A number sign (#) is used with this entry because of evidence that axonal Charcot-Marie-Tooth disease type 2II (CMT2II) is caused by heterozygous mutation in the SLC12A6 gene (604878) on chromosome 15q13.

Axonal Charcot-Marie-Tooth disease type 2II (CMT2II) is an autosomal dominant neurologic disorder characterized by a slowly progressive sensorimotor peripheral neuropathy affecting mainly the lower limbs, resulting in distal muscle weakness and atrophy and subsequent walking difficulties. Some patients may have upper limb involvement with atrophy of the intrinsic hand muscles. The age at onset is highly variable, ranging from infancy to adulthood. Electrophysiologic studies are usually consistent with an axonal process, although some may show intermediate or even demyelinating values (Park et al., 2020; Ando et al., 2022). One family with possible autosomal recessive inheritance has been reported (Bogdanova-Mihaylova et al., 2021).

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

Kahle et al. (2016) reported a 10-year-old boy with onset of a progressive motor-predominant axonal peripheral neuropathy apparent since 9 months of age, when he demonstrated foot dragging followed by foot drop and frequent falls when walking. The disorder was progressive, and he was unable to walk independently by 9 years of age. Physical examination showed distal muscle weakness and atrophy affecting the upper and lower limbs. Deep tendon reflexes were absent, but there were no sensory deficits. Nerve biopsy showed mild loss of myelinated fibers and mild axonal loss, and muscle biopsy was indicative of denervation. Electrophysiologic studies were consistent with a sensorimotor axonal neuropathy with secondary demyelinating features. Brain imaging and cognitive development were normal.

Park et al. (2020) reported 3 unrelated patients, who ranged from 11 to 15 years of age, with onset of a slowly progressive peripheral neuropathy in the first years of life. They had delayed motor development with delayed walking, frequent falls, foot dragging, foot drop, and distal muscle weakness and mild atrophy. Ankle contractures or foot deformities were also present. There was involvement of the upper limbs, manifest as distal muscle weakness and difficulties using the hands; 1 patient had hand deformities and scoliosis. Sensation was variably impaired. Reflexes were decreased in 2 patients, whereas 1 patient (P3) had brisk reflexes and also showed spasticity. Electrophysiologic studies showed an 'intermediate' neuropathy with mixed axonal and demyelinating features. One patient had mild hemolytic anemia and another had EEG abnormalities without clinical seizures. Brain imaging and cognitive development was normal in all patients.

Shi et al. (2021) reported a 31-year-old Chinese man who developed progressive distal muscle weakness and atrophy at 27 years of age. He had episodic muscle cramps, foot drop, loss of the ability to run, steppage gait, and distal sensory impairment. Other features included claw hands, high foot arches, and decreased or absent reflexes. Serum creatine kinase was mildly increased. Nerve conduction studies showed a sensorimotor neuropathy with both axonal and demyelinating features, indicating 'intermediate' CMT. Cognitive development and brain imaging were normal.

Ando et al. (2022) reported 11 patients from 7 unrelated Japanese families with CMT. Clinical details were provided for the 7 probands. The age at onset was highly variable, ranging from 1 to 40 years of age. Patients had frequent falls, difficulty running, steppage gait, and foot deformities. Physical examination showed distal muscle weakness, often accompanied by distal muscle atrophy, variable sensory disturbances, and decreased or absent reflexes. Electrophysiologic studies in most patients were consistent with an axonal sensorimotor neuropathy, although the results in some individuals indicated an intermediate or demyelinating type of neuropathy. One patient became wheelchair-bound in her forties. Four patients had evidence of central nervous system involvement: P1 had poor vision, P2 had poor school performance, P3 had mild intellectual disability (IQ of 71), and P7 had cognitive impairment (IQ of 46) and seizures, as well as hemolytic anemia. Five of the probands had a family history consistent with autosomal dominant inheritance of the disorder, although clinical details and genetic studies were not performed on many of these family members. The disorder occurred sporadically in the probands from families 1 and 7.

Autosomal Recessive CMT2II

Bogdanova-Mihaylova et al. (2021) reported a pair of 27-year-old fraternal twins with onset of a length-dependent sensorimotor axonal peripheral neuropathy in the first decade. Features included difficulty walking and running, difficulty in using the hands, foot deformities, ankle contractures, and decreased reflexes. Brain imaging showed a normal corpus callosum. Targeted next-generation sequencing identified a heterozygous splice site mutation in the SLC12A6 gene (c.1592-2A-G) that was absent in gnomAD and inherited from the unaffected father, and a heterozygous 1.8-Mb deletion of 15q13.3-q14 encompassing multiple genes, including SLC12A6, that was inherited from the unaffected mother. Functional studies of the variants and studies of patient cells were not performed. These authors noted that the phenotype was not consistent with the more severe autosomal recessive disorder ACCPN (218000), but was consistent with a pure neuropathy. The report expanded the phenotypic and genetic spectrum associated with SLC12A6 mutations.

The transmission pattern of in some of the families reported by Ando et al. (2022) was consistent with autosomal dominant inheritance. In addition, heterozygous mutations in the SLC12A6 gene that were identified in some patients reported by Ando et al. (2022) occurred de novo.

In a 10-year-old boy with CMT2II, Kahle et al. (2016) identified a de novo heterozygous missense mutation in the SLC12A6 gene (T991A; 604878.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP, Exome Variant Server, and ExAC. In vitro functional expression studies in patient fibroblasts and HEK293 cells transfected with the T991A mutation showed about 50% reduced phosphorylation of thr991, which in the phosphorylated state inhibits SLC12A6 transporter activity. Cells with the mutation demonstrated increased transporter activity compared to controls, and showed a compromised swelling response to acute hypotonic stress. These findings were consistent with a gain-of-function effect. Kahle et al. (2016) suggested that these alterations could lead to impaired cell volume homeostasis in peripheral nerves that may result in secondary axonal degeneration or loss, as well as altered neuronal excitability.

In 3 unrelated patients with CMT2II, Park et al. (2020) identified de novo heterozygous missense mutations at highly conserved residues in the SLC12A6 gene (R207H; 604878.0012 and Y679C 604878.0013). The mutations, which were found by trio-based exome sequencing, were not present in public databases, including gnomAD. In vitro functional expression studies in transfected Xenopus oocytes showed that both mutations impaired K+ influx under hypotonic shock compared to controls, consistent with a loss-of-function effect. R207H resulted in a complete loss of function, whereas Y679C caused a partial loss of function.

In a 31-year-old Chinese man with CMT2II, Shi et al. (2021) identified a heterozygous R207H mutation in the SLC12A6 gene. Functional studies of the variant were not performed, but molecular modeling suggested that it may interfere with homo- or heterodimer formation and cause a dominant-negative effect.

In 11 patients from 7 unrelated Japanese families with CMT2II, Ando et al. (2022) identified heterozygous mutations in the SLC12A6 gene (see, e.g., 604878.0012; 604878.0014-604878.0015). There were 3 missense variants and 1 in-frame deletion. The mutations were confirmed by Sanger sequencing and segregated with the disorder in 2 families in which genetic material was available from affected individuals. The mutations occurred de novo in 2 of the families. The mutations occurred throughout the gene, affected highly conserved residues, and were absent from the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a cohort of 2,598 individuals with clinically suspected CMT who underwent genetic studies.

Kahle et al. (2016) used CRISPR/Cas9-mediated gene editing to express the T991A human mutation in mice. Fibroblasts from heterozygous mice had increased cellular K+ influx due to constitutive activation of the SLC12A6 transporter. Heterozygous mutant mice did not show impaired motor performance, but homozygous mutant mice had significant motor deficits. Electrophysiologic studies showed motor and sensory conduction defects, and peripheral nerve biopsy showed myelination defects, particularly in homozygous mutant animals.