1/80. Occult presentation of myotonia congenita in a 15-year-old athlete. A case of myotonia congenita in an adolescent athlete was presented. Although this is a rare condition unknown to many treating physicians, the key to diagnosis was provocation of the patient's symptoms of muscle "tightening" and "cramping" during sustained exercise. The diagnosis would have been missed in routine office examinations with the patient at rest. The stereotypic generalized myotonic signs and symptoms were provoked after the patient was asked to play 20 minutes of basketball during one of his office evaluations. The provocative or postexercise examination was critical to the diagnosis as the resting office examination was completely normal. The diagnosis was subsequently confirmed by EMG and genetic testing. myotonia congenita should be considered in the differential diagnosis of athletes with exercise-induced muscle "stiffness" or "cramping," particularly if the course is protracted and initial examinations are unremarkable. A provocative exercise period can be used to make the diagnosis. Once the diagnosis is established, appropriate pharmacologic treatment may improve symptoms and allow return to daily activity without restriction. ( info) |
2/80. Fluctuating clinical myotonia and weakness from Thomsen's disease occurring only during pregnancies. Advances in molecular genetics are allowing better phenotype to genotype correlation of the non-dystrophic myotonic disorders. We report a 32-year-old woman, who first noted myotonia that was associated with weakness during her first pregnancy. The work-up disclosed that she had Thomsen's disease which is not known to be associated with weakness. In addition, her myotonia was of the fluctuating type and occurred (symptomatically) only during two pregnancies. We discuss the evaluation of myotonia in the pregnant woman which led to the diagnosis of Thomsen's disease and we conclude that in exceptional cases, fluctuating myotonia and weakness occurs in autosomal dominant chloride channel myotonia (Thomsen's disease). ( info) |
3/80. Novel mutations in the muscle chloride channel CLCN1 gene causing myotonia congenita in Spanish families. Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, lead to recessive and dominant myotonia congenita. We report four novel mutations identified in this gene, after clinical, electromyographic, and genetic studies performed on 13 unrelated families. Two of the four mutations (2512insCTCA and A218T) were identified in families with Thomsen's disease, one (Q658X) in a family with Becker's disease, and the fourth (R669C) in a presumably sporadic patient with the Becker phenotype. Although identification of the mutations allows us to establish some genotype/phenotype correlations, this does not wholly account for the clinical heterogeneity and the inheritance patterns of the disease. ( info) |
4/80. Novel chloride channel gene mutations in two unrelated Japanese families with Becker's autosomal recessive generalized myotonia. We investigated the skeletal muscle voltage-gated chloride channel gene (CLCN1) in two unrelated Japanese patients with Becker's myotonia congenita. The non-myotonic parents of each patient were consanguineous. The proband of each family shares generalized myotonia, transient weakness after rest, and leg muscle hypertrophy. However, the disease severity related to the degree of myotonia differed, even in view of the response to long train nerve stimulation tests. CLCN1 gene analysis revealed a novel Ala659Val missense mutation identified to be homozygous in the more severe patient, while a novel Gln445Stop nonsense mutation was present in the other patient. Both mutations were absent in 90 Japanese normal controls. This is the first report of Japanese cases of Becker's myotonia congenita with CLCN1 gene mutations. ( info) |
5/80. A "dystrophic" variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene. OBJECTIVES: To identify the disease-causing mutation and its molecular consequence for a clinically distinct type of myotonic myopathy. BACKGROUNDS: The authors encountered a unique myotonic disorder of early onset in a 37-year-old man and his 47-year-old sister. methods: After examining known loci of inherited myotonic disorders, the authors looked for mutations within the CLCN1 gene using single strand conformation polymorphism and direct sequencing. To investigate the disease mechanism, reverse transcriptase PCR analyses of total rna were performed. RESULTS: In the proband and his affected sister, two novel mutations comprising a compound heterozygous state in the CLCN1 gene were identified: 1) a base (G) insertion in exon 7 generating a premature termination codon (fs289X) in the D5 domain, and 2) a C-to-T substitution in exon 23 resulting in a missense mutation (P932L). These mutations accompanied a clinical phenotype that is distinguishable from recessive myotonia congenita by progressive generalized muscle weakness, severe distal muscle atrophy, joint contractures, high serum creatine kinase levels, and conspicuous myopathic changes on muscle histopathology. Reverse transcriptase PCR analyses detected only the P932L mutant mRNA in skeletal muscle, suggesting that the fs289X mRNA is degraded rapidly. CONCLUSIONS: These data suggest that fs289X is a null mutation, rendering the patients with the compound heterozygous genotype of fs289X/P932L to exclusively express P932L homomeric channels that may have caused the "dystrophic" phenotype. ( info) |
6/80. Generalized myopathy and cerebral malformations possibly related to an enteroviral infection. A study was made on a case of generalized muscular hypotonus manifested at birth. Serological findings and epidemiological data suggested an association to a recently described enterovirus infection (enterovirus candidate 71) known to cause neurological disease in man. autopsy revealed cerebral malformations and generalized myopathy compatible with a viral etiology of the disease. ( info) |
7/80. Fine structural alterations of muscle fibers in diseases accompanied by myotonia. The authors have reported the results of examination by electron microscopy of two muscle biopsy specimens from cases of myotonia congenita and three cases of myotonia dystrophica. They have stated that "peripheral annular formation" was a frequently observed alteration in the myotonia congenita cases. In the myotonia dystrophica cases there were additionally disorganized myofibrils in the subsarcolemmal region and inclusion body vacuoles morphologically connected with the sarcolemma. The term "peripheral annular formation" refers to the situation in which the peripheral myofibrils of the muscle fiber fracture and the fragments retract and form a helical sheath around the central myofibrils of the same muscle fiber. ( info) |
8/80. The myotonia congenita mutation A331T confers a novel hyperpolarization-activated gate to the muscle chloride channel ClC-1. Mutations in the muscle chloride channel gene CLCN1 cause myotonia congenita, an inherited disorder of skeletal muscle excitability leading to a delayed relaxation after muscle contraction. Here, we examine the functional consequences of a novel disease-causing mutation that predicts the substitution of alanine by threonine at position 331 (A331T) by whole-cell patch-clamp recording of recombinant mutant channels. A331T hClC-1 channels exhibit a novel slow gate that activates during membrane hyperpolarization and closes at positive potentials. This novel gate acts in series with fast opening and closing transitions that are common to wild-type (WT) and mutant channels. Under conditions at which this novel gate is not activated, i.e., a holding potential of 0 mV, the typical depolarization-induced activation gating of WT hClC-1 was only slightly affected by the mutation. In contrast, A331T hClC-1 channels with an open slow gate display an altered voltage dependence of open probability. These novel gating features of mutant channels produce a decreased open probability at -85 mV, the normal muscle resting potential, leading to a reduced resting chloride conductance of affected muscle fibers. The A331T mutation causes an unprecedented alteration of ClC-1 gating and reveals novel processes defining transitions between open and closed states in ClC chloride channels. ( info) |
9/80. Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. myotonia congenita (MC) is caused by a defect in the skeletal muscle chloride channel function, which may cause sustained membrane depolarisation. We describe a previously healthy 32-year-old woman who developed a life-threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium. The muscle spasms disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a myotonic condition. Myotonia was found on clinical examination and EMG. The diagnosis MC was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of ion channel disorders including malignant hyperthermia and their anaesthetic considerations. ( info) |
10/80. myotonia congenita and myoadenylate deaminase deficiency: case report. Approximately 1-2% of the population has a deficiency of the enzyme myoadenylate deaminase. Early reports suggested that patients with myoadenylate deaminase deficiency had various forms of myalgia, and exercise intolerance. However, a deficiency of the enzyme has been described in many conditions, including myopathies, neuropathies, and motor neuron disease. We report a patient with clinical diagnosis of myotonia congenita and absent myoadenylate deaminase reaction on the muscle biopsy. This is the first description of myoadenilate deaminase deficiency with myotonia congenita. Myoadenylate deaminase deficiency is the most common enzymatic deficit of muscle, and the association with other neuromuscular diseases is coincidental. ( info) |