The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and 
genetically heterogeneous hereditary motor and sensory neuropathies, which are 
mainly characterized by muscle weakness and wasting, foot deformities, and 
electrophysiological, as well as histological, changes. A subtype, CMT2, is 
defined by a slight or absent reduction of nerve-conduction velocities together 
with the loss of large myelinated fibers and axonal degeneration. CMT2 
phenotypes are also characterized by a large genetic heterogeneity, although 
only two genes---NF-L and KIF1Bbeta---have been identified to date. Homozygosity 
mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) 
provided evidence of linkage to chromosome 1q21.2-q21.3 in two families 
(Zmax=4.14). All patients shared a common homozygous ancestral haplotype that 
was suggestive of a founder mutation as the cause of the phenotype. A unique 
homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear 
envelope) was identified in all affected members and in additional patients with 
CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic 
nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong 
reduction of axon density, axonal enlargement, and the presence of nonmyelinated 
axons, all of which were highly similar to the phenotypes of human peripheral 
axonopathies. The finding of site-specific amino acid substitutions in 
limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss 
muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial 
lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional 
domains in lamin A/C that are essential for the maintenance and integrity of 
different cell lineages. To our knowledge, this report constitutes the first 
evidence of the recessive inheritance of a mutation that causes CMT2; 
additionally, we suggest that mutations in LMNA may also be the cause of the 
genetically overlapping disorder CMT2B1.