Charcot-Marie-Tooth Type X-linked Dominant 6 via the PDK3 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; and 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 muscle 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. Diagnosis is based on clinical features, family history, neurological examination, electromyography (EMG), nerve conduction velocity (NCV), and genetic testing (Pareyson and Marchesi, 2009. PubMed ID: 19539237; Bird, 2015. PubMed ID: 20301532). CMT affects approximately 1 in 3,300 people.

Charcot-Marie-Tooth X-linked Dominant 6 (CMTX6) was first described in a large 3 generation family in which linkage analysis and whole exome sequencing were used to discover the causative PDK3 gene (Kennerson et al., 2013). An additional unrelated family with a similar presentation was later described (Kennerson et al., 2016). Affected males had a more severe and earlier onset than carrier females. Typical symptoms included foot deformities, abnormal gait due to distal lower limb muscle weakness and atrophy, sensory abnormalities, and decreased hand grip strength and dexterity. Female carriers did not show symptoms until much later and were mild in comparison, such as hand muscle weakness, hand tremor, and decreased ankle reflexes. The predominant EMG finding was an axonal motor and sensory polyneuropathy with variable mild conduction slowing.

Charcot-Marie-Tooth X-linked Dominant 6 (CMTX6) is inherited in an X-linked manner due to pathogenic variants in PDK3, located on chromosome Xp22.11. The PDK3 gene encodes pyruvate dehydrogenase kinase isoenzyme 3 (PDK3), one of four PDK isoenzymes, which negatively regulates the activity of the pyruvate dehydrogenase complex by reverse phosphorylation. Thus far, the only established pathogenic variant reported in two unrelated families is a missense variant referred to as c.473G>A p.Arg158His, which results in hyperactivity and gain-of-function (Human Gene Mutation Database).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in PDK3 appear to be a rare cause of disease. Analytical sensitivity should be high because all reported pathogenic variants thus far are detectable by sequencing.

Thus far, no large deletions or duplications involving the PDK3 gene have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the PDK3 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).