The clinical spectrum of limb girdle muscular dystrophy. A survey in the Netherlands

A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10-6. The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although half hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement

Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy

Associations between clinical phenotype (muscle weakness, dilated cardiomyopathy) and dystrophin abnormalities in muscle tissue among definite carriers of Duchenne (DMD) and Becker muscular dystrophy (BMD) were investigated. No associations between dystrophin abnormalities and clinical variables in DMD/BMD carriers were found. Because 26% of nonmanifesting carriers have dystrophin-negative fibers, this might be used in suspected DMD/BMD carriers in whom DNA analysis fails to give an answer about their carrier ris

A new hyperekplexia family with a recessive frameshift mutation in the GLRA1 gene

Genetics of disease, diagnosis and treatmen

Cardiac involvement in Dutch patients with sarcoglycanopathy: a cross-sectional cohort and follow-up study

The aim of this study is to describe the frequency, nature, severity, and progression of cardiac abnormalities in a cohort of Dutch sarcoglycanopathy patients. In this cross-sectional cohort study, patients were interviewed using a standardized questionnaire and assigned a functional score. Electrocardiography (ECG), echocardiography, and 24-h ECG were performed. Twenty-four patients with sarcoglycanopathy had a median age of 25 years (range, 8-59 years). Beta blockers were used by 13%, and 17% used angiotensin-converting enzyme inhibitors. ECG abnormalities were present in 5 (21%), and 4 (17%) fulfilled the criteria for dilated cardiomyopathy (DCM). There were no significant differences in median age or severity of disease between patients with or without DCM. Eleven patients were examined earlier. Median follow-up time was 10 years. Two of the 11 patients (18%) developed DCM during follow-up. Seventeen percent of the patients with sarcoglycanopathy were found to have dilated cardiomyopathy. We recommend biannual cardiac monitoring, including ECG and echocardiograph

The validity of ratings of perceived exertion for cross-modal regulation of swimming intensity

Non-dystrophic myotonic syndromes represent a heterogeneous group of clinically quite similar diseases sharing the feature of myotonia. These syndromes can be separated into chloride and sodium channelopathies, with gene-defects in chloride or sodium channel proteins of the sarcolemmal membrane. Myotonia has its basis in an electrical instability of the sarcolemmal membrane. In the present study we examine the discriminative power of the resulting myotonic discharges for these disorders. Needle electromyography was performed by an electromyographer blinded for genetic diagnosis in 66 non-dystrophic myotonia patients (32 chloride and 34 sodium channelopathy). Five muscles in each patient were examined. Individual trains of myotonic discharges were extracted and analyzed with respect to firing characteristics. Myotonic discharge characteristics in the rectus femoris muscle almost perfectly discriminated chloride from sodium channelopathy patients. The first interdischarge interval as a single variable was longer than 30 ms in all but one of the chloride channelopathy patients and shorter than 30 ms in all of the sodium channelopathy patients. This resulted in a detection rate of over 95%. Myotonic discharges of a single muscle can be used to better guide toward a molecular diagnosis in non-dystrophic myotonic syndromes

ANO5 mutations in the Dutch limb girdle muscular dystrophy population

<p>A Dutch cohort of 105 limb girdle muscular dystrophy (LGMD) patients were subject to subsequent genetic investigations. In half the families a causative mutation was found. Recently mutations were identified in ANO5 causing LGMD2L and Miyoshi-like myopathy (MMD3), but could also be found in patients with hyperCKemia only. Therefore, we analysed the index cases of the remaining 31 as yet undiagnosed families from our previously described cohort of LGMD patients for the presence of ANO5 mutations. Detailed history and neurological examination were available for all patients. Serum creatine kinase (CK) activity, skeletal muscle computed tomography (CT) and cardiological investigations were performed. Mutations in ANO5 were found in 16% of the families: 11 index patients and two sibs, eight males and five females. The founder mutation c.191dupA was present in 8 out of 13 patients. Ten different pathogenic mutations were identified of which seven were novel: five missense and two splice site mutations. The age of these patients ranged from 26 to 69 years and the age of onset varied from 21 to 57 years. Symptoms at onset were related to proximal leg weakness. The weakness was slowly progressive. Calf hypertrophy was present in three patients. Males were more severely affected than females. Serum CK activity was highly elevated in the early stage of disease and moderately increased in later stages. Muscle biopsy showed predominantly dystrophic changes. One patient had hypertrophic cardiomyopathy, two others had intraventricular septum thickening. (C) 2013 Elsevier B.V. All rights reserved.</p>

Local dystrophin restoration with antisense oligonucleotide PRO051

Background: Duchenne's muscular dystrophy is associated with severe, progressive muscle weakness and typically leads to death between the ages of 20 and 35 years. By inducing specific exon skipping during messenger RNA (mRNA) splicing, antisense compounds were recently shown to correct the open reading frame of the DMD gene and thus to restore dystrophin expression in vitro and in animal models in vivo. We explored the safety, adverse-event profile, and local dystrophin-restoring effect of a single, intramuscular dose of an antisense oligonucleotide, PRO051, in patients with this disease. Methods: Four patients, who were selected on the basis of their mutational status, muscle condition, and positive exon-skipping response to PRO051 in vitro, received a dose of 0.8 mg of PRO051 injected into the tibialis anterior muscle. A biopsy was performed 28 days later. Safety measures, composition of mRNA, and dystrophin expression were assessed. Results: PRO051 injection was not associated with clinically apparent adverse events. Each patient showed specific skipping of exon 51 and sarcolemmal dystrophin in 64 to 97% of myofibers. The amount of dystrophin in total protein extracts ranged from 3 to 12% of that found in the control specimen and from 17 to 35% of that of the control specimen in the quantitative ratio of dystrophin to laminin alpha 2. Conclusions: Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasibl

Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients

In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10 −6 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes