Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2

Abstract

BackgroundCongenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin α2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. The clinical spectrum of the disease is more heterogeneous than previously thought, particularly in terms of motor achievement and disease progression. We investigated clinical findings and performed molecular genetic analysis in 3 families from Saudi Arabia and 1 from Sudan in whom congenital muscular dystrophy 1A was suspected based on homozygosity mapping and laminin α2 chain deficiency.MethodsWe investigated 9 affected individuals from 1 Sudanese and 3 Saudi families in whom MDC1A was suggested by clinical, neuroimaging and/or pathological findings and by homozygosity mapping at the LAMA2 locus. Morphological and immunohistochemical analysis were performed in 3 patients from the 3 Saudi families. SSCP analysis, DNA sequencing and microsatellite analysis were carried out in the 4 index cases.ResultsA previously described mutation in the LAMA2 gene, a homozygous T > C substitution at position +2 of the consensus donor splice site of exon 26, was found in the 4 index patients. Clinical evaluation of 9 patients from the 4 families revealed variable disease severity particularly as regards motor achievement and disease progression. Microsatellite analysis showed an identical mutation-associated haplotype in the 4 index cases indicating a founder effect of the mutation in all 4 families.ConclusionsOur data provide further evidence that the clinical spectrum of MDC1A due to a single mutation is heterogeneous, particularly in terms of motor achievement and disease progression, making it difficult to give a reliable prognosis even in patients with identical LAMA2-associated haplotype. The c.3924 + 2 T > C mutation to date has been found only in patients originating from the Middle East or Sudan; therefore laminin 2 chain deficiency in patients from those regions should initially prompt a search for this mutation.

LAMA2‐related myopathy: Frequency among congenital and limb‐girdle muscular dystrophies

“…A total of 6 adult CMD patients and 126 adult patients with recessive LGMD are followed in the Neuromuscular Clinic, Rigshospitalet, and all CMD patients were classified diagnostically with either Ullrich myopathy or rigid spine syndrome due to mutations in SEPN1. In the LGMD cohort, 110 of 126 cases were confirmed genetically to be 1 of various subtypes of LGMD; 55 LGMD2I, 16 LGMD2A, 4 LGMD2B, 14 LGMD2L, 10 LGMD2D, 7…”

“…Most children with LAMA2 CMD do not acquire independent ambulation, develop proximal joint contractures and respiratory failure with recurrent chest infections, and the mortality in the first years of life is high . Milder cases of LAMA2 CMD have also been described …”

“…10 Milder cases of LAMA2 CMD have also been described. 2,5,15,16 The prevalence of LGMD due to mutations in LAMA2 is unknown, but it is believed to be very rare. Patients with an LGMD phenotype show a mild phenotype with late onset proximal muscle weakness and delayed motor milestones but achieve independent ambulation.…”

Merosin-negative congenital muscular dystrophy: Report of five cases

“…In literature, several studies have reported respiratory insufficiency, feeding difficulties, cardiomyopathy, sensory and motor demyelinating neuropathy, seizure, and external ophthalmoplegia. [ 3 6 7 8 ]…”

“…Di Blasi et al . [ 8 ] reported 9 patients with MDC1A from 1 Sudanese and 3 Saudi families. Five of the 9 patients achieved independent walking.…”