Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5.

OBJECTIVE: Description of 8 new ANO5 mutations and significant expansion of the clinical phenotype spectrum associated with previously known and unknown mutations to improve diagnostic accuracy. METHODS: DNA samples of 101 patients in 95 kindreds at our quaternary referral center in Finland, who had undetermined limb-girdle muscular dystrophy (LGMD), calf distal myopathy, or creatine kinase (CK) elevations of more than 2,000 IU/L, were selected for ANO5 genetic evaluation, and the clinical findings of patients with mutations were retrospectively analyzed. RESULTS: A total of 25 patients with muscular dystrophy caused by 11 different recessive mutations in the ANO5 gene were identified. The vast majority of mutations, 8 of 11, proved to be previously unknown new mutations. The most frequent mutation, c.2272C>T (p.R758C), was present in 20 patients. The phenotypes associated with this and the common European mutation, c.191dupA, varied from nearly asymptomatic high hyperCKemia to severe LGMD with consistently milder phenotypes in female patients. CONCLUSIONS: Mutations in ANO5 are a frequent cause of undetermined muscular dystrophy, with both distal and proximal presentation. Other types include high hyperCKemia, myalgia, or calf hypertrophy over decades without significant weakness, especially in female patients. Mutations are distributed all over the gene, indicating that muscular dystrophy caused by ANO5 can be expected to occur in all populations.

Autonomic nerve function in adults with cyclic vomiting syndrome: a prospective study.

BACKGROUND: Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder that is characterized by recurrent episodes of intense vomiting. There are several postulated mechanisms involved in its pathogenesis and one potential explanation for this disorder may be linked to autonomic dysfunction. The aim of our study was to evaluate autonomic nerve function in patients with CVS prospectively. METHODS: We tested the sympathetic nervous system through postural changes in heart rate (HR) and blood pressure and the thermoregulatory sweat test. The parasympathetic nervous system was tested through the HR response to deep breathing (R-R variability on EKG). KEY RESULTS: A total of 20 patients who met Rome III criteria for CVS, 14 (70%) women and 6 (30%) men, and 20 controls were enrolled in the study. A total of 17 (85%) CVS subjects and 2 (10%) controls had abnormalities on thermoregulatory sweat testing (P < 0.001). A total of 7 (35%) patients and one control subject had evidence of postural tachycardia (P = 0.04) with an increase in HR > 30 on standing. Of the subjects, 18 (90%) had either abnormal sudomotor function or postural tachycardia or both. The HR response to deep breathing was normal in 19 (95%) subjects with CVS and 18 (95%) controls. CONCLUSIONS & INFERENCES: The results of this study suggest that the majority of subjects (90%) with CVS have impairment of the sympathetic nervous system with postural tachycardia and/or sudomotor dysfunction while parasympathetic nerve function appears to be intact. These findings of dysautonomia in CVS have implications in both the diagnosis and treatment of these patients.

A comparison of stroke risk factors in patients enrolled in stroke prevention trials.

The high prevalence of stroke risk factors may explain, in part, the high incidence of stroke in African Americans. To further investigate the role of stroke risk factors, we compared stroke risk factor profiles of patients in the African-American Antiplatelet Stroke Prevention Study (AAASPS) with those in other stroke prevention studies in which the enrollees were predominately white. The baseline characteristics of the AAASPS enrollees obtained from an interim AAASPS database of 1,087 patients from 65 centers in the U.S. between December 1995 and June 1999 was compared to the baseline characteristics of 53,293 predominantly non-African American patients enrolled in 23 other stroke prevention studies (pNAA). Percentages were reported for qualitative characteristics, and means and standard deviations (SDs) for quantitative characteristics. For selected qualitative characteristics, 95% confidence intervals were given for population percentages in each study. The comparison of baseline characteristics showed that hypertension was more prevalent in AAASPS (84% [95% CI 82.2, 86.61) compared to pNAA trial patients (range of 27% to 67%). Diabetes mellitus was more common in AAASPS (39.1%) compared to pNAA trial patients (17.1%). Cardiac disease, however, was less common in AAASPS than in pNAA trials. The frequency of baseline characteristics of AAASPS patients is different from those of pNAA studies. Risk factor profiles are important as they may help to predict stroke subtype and outcome. Furthermore, the differences in baseline characteristics may portend differences in response to treatment and incidence of adverse events.

HMG-CoA Reductase Inhibitor Myopathy: Clinical, Electrophysiological, and Pathologic Data in Five Patients.

OBJECTIVES: To define the clinical, electrophysiological, and pathologic features of the myopathy associated with the use of HMG CoA reductase inhibitors. METHODS: Five patients with myopathy associated with HMG CoA reductase inhibitors were evaluated. Complete histories, physical examinations, manual muscle testing, serum creatine kinase, urine myoglobin measurements, electrodiagnostic studies, and muscle biopsy were performed. RESULTS: Consistent features in our patients included a subacute onset of myalgias and weakness, electromyography demonstrating electrical myotonia, elevated creatine kinase levels, and in some patients myoglobinuria despite a relative lack of muscle necrosis on muscle biopsy and preserved myofibrillatory architecture by electron microscopy. All patients experienced resolution of symptoms within 3 weeks of drug discontinuation. CONCLUSIONS: We postulate that the constellation of clinical, electrophysiological, and pathologic findings among our patients with HMG CoA reductase inhibitor myopathy may be explained by the early toxic effects of HMG CoA reductase inhibitors on muscle membrane organelles and sarcolemmal function. Patients on concurrent therapy with cyclosporine, gemfibrozil, and antifungal agents of the azole groups are at an increased risk of developing this toxic myopathy.