Charcot-Marie-Tooth Disease via the COX6A1 Gene

Charcot Marie Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN) is a large group of inherited disorders of the peripheral nerves. The progressive degeneration of motor nerves results in weakness and atrophy of the distal muscles. The degeneration of sensory nerves leads to decreased sensation, tingling and numbness in the legs, feet, arms and hands and neuropathic pain. The age of onset varies from childhood to mid adulthood. Symptoms usually begin with weakness and atrophy in the muscles of the legs and feet. As the disease progresses, weakness and atrophy of the muscles of the arms and hands may occur. CMT is heterogeneous in regards to symptoms, severity and progression rate. Although the disease may lead to disability and respiratory difficulty, life expectancy is usually unaffected. Most common symptoms include foot deformity, loss of balance, hammertoes, foot drop, frequent tripping and falls, and reduced manual dexterity (Bird 2015). Diagnosis is based on clinical features, family history, neurological examination, and electromyography (EMG) and nerve conduction velocity (NCV) findings (Pareyson and Chiara 2009). CMT affects approximately 1 in 3,300 people (Bird 2015).

Tamiya et al. (2014) reported 3 patients from 2 unrelated consanguineous Japanese families with early-onset peripheral neuropathy due to a homozygous COX6A1 pathogenic variant. Affected individuals showed distal muscle weakness and atrophy, pes cavus, steppage gait, clawing of the toes, distal sensory impairment, and areflexia of the lower limbs. Disease progression was slow over 2 decades in all individuals. Affected members of one family had onion bulb formation in the sural nerve biopsy. The female proband in the second family had mildly slowed NCV consistent with an axonal neuropathy, but a sural nerve biopsy was not performed (Tamiya et al. 2014). NCV values ranged from 35.7 m/s to 49.6 m/s depending on patient age and nerve studied. COX6A1 therefore causes an intermediate form of CMT. In an additional report, a separate group reported similar clinical features in a 37 year old patient that was homozygous for the same pathogenic COX6A1 variant seen in the the previously reported individuals (Lassuthova et al. 2015).

Charcot-Marie-Tooth, Intermediate type D is inherited in an autosomal recessive manner due to pathogenic variants in COX6A1, located on chromosome 12q24.2 (Tamiya et al. 2014). The COX6A1 gene encodes the cytochrome oxidase subunit VIa polypeptide I which is required for stability of the cytochrome c oxidase holoenzyme. A small intronic deletion near the consensus acceptor splice site (c.247-7_c.247-3del) is the only reported pathogenic variant so far. Haplotype analysis suggests this variant arose independently in the reported three affected families and is a mutational hotspot (Lassuthova et al. 2015; Tamiya et al. 2014).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity may be high because the only reported pathogenic variant thus far is detectable by sequencing.

This test provides full coverage of all coding exons of the COX6A1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).