The proteoglycan–dystrophin complex in genetic cardiomyopathies—lessons from three siblings with limb-girdle muscular dystrophy-2I (LGMD-2I)

Abstract

The term limb-girdle muscular dystrophy (LGMD) is used to describe neuromuscular disorders that are characterized by muscle weakness and wasting predominantly affecting the extremities (proximal to a greater extent than distal). The LGMD family consists of seven autosomal-dominant and 13 autosomal-recessive forms, and a distinction between the different types on clinical criteria alone is difficult and requires protein analysis in muscle biopsies and genetic studies. LGMD has to be distinguished from the much more frequent X-linked dystrophinopathies (e.g. Duchenne muscular dystrophy, DMD) although the clinical picture may be quite similar. Former studies suggested that the prevalence rate of all forms of LGMD disorders is *7:100.000 [1]. However, since diagnostic capabilities have tremendously improved in the past years, a higher prevalence rate is likely. LGMD-2I is one of the autosomal recessive forms of the LGMD family and caused by mutations in the Fukutinrelated protein gene (FKRP) on chromosome 19q. The most common genetic finding in northern Europe is the homozygous mutation (C826A) in FKRP and is mostly associated with a milder phenotype of muscular dystrophy compared with those who are compound heterozygous. FKRP encodes a putative Golgi-based glycosyltransferase and is involved in posttranslational glycosylation of a-dystroglycan. Mutations in FKRP lead to a glycosylation defect and subsequently downregulation of a-dystroglycan which constitutes an essential component of the proteoglycan–dystrophin complex. The clinical picture of patients with LGMD-2I resembles DMD. Major causes of morbidity and mortality are cardiac and/or respiratory failure. Respiratory involvement with a forced vital capacity lower than 75% has been described in about 50% of affected individuals in one prior study [2]. Although previous studies suggested cardiac involvement to be a frequent finding (in up to 60%) in patients with LGMD-2I [2, 3], the morphological pattern of cardiomyopathy as well as the underlying pathophysiology has not been sufficiently evaluated so far. Currently, we are performing a cardiovascular magnetic resonance imaging (CMR) study on patients with neuromuscular disorders with special focus on the presence and presentation pattern of cardiomyopathy. The following three siblings with genetically proven LGMD-2I (homozygous C826A mutation on chromosome 19q3) participated in this ongoing research project and underwent a comprehensive CMR study on a clinical scanner (1.5-T Sonata, Siemens, Germany) after obtaining written informed consent. The first and youngest patient, a 38-year-old male suffered only from minor skeletal muscle weakness (predominantly in the lower extremities) with rapid exhaustion following exercise, and he was still able to walk and slowly climb stairs. Already 5 years previously, a biventricular dilation with impaired left ventricular (LV) systolic function was diagnosed and he was at that time taking an ACEinhibitor and a b-blocker. Apart from minor dyspnea on exertion, he had no cardiac complaints. In particular, there were no chest pain symptoms and no clinical signs suggestive of myocarditis. A. Yilmaz (&) S. Rosch U. Sechtem Division of Cardiology, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, 70376 Stuttgart, Germany e-mail: ali.yilmaz@rbk.de