Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

Abstract

Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in a-dystroglycan (a-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent a-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.

Limb girdle muscular dystrophy due to mutations in POMT2

“…Dilated cardiomyopathy has been reported in patients with mutations in the FKTN gene,24 25 and a third of patients with LGMD2I develop cardiomyopathy 26–28. Two patients with POMT1 mutations and a LGMD phenotype have also been reported with ventricular dilatation of the heart 29. In the present study, two cases had reduced LVEF (cases 5 and 7), suggesting that patients with LGMD2N are at risk of developing pump failure.…”

B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype–phenotype associations in the muscular dystrophy-dystroglycanopathies

“…Remarkably, the patients present with psychomotor and speech delay, epilepsy, and behavior problems, but no signs of muscular dystrophy and ocular problems, a presentation not previously associated with MDDG syndromes. Although late-onset manifestation of muscular dystrophy in the presented cases, particularly the younger individuals, cannot be excluded, the muscle defects are typically more prevalent than structural brain anomalies and cognitive impairments in previously reported forms of MDDG [ 18 – 23 ]. Two of the patients from these two families had signs of white matter signal intensity changes at a younger age, but these were not seen at a later age.…”

Computer task performance by subjects with Duchenne muscular dystrophy

“…Several studies have recently described DMD phenotype and genotype, 5 , 6 heart problems, 7 postural adjustment, 8 physical training, 9 multidisciplinary clinical evaluations, 10 , 11 therapeutic treatments, 12 and drug treatment. 13 – 15 However, there is growing interest in the use of computers by subjects with DMD.…”