MPZ-Related Neuropathies via the MPZ 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 Marchesi 2009). CMT affects approximately 1 in 3,300 people (Bird 2015).

MPZ genetic defects can cause CMT1B, Dejerine-Sottas syndrome, congenital hypomyelinating neuropathy, and CMT2I/CMT2J (Lupski and Garcia 2014). The variation in disease presentation typically correlates with NCV findings. Very slow NCVs are seen in patients with severe, early onset disease and a later onset, mild phenotype is observed in those with near-normal NCV (Bird 2015). CMT2 caused by MPZ pathogenic variants has also been reported in some families with differing onset and presentation, including many of the features listed above. The axonal forms of CMT caused by MPZ, may also present with hearing loss and pupillary abnormalities (Bird 2015; Siskind et al. 2013).

Pathogenic variants in MPZ commonly cause autosomal dominant CMT1B (Bird 2015). However, more severe neuropathies such as Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy are also caused by MPZ genetic defects and can exhibit both autosomal dominant and recessive inheritance (McMillan et al. 2010). CMT2I and CMT2J are axonal forms of CMT also caused by pathogenic variants in MPZ (Auer-Grumbach et al. 2003). The MPZ gene has 6 coding exons that encode myelin protein-zero (MPZ) which is the major structural protein of peripheral myelin (Lupski and Garcia 2014). This protein accounts for greater than 50% of the protein present in the sheath of peripheral nerves. MPZ is expressed in Schwann cells, and is not found in the central nervous system. Genetic defects of MPZ found to date include missense, nonsense, splicing and small deletion/insertions (Human Gene Mutation Database). A few large deletions/insertions involving the MPZ gene have also been reported.

In three different large cohort studies, MPZ was found to be the causative gene in 4-5% of patients with a clinical diagnosis of CMT (Rossor et al. 2013; DiVincenzo et al. 2014; Fridman et al. 2015). CMT1B represents about 6%-10% of CMT1 cases (Mandich et al. 2009). It is considered the fourth most common type of CMT (Siskind et al. 2013). Analytical sensitivity should be high since the vast majority of reported variants are detectable by sequencing.

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