LMNA – Congenital muscular dystrophy due to LMNA mutation

LMNA (HGNC:6636) is associated with congenital muscular dystrophy due to LMNA mutation (MONDO_0013178), the most severe skeletal muscle laminopathy. Affected infants present with floppy infant syndrome marked by profound hypotonia, delayed motor milestones, poor head control, and elevated serum creatine kinase. Early recognition of this phenotype is critical for molecular diagnosis and management.

In a cohort of 15 Polish patients from 13 unrelated families, floppy infant syndrome was the first manifestation in all cases (motor delay [HP:0001270]; poor head control [HP:0002421]; infantile muscular hypotonia [HP:0008947]; elevated CK [HP:0003236]) (PMID:33940562). Two additional unrelated patients with dropped head syndrome due to LMNA mutations further support the clinical spectrum (PMID:20886652).

LMNA-related congenital muscular dystrophy follows an autosomal dominant inheritance with 11 de novo and 4 familial cases in the Polish cohort; one family showed segregation in an affected sister, and one parent exhibited somatic mosaicism. The earlier series described two unrelated probands with novel and recurrent LMNA missense variants, confirming AD transmission. In total, 17 probands across 15 families have been reported ([PMID:33940562]; [PMID:20886652]).

Pathogenic variants are exclusively missense changes clustering in the rod and tail domains. Reported alleles include c.116A>G (p.Asn39Ser) ([PMID:33940562]), c.745C>T (p.Arg249Trp), c.1072G>A (p.Glu358Lys), c.1357C>T (p.Arg453Trp), and three novel variants c.121C>G (p.Arg41Gly), c.1127A>G (p.Tyr376Cys), c.1160T>C (p.Leu387Pro) ([PMID:33940562]). Segregation analysis confirmed variant co-segregation in one additional affected relative ([PMID:33940562]).

Functional studies of muscle-related LMNA variants reveal that p.Arg453Trp impairs C2C12 myoblast differentiation, leading to failed myotube formation, cell cycle arrest, and apoptosis, consistent with a dominant-negative mechanism in muscle tissue (PMID:14749366).

Together, the strong genetic evidence from 17 probands and moderate functional data support a pathogenic role for heterozygous LMNA missense variants in autosomal dominant congenital muscular dystrophy. These findings justify inclusion of LMNA in diagnostic panels for neonatal hypotonia and prompt early clinical surveillance, including cardiac monitoring given overlapping laminopathy risks.

Key take-home: Heterozygous pathogenic LMNA missense variants cause autosomal dominant congenital muscular dystrophy, and LMNA sequencing should be prioritized in infants with floppy infant syndrome.

References

• European journal of paediatric neurology • 2021 • Floppy infant syndrome as a first manifestation of LMNA-related congenital muscular dystrophy. PMID:33940562
• Muscle & nerve • 2010 • Two children with "dropped head" syndrome due to lamin A/C mutations. PMID:20886652
• Molecular and cellular biology • 2004 • Expression of a mutant lamin A that causes Emery-Dreifuss muscular dystrophy inhibits in vitro differentiation of C2C12 myoblasts. PMID:14749366

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