Charcot-Marie-Tooth Type 4B1 via the MTMR2 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), and nerve conduction velocity (NCV) findings (Pareyson and Marchesi 2009; Bird 2015). CMT affects approximately 1 in 3,300 people.

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a demyelinating form of CMT that primarily affects the myelin sheath of the peripheral nerve. Patients with CMT4B1 will exhibit the typical slow nerve conduction velocities (NCV) of a demyelinating neuropathy, distal muscle weakness and atrophy, depressed deep tendon reflexes, and sensory impairment (Bolino et al. 2000). Sural nerve biopsy will show myelin outfoldings, which are a hallmark of CMT4B. Of note, vocal cord palsy is observed in many of these patients. The onset is typically in infancy or early childhood (Zambon et al. 2017).

Charcot-Marie-Tooth type 4B1 (CMT4B1) is inherited in an autosomal recessive manner due to pathogenic variants in MTMR2, located on chromosome 11q22. The MTMR2 gene encodes myotubularin-related protein 2 which is involved in cytokine signaling and tumor suppression; however, the exact cellular role is not fully understood. Thus far, reported pathogenic variants include missense, nonsense, splicing, small deletions and duplications that result in a frameshift, and a large insertion of a LINE in exon 8 (Human Gene Mutation Database).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in MTMR2 appear to be a rare cause of disease. Analytical sensitivity should be high because almost all reported pathogenic variants thus far are detectable by sequencing.

Thus far, no large deletions or duplications involving the MTMR2 gene have been reported. A large insertion of a LINE element has been reported in exon 8 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the MTMR2 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).