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To assess whether exon deletions or duplications in CLCN1are associated with recessive myotonia congenita (MC).

Acetazolamide has been the most commonly used treatment for hypokalemic periodic paralysis since 1968. However, its mechanism of efficacy is not fully understood, and it is not known whether therapy response relates to genotype. We undertook a clinical and genetic study to evaluate the response rate of patients treated with acetazolamide and to investigate possible correlations between response and genotype.

To assess the clinical course and genotype–phenotype correlations in patients with selenoprotein-related myopathy (SEPN1-RM) due to selenoprotein N1 gene (SEPN1) mutations for a retrospective cross-sectional study.

Episodic ataxia type 1 (EA1) is a monogenic channelopathy caused by mutations of the potassium channel gene KCNA1. Affected individuals carrying the same mutation can exhibit considerable variability in the severity of ataxia, neuromyotonia, and other associated features. We investigated the phenotypic heterogeneity of EA1 in 2 sets of identical twins to determine the contribution of environmental factors to disease severity. One of the mutations was also found in a distantly related family, providing evidence of the influence of genetic background on the EA1 phenotype.

Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome coxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease.

Objective To characterise the phenotype of a family with paroxysmal exercise induced dystonia (PED) and migraine and establish whether it is linked to the paroxysmal non-kinesigenic dyskinesia (PNKD) locus on chromosome 2q33-35, the familial hemiplegic migraine (FHM) locus on chromosome 19p, or the familial infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome) locus on chromosome 16. Methods A family, comprising 30 members, was investigated. Fourteen family members in two generations including three spouses were examined. Haplotypes were reconstructed for all the available family members by typing several microsatellite markers spanning the PNKD, FHM, and ICCA loci. Additionally, the four exons containing the known FHM mutations were sequenced. Results Of 14 members examined four were definitely affected and one member was affected by history. The transmission pattern in this family was autosomal dominant with reduced penetrance. Mean age of onset in affected members was 12 (range 9-15 years). Male to female ratio was 3:1. Attacks of PED in affected members were predominantly dystonic and lasted between 15 and 30 minutes. They were consistently precipitated by walking but could also occur after other exercise. Generalisation did not occur. Three of the affected members in the family also had migraine without aura. Linkage of the disease to the PNKD, FHM, or ICCA loci was excluded as no common haplotype was shared by all the affected members for each locus. In addition, direct DNA sequential analysis of the FHM gene (CACNL1A4) ruled out all known FHM point mutations. Conclusions This family presented with the classic phenotype of PED and is not linked to the PNKD, FHM, or ICCA loci. A new gene, possibly coding for an ion channel, is likely to be the underlying cause of the disease.

Objectives To characterise the clinical and electrophysiological features and to determine the molecular genetic basis of pure paramyotonia congenita in a previously unreported large Irish kindred. Methods Clinical and neurophysiological examination was performed on three of the five affected family members. Five unaffected and three affected members of the family were available for genetic testing. Direct sequence analysis of the SCN4A gene on chromosome 17q, was performed on the proband's DNA. Restriction fragment length polymorphism (RFLP) analysis was used to screen other family members and control chromosomes for the SCN4A mutation identified. Results Each affected member had clinical and examination features consistent with pure paramyotonia congenita. Electrophysiological studies disclosed a 78% drop in compound muscle action potential (CMAP) amplitude on cooling to 20°C. DNA sequence analysis identified a heterozygous point mutation G4367A in exon 24 of the SCN4A gene which segregated with paramyotonia and was absent in 200 control chromosomes. The mutation is predicted to result in a radical amino acid substitution at a highly conserved position within the voltage sensing fourth transmembrane segment of the fourth repeated domain of the sodium channel. Conclusions The G4367A mutation is likely to be pathogenic and it associates with a pure paramyotonia phenotype. In keeping with other paramyotonia mutations in this region of the skeletal muscle sodium channel, it is predicted that this mutation will impair voltage sensing or sodium channel fast inactivation in a temperature dependent fashion. This study provides further evidence that exon 24 in SCN4A is a hot spot for paramyotonia mutations and this has implications for a DNA based diagnostic service.

We have identified the first stop-codon point mutation in mtDNA to be reported in association with human disease. A 36-year-old woman experienced episodes of encephalopathy accompanied by lactic acidemia and had exercise intolerance and proximal myopathy. Histochemical analysis showed that 90% of muscle fibers exhibited decreased or absent cytochrome c oxidase (COX) activity. Biochemical studies confirmed a severe isolated reduction in COX activity. Muscle immunocytochemistry revealed a pattern suggestive of a primary mtDNA defect in the COX-deficient fibers and was consistent with either reduced stability or impaired assembly of the holoenzyme. Sequence analysis of mtDNA identified a novel heteroplasmic G→A point mutation at position 9952 in the patient's skeletal muscle, which was not detected in her leukocyte mtDNA or in that of 120 healthy controls or 60 additional patients with mitochondrial disease. This point mutation is located in the 3′ end of the gene for subunit III of COX and is predicted to result in the loss of the last 13 amino acids of the highly conserved C-terminal region of this subunit. It was not detected in mtDNA extracted from leukocytes, skeletal muscle, or myoblasts of the patient's mother or her two sons, indicating that this mutation is not maternally transmitted. Single-fiber PCR studies provided direct evidence for an association between this point mutation and COX deficiency and indicated that the proportion of mutant mtDNA required to induce COX deficiency is lower than that reported for tRNA-gene point mutations. The findings reported here represent only the second case of isolated COX deficiency to be defined at the molecular genetic level and reveal a new mutational mechanism in mitochondrial disease.

Objectives To define the molecular genetic basis of the MELAS phenotype in five patients without any known mutation of mitochondrial DNA. Methods Systematic automated mitochondrial DNA sequencing of all mitochondrial transfer RNA and cytochrome c oxidase genes was undertaken in five patients who had the MELAS phenotype. Results A novel heteroplasmic mitochondrial DNA mutation was identified in the transfer RNA gene for phenylalanine in one case (patient 3). This mutation was not detected in the patient's blood or in her mother's blood. No pathogenic mutations were identified in the other four patients. Conclusions This is the first point mutation in the transfer RNA gene for phenylalanine to be associated with MELAS. The absence of mutations in the remaining four patients suggests that there is further genetic heterogeneity associated with this mitochondrial phenotype.

Presently there is a lack of effective, noninvasive tests for the detection and monitoring of bladder cancer. Measurement of fibrin/fibrinogen degradation products in urine has been shown to be a useful indicator of bladder carcinoma. The objective of this study was to evaluate the AuraTek FDP rapid immunoassay device for the detection of urinary fibrin/fibrinogen degradation products associated with bladder cancer.

Adrenomyeloneuropathy is a peroxisomal disorder that causes demyelination, with no proven therapy. Oral modified cobratoxin was assessed in a double-blind, randomized, crossover study of eight patients. Treatment was well tolerated. There were no significant improvements with therapy. The authors do not confirm previous anecdotal reports of dramatic improvement with modified cobratoxin.

A patient is described with a novel syndrome characterised by progressive muscular weakness, contractures, pupillary muscle dysfunction, and skeletal deformity. The main myopathological feature was an abundance of tubular aggregates in both type I and type II muscle fibres. Myopathies in which tubular aggregates are the defining feature are rare and either present with progressive muscle weakness or exercise induced myalgia. Tubular aggregate myopathy with symptomatic smooth muscle dysfunction and skeletal deformities has not been described before.

Polymyositis and inclusion body myositis have rarely been described in association with human T cell leukaemia virus type I (HTLV-I) infection. Most of such patients have coexisting HTLV-I associated myelopathy (HAM). Two patients with HTLV-I infection, myopathy, and respiratory failure are described. The muscle biopsy specimen of the first patient bore the histological features of inclusion body myositis and there was no evidence of concurrent myelopathy. The second patient had HAM, and her muscle biopsy showed non-specific myopathic and neuropathic changes. Both patients developed respiratory muscle weakness over eight years after diagnosis of myopathy, leading to hypercapnic respiratory failure requiring mechanical ventilatory support. Respiratory failure as a complication of HTLV-I associated myopathy has not previously been described.

Disproportionate exercise limitation in patients with cardiovascular disease is a common problem faced by clinical cardiologists and other physicians. Symptoms may be attributed to psychological factors or hypothetical pathophysiological mechanisms that are difficult to confirm clinically. This case report describes how the use of metabolic exercise testing in a 28 year old woman with morphologically and haemodynamically mild hypertrophic cardiomyopathy and severe exercise limitation led to the diagnosis of an alternative cause for the patient's symptoms, namely a primary disturbance of the mitochondrial respiratory chain probably caused by a nuclear encoded gene defect.

A 35 year old woman with clinical features of hyperkalaemic periodic paralysis confirmed on provocative exercise testing was investigated. DNA sequence analysis of the gene for the α-subunit of the skeletal muscle voltage gated sodium channel (SCN4A) on chromosome 17q23 identified a point mutation at nucleotide position 2188. This results in a threonine to methionine substitution at amino acid position 704. The patient was intolerant of diuretic medication but showed a striking clinical and electrophysiological improvement with salbutamol therapy. Treatment with β-adrenergic agents should be considered in patients with hyperkalaemic periodic paralysis who are intolerant of, or resistant to, diuretic medications.

GASTROENTEROLOGY 1999;117:1017