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Laminin alpha 2-chain gene mutations in two siblings presenting with limb-girdle muscular dystrophy
I Naom1, M D'Alessandro, C A Sewry
1Department of Paediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Insights
Two siblings initially diagnosed with muscular dystrophy were found to have merosin-deficient congenital muscular dystrophy due to LAMA2 gene mutations. Partial laminin alpha 2 deficiency can present with milder symptoms, mimicking limb-girdle muscular dystrophy.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Muscular dystrophies encompass a group of genetic disorders characterized by progressive muscle weakness.
- Limb-girdle muscular dystrophy (LGMD) and Duchenne muscular dystrophy (DMD) are common forms with distinct genetic origins.
- Merosin-deficient congenital muscular dystrophy (MDC1A) is typically associated with severe early-onset muscle weakness.
Observation:
- Two siblings initially diagnosed with Duchenne muscular dystrophy and limb-girdle muscular dystrophy, respectively, presented with static conditions.
- Recent investigations revealed slowed peripheral motor nerve conduction velocities and white matter abnormalities on brain MRI, suggestive of merosin-deficient CMD.
- Immunolabeling showed reduced expression of laminin alpha 2, particularly a 300-kDa fragment, indicating partial deficiency.
Findings:
- Genetic analysis identified two LAMA2 gene mutations in the siblings: a splice site mutation affecting exon 29 and a nonsense mutation in exon 37.
- These mutations resulted in partial skipping of exon 29, preserving the open reading frame, and a premature stop codon.
- The identified mutations led to a milder phenotype than classical merosin-deficient CMD, with preserved dystrophin and sarcoglycan expression.
Implications:
- Mutations in the LAMA2 gene can cause milder forms of congenital muscular dystrophy with later onset and slower progression.
- Partial laminin alpha 2 deficiency should be considered in the differential diagnosis of limb-girdle muscular dystrophy, especially when typical LGMD markers are absent.
- These findings expand the phenotypic spectrum of LAMA2-related muscular dystrophies and underscore the importance of genetic testing for accurate diagnosis.
Abstract:
We report two siblings, an 11-year-old boy and his 7-year-old sister, referred to us with a diagnosis of muscular dystrophy. The boy presented at 22 months with delay in walking. A very high serum creatine kinase (CK) level and a dystrophic muscle biopsy lead to a diagnosis of Duchenne muscular dystrophy prior to the identification of the dystrophin gene. Two years later his sister presented with similar problems. A diagnosis of limb-girdle muscular dystrophy was made when they were shown to have inherited different X-chromosomes and normal expression of dystrophin and all sarcoglycans. Their conditions remained static. Recently a slowing of the peripheral motor nerve conduction velocities and T2-weighted brain magnetic resonance imaging showed increased signal of the white matter, both of which are features of merosin-deficient congenital muscular dystrophy. Immunolabelling using a C-terminal laminin alpha 2 chain antibody showed a reduction in expression, while labelling with another antibody that recognises a 300-kDa fragment showed a very significant reduction. Mutational analysis of the LAMA2 gene showed two mutations: one was a G-->C point mutation at position -1 of intron 28 acceptor splicing site. This mutation induced activation of a cryptic splice at nucleotide 4429 of exon 29 and partial skipping of this exon, with conservation of the open reading frame. The other was a nonsense mutation due to a C_T transition at position 5525 of the cDNA sequence (exon 37), resulting in a stop codon. These data confirm that mutations of the LAMA2 gene that do not completely disrupt the production of the protein can give rise to phenotypes considerably milder than classical merosin-deficient congenital muscular dystrophy. Partial laminin alpha 2 deficiency should be considered in the differential diagnosis of limb-girdle muscular dystrophy.