Dihydropyridine Receptor Congenital Myopathy In A Consangineous Turkish Family

Abstract

Dihydropyridine receptor congenital myopathy is a recently described congenital myopathy caused by dominant or recessive mutations in the CACNA1S gene. To date, only 11 cases from 7 families were described in a single report. Here, we describe a consanguineous family with three affected children, presenting congenital hypotonia, contractures, ophthalmoplegia and respiratory insufficiency, with a novel homozygous mutation in the CACNA1S gene. They also showed cognitive delay, pes equinovarus deformity and neurogenic changes that have not been associated with this myopathy in the previous reports. This report expands the phenotypic spectrum of dihydropyridine receptor congenital myopathy and underscores the importance of whole exome sequencing in early onset neuromuscular disorders.

Fig. 1

Muscle biopsy of Proband 2: A. Note the marked variation in fiber size and shape (HE × 200). There were also hypercontracted fibers and increased fibrous tissue. B. There are no marked myofibrillary irregularities (NADH-TR × 200), C. Normal sarcolemmal expression of merosin as well as grouping of large and small myofiber fascicles (DAB × 200), D. Note the presence of huge type 1 fibers with fast myosin antibody (DAB × 100).

Fig. 2

A-B: proband 2 with tracheostomy and nasogastric feeding. No anti-gravity movements are avaliable. She also has congenital onset pes equinus deformity. C: proband 3 has severe respiratory insufficiency. She also has congenital onset pes equinus deformity.

Fig. 3

a) Pedigree and Sanger sequencing validation of WES results for CACNA1S c.2366G>A mutation. b) ClustalOmega multiple protein sequence alignment of the regions flanking the “critical region”, which is required for binding to Stac3, of human CACNA1S, human CACNA1C, human CACNA1D, mouse CACNA1S and zebrafish CACNA1Sb. Note that the region C-terminal to the critical region, that contains R789, is highly conserved. Darker colors indicate higher level of consensus between sequences. Lower panel indicates the level of consensus as a bar-graph.

Fig. 4

Localization of R789H mutation on the cytosolic loop II-III and distribution of previously reported CACNA1S/Cav1.1 mutations.