LMNA – Charcot-Marie-Tooth Disease Type 2B1

LMNA encodes the A-type lamins critical for nuclear envelope integrity. Charcot-Marie-Tooth disease type 2B1 (CMT2B1) is an autosomal recessive axonal neuropathy characterized by distal muscle weakness, foot deformities, and reduced large myelinated fibers. Early mapping localized CMT2B1 to 1q21.2–q21.3, implicating LMNA in peripheral nerve maintenance.

Genetic evidence supports a recessive loss-of-function mechanism. Homozygosity mapping in two consanguineous Algerian families (Zmax = 4.14) and a third unrelated family identified a unique LMNA missense variant, c.892C>T (p.Arg298Cys), in all affected members ([PMID:11799477]). Subsequent screening in 25 additional North-Western African families confirmed a founder effect for c.892C>T in 42 homozygous individuals ([PMID:18549403]). Further phenotypic studies describe 21 patients from 7 unrelated families demonstrating marked variability in age at onset and disease severity, yet all carried homozygous p.Arg298Cys ([PMID:14607793]).

Inheritance is autosomal recessive with robust segregation: 63 affected individuals across 32 families confirm full co-segregation of the homozygous variant and CMT2B1. All cases showed concordance between genotype and phenotype, without heterozygous carriers manifesting neuropathy.

The variant spectrum for CMT2B1 is restricted to a single recurrent missense allele, c.892C>T (p.Arg298Cys), which substitutes a conserved arginine in the rod domain of lamin A/C. No other LMNA variants have been reported for this subtype, underscoring the allelic specificity and founder nature of p.Arg298Cys.

Functional studies reinforce the pathogenic mechanism. Lmna-null (–/–) mice exhibit peripheral nerve ultrastructural abnormalities—reduced axon density, axonal enlargement, and unmyelinated fibers—closely recapitulating the human CMT2B1 phenotype ([PMID:11799477]). These data implicate loss of lamin A/C in axonal integrity and nerve fiber maintenance.

No conflicting clinical or genetic data have been reported. The cumulative evidence over two decades, including >60 affected individuals, homozygous segregation in multiple families, and a faithful mouse model, supports a definitive gene-disease relationship. Key Take-home: Homozygous LMNA c.892C>T (p.Arg298Cys) is a definitive cause of autosomal recessive CMT2B1, informing diagnosis, genetic counseling, and targeted research.

References

• American Journal of Human Genetics • 2002 • Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. PMID:11799477
• Annals of Human Genetics • 2008 • Founder effect and estimation of the age of the c.892C>T (p.Arg298Cys) mutation in LMNA associated to Charcot-Marie-Tooth subtype CMT2B1 in families from North Western Africa. PMID:18549403
• Brain • 2004 • Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. PMID:14607793

Evidence Based Scoring (AI generated)