Ibrahim Mahjneh

A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B

The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B ). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name `dysferlin combines the role of the gene in producing muscular dystrophy with its C. elegans homology.

Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies)

Dysferlin is the protein product of the gene (DYSF) that is defective in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Calpain 3 is the muscle-specific member of the calcium activated neutral protease family and primary mutations in the CAPN3 gene cause limb girdle muscular dystrophy type 2A. The functions of both proteins remain speculative. Here we report a secondary reduction in calpain 3 expression in eight out of 16 patients with a primary dysferlinopathy and clinical features characteristic of limb girdle muscular dystrophy type 2B or Miyoshi myopathy. Previously CAPN3 analysis had been undertaken in three of these patients and two showed seemingly innocuous missense mutations, changing calpain 3 amino acids to those present in the sequences of calpains 1 and 2. These results suggest that there may be an association between dysferlin and calpain 3, and further analysis of both genes may elucidate a novel functional interaction. In addition, an association was found between prominent expression of smaller forms of the 80 kDa fragment of laminin alpha 2 chain (merosin) and dysferlin-deficiency.

Dysferlinopathy (LGMD2B): a 23-year follow-up study of 10 patients homozygous for the same frameshifting dysferlin mutations

The limb-girdle muscular dystrophies are a group of inherited neuromuscular disorders which are clinically and genetically heterogeneous. We have been able to carry out a follow-up study on 10 patients from a large Palestinian family with a confirmed mutation in the dysferlin gene. These patients have been followed for more than 23 years since the onset of the disease. They all had normal developmental milestones. The onset of the disease was usually in the second decade, more rarely in the third and fourth decades. The first symptoms were difficulty with running and climbing stairs. Patients showed a distinct type of gait due to the unique pattern of muscle involvement which was characterised by early involvement of the posterior muscle compartment of the thighs and legs (hamstrings, adductors, gastrocnemius and soleus). The shoulder and upper limb musculature became involved later, especially supra and infraspinatus and biceps. In the early stages of disease these patients may clinically show only proximal lower limb-girdle muscle weakness; however, the use of muscle imaging techniques were very important, always detecting in these patients also distal lower limb muscle involvement, so that the pattern of muscle involvement found in dysferlin deficiency may not strictly conform to the definition of limb-girdle muscular dystrophy. The pattern of muscular dystrophy is essentially uniform and has clearly distinct features (involving mainly the initial pattern of muscle involvement and the mode of gait) which differ significantly from the well reported clinical features associated with sarcoglycanopathy, calpainopathy and Miyoshi myopathy.

The phenotype of chromosome 2P-linked limb-girdle muscular dystrophy

This study reports on a detailed clinical, electrophysiological, muscle computed tomography (CT) and laboratory investigation carried out on five families with definite linkage to chromosome 2p. Some clinical and laboratory features were common to most of the patients, such as the very high serum creatine kinase (CK) levels (mean 43.70 times the normal). The onset was most frequently in the late teens or early twenties with weakness and wasting of the pelvic girdle muscles. All patients had normal motor milestones and had not complained of any symptoms of muscle disease in early childhood. The clinical course was variable both between and within some families, but was most often slowly progressive. Some variability in the pattern of muscle involvement between the different families has also been observed.

A large inbred Palestinian family with two forms of muscular dystrophy

This paper reports the results of a clinical, genetic and histopathological study of 19 patients belonging to a large inbred Palestinian family living in Um-El-Fahem, a town located in Israel, which is solely inhabited by Arabs. Their custom of marrying only among relatives has kept the genetic homogeneity of the families intact. There were ten cases of congenital muscular dystrophy (CMD) and nine cases of adult limb-girdle muscular dystrophy (LGMD) belonging to two generations of the same family. Both forms showed autosomal recessive inheritance. The patients with congenital muscular dystrophy had generalized muscular weakness and hypotonia at birth without arthrogryposis or CNS involvement and then had a relatively benign evolution with stabilization of the clinical picture at different ages and variable degree of severity. Muscle biopsy showed a dystrophic pattern. The other nine patients presented with the picture of adult limb-girdle muscular dystrophy but with an unusual tendency to the stabilization of symptoms.

Limb‐girdle muscular dystrophy: a follow‐up study of 79 patients

The limb‐girdle muscular dystrophies (LGMD) are autosomally inherited neuromuscular diseases. Recently six different loci for LGMD have been reported: 5q (LGMD1A), 15q (LGMD2A), 2p (LGMD2B), 13q (LGMD2C), 17q (LGMD2D) and 4p‐14‐q21.2 (LGMD2E) respectively. We have studied 79 patients affected by LGMD during the period 1976 to 1995. All patients were examined clinically, and various investigations, including genetics were performed. According to their data we divided them as follow: 1) Cases with autosomal recessive inheritance (34.19%) of these two families are linked to chromosome 2p and the others were subdivided according to the age at onset into childhood LGMD and juvenile‐adult LGMD; 2) Cases with dominant inheritance (13.92%); 3) Sporadic cases (51.89%). Onset of symptoms occurs from the first to the third decade. The clinical course varies considerably, as does the degree of disability. Our study allowed to identify two different groups of patients who relatively homogeneous with respect to their clinical and laboratory characteristics.