Autosomal Dominant Limb-girdle Dystrophy Research Articles

Evidence for anticipation in autosomal dominant limb-girdle muscular dystrophy.

Anticipation, an increase in severity or decrease in age of onset (AO) inherent in the transmission of the disease gene from affected parent to affected child, has been increasingly described...

Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of myopathies, including autosomal dominant and recessive forms. To date, two autosomal dominant forms have been recognized: LGMD1A, linked to chromosome 5q, and LGMD1B, associated with cardiac defects and linked to chromosome 1q11-21. Here we describe eight patients from two different families with a new form of autosomal dominant LGMD, which we propose to call LGMD1C, associated with a severe deficiency of caveolin-3 in muscle fibres. Caveolin-3 (or M-caveolin) is the muscle-specific form of the caveolin protein family, which also includes caveolin-1 and -2. Caveolins are the principal protein components of caveolae (50-100 nm invaginations found in most cell types) which represent appendages or sub-compartments of plasma membranes. We localized the human caveolin-3 gene (CAV3) to chromosome 3p25 and identified two mutations in the gene: a missense mutation in the membrane-spanning region and a micro-deletion in the scaffolding domain. These mutations may interfere with caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane.

A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement

Sixty-five members of three families with limb girdle muscular dystrophy (LGMD) underwent neurological, cardiological, and ancillary investigations. Thirty-five individuals were diagnosed as having slowly progressive autosomal dominant LGMD. Symmetrical weakness started in the proximal lower limb muscles, and gradually upper limb muscles also became affected. Early contractures of the spine were absent. Contractures of elbows and Achilles tendons were either minimal or late. Serum creatine kinase activity was normal to moderately elevated. Electromyogram and muscle biopsy were consistent with a mild muscular dystrophy. Cardiological abnormalities, found in more than one-half the patients, included dysrhythmias and atrioventricular (AV) conduction disturbances presenting as bradycardia, syncopal attacks necessitating pacemaker implantation, and sudden cardiac death. There was a significant relation between the severity of AV conduction disturbances and age. In nearly all patients, neuromuscular symptomatology preceded cardiological involvement. The early recognition of this previously not described, autosomal dominant LGMD with life-threatening cardiac involvement offers an opportunity for therapeutic intervention.

A YAC contig of approximately 3 Mb from human chromosome 5q31-->q33.

The human chromosome 5q31--q33 region contains an interesting cluster of growth factor and receptor genes. In addition, several genetic disease loci have been localized within this region, but have not as yet been isolated as molecular clones. These include those loci involved in autosomal dominant limb-girdle muscular dystrophy, diastrophic dysplasia, Treacher Collins syndrome, and myeloid disorders associated with the 5q- syndrome. A yeast artificial chromosome (YAC) contig of this region would assist in the further localization and isolation of these genes. We have used YACs isolated from the Washington University and Centre d'Etude du Polymorphisme Humain YAC libraries, including YACs from the large insert (mega) YAC library to build a contig greater than 3 Mb in size. An STS content strategy coupled with limited walking from YAC ends was used to isolate 22 overlapping YACs with as much as sixfold coverage. A total of 20 STSs, derived from genes, anonymous sequences, and vector Alu-PCR or inverse PCR products, were used to compile this contig. The order of loci, centromere-GRL-D5S207-D5S70-D5S545-D5S546- D5S547-D5S68-D5S548-D5S210-D5S549- D5S686-ADRB2-D5S559-CSF1R-D5S551-RPS14+ ++-D5S519-SPARC-telomere, was derived from the overlapping clones. This contig and clones derived from it will be useful substrates in selecting candidate cDNAs for the disease loci in this interval.

Limb girdle muscular dystrophy with autosomal dominant inheritance

We describe a patient suffering from limb-girdle muscular dystrophy with autosomal dominant inheritance proved by the presence of other similar cases in both sexes scattered over 4 generations of his family tree. In all patients the symptoms appeared in adult age and pelvi-femoral preceded scapulo-humeral involvement. Clinical expressivity has been variable, but rather benign without any reduction in life expectancy. Myopathic changes with vacuoles were present in muscle on light and electron microscopic examination. In the literature we found at least another 5 genealogies with autosomal dominant LGMD which had similar clinical and pathological features to those of our patient.

Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy is a syndrome of progressive myopathic weakness affecting shoulder and hip girdle and proximal arm and leg muscles. The disease occurs either sporadically or inherited as an autosomal recessive trait. Autosomal dominant inheritance is rare. We report a large family with apparent autosomal dominant inheritance. Sixteen members were affected with a disease characterized by proximal weakness, leg greater than arm, onset in the third decade, elevated CK and CK MB levels, and myopathic EMGs and muscle biopsies. Linkage analysis revealed no conclusive linkage.