Atypical phenotype in two patients with LAMA2 mutations

Area of Science:

• Genetics
• Neurology
• Cardiology

Background:

• Congenital muscular dystrophy type 1A (MDC1A) is primarily caused by mutations in the LAMA2 gene, encoding laminin subunit alpha-2.
• Laminin-α2 is crucial for muscle basement membrane integrity and neuromuscular junction stability.

Observation:

• Two patients presented with partial laminin-α2 deficiency and atypical phenotypes.
• Patient 1 exhibited predominantly central nervous system involvement (cognitive impairment, epilepsy) with normal muscle function.
• Patient 2 displayed significant cardiac dysfunction, rigid spine syndrome, and limb-girdle weakness.

Findings:

• Both patients carried heterozygous LAMA2 variants, including a shared missense mutation (c.2461A>C; p.Thr821Pro) in exon 18.
• Brain MRI proved essential for diagnosis, especially in Patient 1 with initially normal motor skills.
• Phenotypic variability may stem from the distinct combinations of LAMA2 mutations (two missense vs. one missense and one truncating).

Implications:

• This expands the known phenotypic spectrum of LAMA2-related muscular dystrophies.
• Highlights the importance of comprehensive genetic and imaging evaluations for diagnosing atypical presentations.
• Suggests that specific LAMA2 variant combinations influence disease manifestation and severity.