscular disorders. Herein, the authors report a case of an infant patient with Duchenne muscular dystrophy with a highly elevated creatine kinase level but no obvious symptoms of muscle weakness. The patient was diagnosed with Duchenne muscular dystrophy via next-generation sequencing and chromosomal microarray analysis to identify possible inherited metabolic and neuromuscular diseases related to profound hyperCKemia. The patient is enrolled in a rehabilitation program and awaits the approval of the genetic treatment in Korea. This is the first report of an infantile presymptomatic Duchenne muscular dystrophy diagnosis using next-generation sequencing and chromosomal microarray analysis. [ABSTRACT FROM AUTHOR]

Myotonia congenita (MC) is a genetic disease that displays impaired relaxation of skeletal muscle and muscle hypertrophy. This disease is mainly caused by mutations of CLCN1 that encodes human skeletal muscle chloride channel (CLC- 1). CLC-1 is a voltage gated chloride channel that activates upon depolarizing potentials and play a major role in stabilization of resting membrane potentials in skeletal muscle. In this study, we report 4 unrelated Korean patients diagnosed with myotonia congenita and their clinical features. Sequence analysis of all coding regions of the patients was performed and mutation, R47W and A298T, was commonly identified. The patients commonly displayed transient muscle weakness and only one patient was diagnosed with autosomal dominant type of myotonia congenita. To investigate the pathological role of the mutation, electrophysiological analysis was also performed in HEK 293 cells transiently expressing homo-or heterodimeric mutant channels. The mutant channels displayed reduced chloride current density and altered channel gating. However, the effect of A298T on channel gating was reduced with the presence of R47W in the same allele. This analysis suggests that impaired CLC-1 channel function can cause myotonia congenita and that R47W has a protective effect on A298T in relation to channel gating. Our results provide clinical features of Korean myotonia congenita patients who have the heterozygous mutation and reveal underlying pathophyological consequences of the mutants by taking electrophysiological approach. [ABSTRACT FROM AUTHOR]

This paper reports the brain magnetic resonance imaging (MRI) findings of a case of merosin-deficient congenital muscular dystrophy (MDCMD) in a neonate and discusses the spectrum of brain involvement in MDCMD. A neonate presented hypotonia, increased serum creatine kinase levels, and polymicrogyria and subcortical heterotopia on brain MRI involving both posterior temporal and occipital lobes. Although these findings suggested Fukuyama muscular dystrophy, muscle biopsy showed dystrophic changes and an absence of merosin staining. We found that compound heterozygous mutation for c.2049_2050delAG (p.R683fs) and c.5866-2A>G in the LAMA2 gene which encodes Laminin-a2. To our knowledge, this is the second Korean case of MDCMD with polymicrogyria and subcortical heterotopias. This case shows that a range of brain structural malformations can be found in children with MDCMD and that the classification of congenital muscular dystrophy (CMD) is not complete yet, as indicated previously in reports suggesting other unclassified forms of CMD. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated in mdx mice (murine model for DMD) significant morphologic alterations at the motor endplate of the neuromuscular junction (NMJ) and corresponding NMJ transmission failure after injury. Here we extend these initial observations at the motor endplate to gain insight into the pre- vs. postsynaptic morphology, as well as the subsynaptic nuclei in healthy (WT) vs. mdx mice. We quantified the discontinuity and branching of the terminal nerve in adult mice. We report mdx- and age-dependent changes for discontinuity and an increase in branching when compared to WT. To examine mdx- and age-dependent changes in the relative localization of pre- and postsynaptic structures, we calculated NMJ occupancy, defined as the ratio of the footprint occupied by presynaptic vesicles vs. that of the underlying motor endplate. The normally congruent coupling between presynaptic and postsynaptic morphology was altered in mdx mice, independent of age. Finally we found an almost two-fold increase in the number of nuclei and an increase in density (nuclei/area) underlying the NMJ. These outcomes suggest substantial remodeling of the NMJ during dystrophic progression. This remodeling reflects plasticity in both pre- and postsynaptic contributors to NMJ structure, and thus perhaps also NM transmission and muscle function. [ABSTRACT FROM AUTHOR]

ClC-1 is a member of a large family of voltage-gated chloride channels, abundantly expressed in human skeletal muscle. Mutations in ClC-1 are associated with myotonia congenita (MC) and result in loss of regulation of membrane excitability in skeletal muscle. We studied the electrophysiological characteristics of six mutants found among Korean MC patients, using patch clamp methods in HEK293 cells. Here, we found that the autosomal dominant mutants S189C and P480S displayed reduced chloride conductances compared to WT. Autosomal recessive mutant M128I did not show a typical rapid deactivation of Cl- currents. While sporadic mutant G523D displayed sustained activation of Cl- currents in the whole cell traces, the other sporadic mutants, M373L and M609K, demonstrated rapid deactivations. V1/2 of these mutants was shifted to more depolarizing potentials. In order to identify potential effects on gating processes, slow and fast gating was analyzed for each mutant. We show that slow gating of the mutants tends to be shifted toward more positive potentials in comparison to WT. Collectively, these six mutants found among Korean patients demonstrated modifications of channel gating behaviors and reduced chloride conductances that likely contribute to the physiologic changes of MC. [ABSTRACT FROM AUTHOR]

Loss of muscle force is a salient feature of Duchenne muscular dystrophy (DMD), a fatal disease caused by dystrophin deficiency. Assessment of force production from a single intact muscle has been considered as the gold standard for studying physiological consequences in murine models of DMD. Unfortunately, equivalent assays have not been established in dystrophic dogs. To fill the gap, we developed a novel in situ protocol to measure force generated by the extensor carpi ulnaris (ECU) muscle of a dog. We also determined the muscle length to fiber length ratio and the pennation angle of the ECU muscle. Muscle pathology and contractility were compared between normal and affected dogs. Absence of dystrophin resulted in marked histological damage in the ECU muscle of affected dogs. Central nucleation was significantly increased and myofiber size distribution was altered in the dystrophic ECU muscle. Muscle weight and physiological cross sectional area (PCSA) showed a trend of reduction in affected dogs although the difference did not reach statistical significance. Force measurement revealed a significant decrease of absolute force, and the PCSA or muscle weight normalized specific forces. To further characterize the physiological defect in affected dog muscle, we conducted eccentric contraction. Dystrophinnull dogs showed a significantly greater force loss following eccentric contraction damage. To our knowledge, this is the first convincing demonstration of force deficit in a single intact muscle in the canine DMD model. The method described here will be of great value to study physiological outcomes following innovative gene and/or cell therapies. [ABSTRACT FROM AUTHOR]

The article focuses on Duchenne muscular dystrophy (DMD), which is the most common lethal childhood muscle disease caused by dystrophin deficiency. It reports thta mdx, mdx3cv, and mdx4cv mice are among the most commonly used models for the study of DMD. It states that current methods require multiple polymerase chain reactions (PCRs), post-PCR manipulations, and/or special equipment/reagents.

Lee J-H, Shin J-H, Park K-P, Kim I-J, Kim C-M, Lim J-G, Choi Y-C, Kim D-S. Phenotypic variability in Kennedy's disease: implication of the early diagnostic features.Acta Neurol Scand 2005: 112: 57–63.© Blackwell Munksgaard 2005.The clinical diagnosis of Kennedy's disease (KD) is not easy when the typical manifestations are lacking, especially in early stage of the disease. In our study, we tried to identify the relative frequency of common clinical features and early symptoms in KD.Eighteen Korean patients with KD were included. Clinical findings were subdivided into two parts: the age at onset of each clinical symptoms and characteristic signs on investigations. With detailed clinical examinations, the serum creatine kinase (CK) level, electrophysiologic study and DNA analysis were performed and analyzed in detail.In KD, the most consistent clinical findings at evaluations included perioral fasciculation with variable bulbar paresis, limb weakness with wasting, hyporeflexia, hand tremor, and elevated CK level. Some distinguishing features, such as X-linked family history, gynecomastia, and sensory abnormalities were absent in a half of cases. Frequent initial clinical findings include tremor (50%) and symptoms other than weakness, such as cramps and fatigability (33.3%).We conclude that KD shows variable clinical and electrophysiological features. Our description on the onset and subsequent progression of each clinical finding might help to identify KD in early stage and avoid misdiagnosis. [ABSTRACT FROM AUTHOR]