A newly identified chromosomal microdeletion of the rapsyn gene causes a congenital myasthenic syndrome.

The objective is mutation analysis of the RAPSN gene in a patient with sporadic congenital myasthenic syndrome (CMS). Mutations in various genes encoding proteins expressed at the neuromuscular junction may cause CMS. Most mutations affect the epsilon subunit gene of the acetylcholine receptor (AChR) leading to endplate AChR deficiency. Recently, mutations in the RAPSN gene have been identified in several CMS patients with AChR deficiency. In most patients, RAPSN N88K was identified, either homozygously or heteroallelic to a second missense mutation. A sporadic CMS patient from Germany was analyzed for RAPSN mutations by RFLP, long-range PCR and sequence analysis. Clinically, the patient presents with an early onset CMS, associated with arthrogryposis multiplex congenita, recurrent episodes of respiratory insufficiency provoked by infections, and a moderate general weakness, responsive to anticholinesterase treatment. The mutation RAPSN N88K was found heterozygously to a large deletion of about 4.5 kb disrupting the RAPSN gene. Interestingly, an Alu-mediated unequal homologous recombination may have caused the deletion. We hypothesize that numerous interspersed Alu elements may predispose the RAPSN locus for genetic rearrangements.

Transcriptional profiles from patients with dystrophinopathies and limb girdle muscular dystrophies as determined by qRT-PCR.

Mutations in genes coding for the dystrophin-glycoprotein complex (DGC) cause inherited muscular dystrophies (MD), including Morbus Duchenne (DMD) and M. Becker (BMB) as well as limb-girdle muscular dystrophies (LGMD). New insights into the pathophysiology of the dystrophic muscle, the identification of compensatory mechanisms and additional proteins interacting with dystrophin are essential for developing new treatments. In order to define molecular mechanisms induced by lack of dystrophin and the subsequent counter-regulatory transcriptional response of degenerating muscle fibres, we have investigated the mRNA expression of 19 functionally linked genes in biopsies of patients with MD by means of real time qRT-PCR. Our results define a uniform transcriptional profile of the dystrophic muscle characterized by degeneration and regeneration. Several genes encoding structural proteins appear remarkably highly expressed.

Severe mucous membrane involvement in epidermolysis bullosa simplex with muscular dystrophy due to a novel plectin gene mutation.

UNLABELLED: Epidermolysis bullosa simplex with muscular dystrophy (OMIM 226670) is an autosomal recessive disorder caused by mutations of the human plectin gene on chromosome 8q24. Here, we report a 3-year-old girl, offspring of a consanguineous Lebanese family, who presented with skin blistering and recurrent episodes of severe respiratory distress necessitating tracheotomy at the age of 2 years. Repeated examination did not provide any evidence of muscle involvement. Indirect immunofluorescence analysis of a diagnostic skin biopsy with four different domain specific plectin antibodies showed a complete absence of plectin staining. Mutation analysis revealed a novel homozygous single guanine insertion mutation (5588insG/5588insG) residing in the N-terminal part of exon 31 of the plectin gene. CONCLUSION: The complete lack of protein expression, which may be attributed to a nonsense-mediated plectin mRNA decay, is likely to cause muscular dystrophy and other multisystem involvement later in life.

X-linked myotubular myopathy in a female infant caused by a new MTM1 gene mutation.

X-linked myotubular myopathy usually affects male infants with a severe phenotype leading to early death or survival with severe handicaps. Female carriers have been reported manifesting in childhood with slowly progressive muscle weakness only. The authors describe a now 5-year-old girl with prenatal/neonatal onset of an X-linked myotubular myopathy due to a 605delT mutation in the myotubularin gene.

Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase.

Congenital myasthenic syndromes are caused by different genetic defects affecting proteins expressed at the neuromuscular junction. Recently, the first molecular genetic defect resulting in a presynaptic congenital myasthenic syndrome has been reported: Recessive loss-of-function mutations in CHAT, the gene encoding choline acetyltransferase, were described in five congenital myasthenic syndrome families. In this study, we investigated three patients from two independent Turkish kinships. Clinically, all patients presented with moderate myasthenic symptoms including ptosis and muscle weakness with increased fatigability. Multiple episodes of sudden apnea were reported for all patients. One child suffering from a second, unrelated disorder, i.e. hepatocellular carcinoma, showed a severe myasthenic phenotype, requiring permanent ventilation. Genetically, we identified a novel missense mutation (I336T) in the CHAT gene homozygously in all three patients. Haplotype analysis revealed that the mutant allele cosegregates with the clinical phenotype in both families (maximum combined two-point LOD-score of 2.46 for D10S1793). In summary, we confirm that CHAT mutations are responsible for a clinically distinct form of congenital myasthenic syndrome, characterized by episodic apnea. Infections and stress may lead to a life-threatening failure of neuromuscular transmission in congenital myasthenic syndrome with episodic apnea. The observation of the same mutation (I336T) in two independent Turkish kinships may suggest a common origin, i.e. founder.

Consequences of a novel caveolin-3 mutation in a large German family.

Mutations in the human caveolin-3 gene (cav-3) on chromosome 3p25 have been described in limb girdle muscular dystrophy, rippling muscle disease, hyperCKemia, and distal myopathy. Here, we describe the genetic, myopathological, and clinical findings in a large German family harboring a novel heterozygous mutation (GAC-->GAA) in codon 27 of the cav-3 gene. This missense mutation causes an amino acid change from asparagine to glutamate (Asp27Glu) in the N-terminal region of the Cav-3 protein, which leads to a drastic decrease of Cav-3 protein expression in skeletal muscle tissue. In keeping with an autosomal dominant mode of inheritance, this novel cav-3 mutation was found to cosegregate with neuromuscular involvement in the reported family. Ultrastructural analysis of Cav-3-deficient muscle showed an abnormal folding of the plasma membrane as well as multiple vesicular structures in the subsarcolemmal region. Neurological examination of all nine subjects from three generations harboring the novel cav-3 mutation showed clear evidence of rippling muscle disease. However, only two of these nine patients showed isolated signs of rippling muscle disease without muscle weakness or atrophy, whereas five had additional signs of a distal myopathy and two fulfilled the diagnostic criteria of a coexisting limb girdle muscular dystrophy. These findings indicate that mutations in the human cav-3 gene can lead to different and overlapping clinical phenotypes even within the same family. Different clinical phenotypes in caveolinopathies may be attributed to so far unidentified modifying factors/genes in the individual genetic background of affected patients.

Rippling muscle disease in childhood.

Rippling muscle disease is a rare autosomal dominant disorder first described in 1975. Recently, it could be classified as a caveolinopathy; in European families, mutations in the caveolin-3 gene were revealed as causing this disease. Although clinical symptoms were almost all described in adulthood, we are now reporting clinical data of seven children with rippling muscle disease owing to mutations in the caveolin-3 gene. Initial symptoms were frequent falls, inability to walk on heels, tiptoe walking with pain and a warm-up phenomenon, calf hypertrophy, and an elevated serum creatine kinase level. Percussion-/pressure-induced rapid contractions, painful muscle mounding, and rippling could be observed even in early childhood. The diagnosis can be confirmed by molecular genetic analysis. Muscle biopsy must be considered in patients without muscle weakness or mechanical hyperirritability to differentiate between rippling muscle disease and limb-girdle muscular dystrophy 1C.

Effect of high-dose creatine therapy on symptoms of exercise intolerance in McArdle disease: double-blind, placebo-controlled crossover study.

BACKGROUND: In a recent study, we showed that administration of low-dose creatine (Cr) (60 mg/kg daily) improved work capacity in patients with McArdle disease. OBJECTIVE: To assess the efficacy of high-dose Cr therapy in McArdle disease. DESIGN: Randomized, double-blind, placebo-controlled crossover study. PATIENTS: Nineteen patients with McArdle disease. INTERVENTION: Treatment with Cr, 150 mg/kg daily. Each treatment phase with Cr or placebo lasted 5 weeks. MAIN OUTCOME MEASURES: The patient's daily rating of symptoms of exercise intolerance. At the end of each treatment phase, serum creatine and serum creatine kinase levels, phosphorus 31 magnetic resonance spectroscopy, and surface electromyograms were assessed. RESULTS: Clinical end points revealed increases in the intensity of exercise-induced pain in working muscles (mean treatment-induced difference [d], 0.30 in log(score); 95% confidence interval [CI], 0.05-0.55; P =.02), the limitation of daily activities (d, 0.59; 95% CI, 0.22-0.97;P =.005), and body mass index (d, 0.33 kg/m2, 95% CI, 0.10-0.56 kg/m2; P =.008) with Cr use. Surface electromyograms revealed a smaller increase in the electromyographic amplitude over time during muscle contraction with Cr use (d, -13.52%/min; 95% CI, -23.71%/min to -3.34%/min; P =.01). There were no significant changes in phosphorus 31 magnetic resonance spectroscopy variables. CONCLUSIONS: Administration of high-dose Cr worsened the main clinical symptoms of exercise intolerance in McArdle disease. These neurologic adverse effects represent a major dose-limiting factor in Cr therapy for McArdle disease. Taken together with results of a previous study, the indication for symptomatic therapy with Cr needs to be clarified. An effective Cr dosage without adverse effects may be between 60 and 150 mg/kg daily.