Novel cardiovascular findings in association with a POMT2 mutation: three siblings with α-dystroglycanopathy

Abstract

Dystroglycanopathies are a genetically heterogeneous subset of congenital muscular dystrophies that exhibit autosomal recessive inheritance and are characterized by abnormal glycosylation of a-dystroglycan. In particular, POMT2 (protein O-mannosyltransferase-2) mutations have been identified in congenital muscular dystrophy patients with a wide range of clinical involvement, ranging from the severe muscle-eye-brain disease and Walker-Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. Cardiovascular disease is thought to be uncommon in congenital muscular dystrophy, with rare reports of cardiac involvement. We describe three brothers aged 21, 19, and 17 years with an apparently homozygous POMT2 mutation who all presented with congenital muscular dystrophy, intellectual disabilities, and distinct cardiac abnormalities. All three brothers were homozygous for a p.Tyr666Cys missense mutation in exon 19 of the POMT2 gene. On screening echocardiograms, all siblings demonstrated significant dilatation of the aortic root and depressed left ventricular systolic function and/or left ventricular wall motion abnormalities. Our report is the first to document an association between POMT2 mutations and aortopathy with concomitant depressed left ventricular systolic function. On the basis of our findings, we suggest patients with POMT2 gene mutations be screened not only for myocardial dysfunction but also for aortopathy. In addition, given the potential for progression of myocardial dysfunction and/or aortic dilatation, longitudinal surveillance imaging is recommended both for patients with disease as well as those that have normal baseline imaging.

Limb girdle muscular dystrophy due to mutations in POMT2

“…In accordance with this, Martinez et al recently reported three siblings with a CMD phenotype and a homozygous c.1997A>G mutation in POMT2 , which was also present in case 3 in our study. The three siblings had reduced LVEF, dilatation of the aortic root and/or left ventricular wall motion abnormalities 30. These and our findings suggest that regular cardiac investigations should be carried out in patients with LGMD2N.…”

Heart Disease in Disorders of Muscle, Neuromuscular Transmission, and the Nerves

“…CI has been reported in various types of CMD. Cardiac involvement, in particular, appears to occur in patients carrying mutations in the LMNA (arrhythmias, dCMP), 72) COL6A (dCMP, systolic dysfunction requiring HTX), 73) 74) POMT1 (aortic root ectasia, systolic dysfunction), 75) CHKB (dCMP, systolic dysfunction, congenital heart defects), 76) and LAMA2 (dCMP) 77) 78) genes. Additionally, CI has been reported in patients with Fukuyama congenital muscular dystrophy (dCMP, systolic dysfunction) due to FKTN mutations, 79) congenital muscular dystrophy with alpha-dystroglycan deficiency (dCMP, CCDs, mitral regurgitation), 80) and in merosin-positive congenital muscular dystrophy (systolic and diastolic dysfunction).…”

Structure of the eukaryotic protein O-mannosyltransferase Pmt1−Pmt2 complex

“…Based on the clinical phenotypes, these diseases include Walker-Warburg syndrome, muscle-eye-brain disease, and less severe forms of muscular dystrophy. We surveyed the reported POMT1–POMT2 mutations of hundreds of CMD patients and identified dozens of missense mutations in POMT1 and POMT2 42–65 (Supplementary Table 1). Many of these mutations either reduced or abolished the enzyme activity.…”