A number sign (#) is used with this entry because of evidence that axonal Charcot-Marie-Tooth disease type 2X (CMT2X) is caused by homozygous or compound heterozygous mutation in the SPG11 gene (610844) on chromosome 15q21.

Biallelic mutations in the SPG11 gene can also cause autosomal recessive spastic paraplegia-11 (SPG11; 604360) and juvenile amyotrophic lateral sclerosis-5 (ALS5; 602099), both of which show overlapping features with CMT2X.

Charcot-Marie-Tooth disease type 2X (CMT2X) is an autosomal recessive, slowly progressive, axonal peripheral sensorimotor neuropathy characterized by lower limb muscle weakness and atrophy associated with distal sensory impairment and gait difficulties. Some patients also have involvement of the upper limbs. Onset usually occurs in the first 2 decades of life, although later onset can also occur (summary by Montecchiani et al., 2016)

For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Montecchiani et al. (2016) reported 29 affected individuals from 12 unrelated families of various ethnic origins with slowly progressive axonal peripheral neuropathy. Nine of the families were consanguineous. The mean age at disease onset was 11.4 years (range, 4-35) and there was phenotypic variability. All had distal lower limb weakness, often with distal muscle atrophy in the lower limbs, resulting in foot drop and impaired gait. Sixteen patients also had upper limb weakness, often associated with atrophy in the intrinsic hand muscles. Eight patients had fasciculations in the lower limbs, and 4 had proximal muscle weakness of the lower limbs. Additional common features included foot deformities (79%), usually pes cavus, kyphoscoliosis (59%), ankle contractures (48%), and tremor (34%). Hand deformities were present in 7 patients with longer disease duration. About a third of individuals had bladder and/or sexual dysfunction. Three Italian sibs showed thin corpus callosum on brain imaging and mild cognitive impairment, but this was not observed in any other patients or families. Only 1 patient was wheelchair-bound, and no patients had pontobulbar signs or spasticity, although 2 unrelated patients had extensor plantar responses. Electrophysiologic studies were consistent with a motor and sensory axonal neuropathy, more prominent in the lower limbs, with low amplitudes of compound motor and sensory nerve action potentials. Nerve conduction velocities were normal or slightly reduced, consistent with a secondary demyelinating process. EMG showed evidence of chronic denervation/renervation, and sural nerve biopsies showed loss of large-caliber myelinated fibers.

The transmission pattern of CMT2X in the families reported by Montecchiani et al. (2016) was consistent with autosomal recessive inheritance.

By linkage analysis of 9 consanguineous families with autosomal recessive axonal CMT, Montecchiani et al. (2016) found significant linkage to a region on chromosome 15q (2-point lod score of 11.76 at marker D15S537).

In affected members of 12 unrelated families with CMT2X, Montecchiani et al. (2016) identified 15 different biallelic mutations in the SPG11 gene (see, e.g., 610844.0001-610844.0003 and 610844.0014-610844.0015). Thirteen mutations had previously been reported as causative of SPG11 or ALS5; 2 mutations were novel. Montecchiani et al. (2016) commented that identical mutations can cause different phenotypes, indicating that genotype/phenotype correlations are often unpredictable. All mutations except 1 were predicted to result in a truncated protein with loss of function; functional studies of the variants were not reported. The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. The families showed different ethnic origins, including Italy, Brazil, Canada, England, Iran, and Japan.