PMP22-Related Neuropathies via the PMP22 Gene

PMP22-related neuropathies can be grouped into three different categories: Hereditary neuropathy with liability to pressure palsies commonly caused by a PMP22 deletion, Charcot Marie Tooth 1A caused by a PMP22 duplication, and Charcot Marie Tooth 1E due to various other pathogenic sequence variants.

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in a single nerve. The most vulnerable nerves are the peroneal and ulnar, followed by the brachial plexus nerve, radial nerve, and median nerve. Common symptoms include focal numbness, muscular weakness, atrophy, pes cavus, and reduced/absent tendon reflexes. Nerve conduction studies typically show prolongation of distal nerve conduction latencies and focal slowing of conduction velocity at the site of compression. The presence of tomacula structures in the peripheral nerve myelin from sural nerve biopsies is a classic pathological feature. Onset is normally in the second or third decade. However, the age range of presentation is 2-70 years (Li et al. 2013; van Paassen et al. 2014; Bird 2015; Lupski and Garcia 2014; Wiszniewski et al. 2013).

Charcot Marie Tooth 1A (CMT1A) is the most common form of CMT1. Age of onset is usually within the first two decades, and many individuals present in the first 10 years of life. Typically, presentation includes difficulty in walking or running, weakness of the distal leg muscles, sensory loss, and slow nerve conduction velocity (less than 38m/s). Distal muscle weakness and wasting is normally symmetrical with legs being more severely affected than upper extremities. Pes cavus and hammertoes are cardinal features of CMT1A. Phenotype variability is common with some patients having a severe phenotype in infancy while others are only minimally disabled through life (Li et al. 2013; van Paassen et al. 2014; Bird 2015; Lupski and Garcia 2014; Wiszniewski et al. 2013).

Charcot Marie Tooth 1E (CMT1E) often presents similarly to other subtypes of CMT1. Depending on the pathogenic variant, patients can present with classic CMT or HNPP or even an overlap between the two phenotypes. Some patients present with a mild HNPP-like neuropathy while others have a severe early onset dysmyelinating neuropathy like Dejerine-Sottas disease. Patients present with impaired motor development, distal muscle weakness, foot deformities, and loss of deep tendon reflex. Sensory deficits have also been observed. In a small subset of CMT1E patients, clinical symptoms have been suggestive of an axonal neuropathy (Li et al. 2013; van Paassen et al. 2014; Bird 2015; Lupski and Garcia 2014; Wiszniewski et al. 2013).

HNPP is inherited in an autosomal dominant manner. In about 80% of patients with HNPP, the most common pathogenic variant is a 1.5 Mb deletion of chromosome 17p11.2 (Bird 2015). In the remaining 20% of patients with HNPP, single nucleotide variants such as missense, nonsense, splicing, and small insertions/deletions detectable by sequencing have been reported (Human Gene Mutation Database; Bird 2015). Prevalence is estimated to be 7.3:100,000 to 16:100,000 (Bird 2015; Li et al. 2013; van Paassen et al. 2014).

CMT1A is inherited in an autosomal dominant manner. CMT1A is most commonly caused by a 1.5 Mb duplication of chromosome 17p11.2 which includes PMP22. The duplication occurs due to unequal crossing over of homologous chromosomes at regions of repetitive elements. About one-third of these cases occur de novo. Other smaller duplications of the PMP22 gene have been reported in a few cases. Approximately 70% of CMT1 is caused by the recurrent PMP22 duplication (Bird 2015; Li et al. 2013; van Paassen et al. 2014).

CMT1E is inherited in an autosomal dominant manner and caused by sequence variants in the PMP22 gene. It is considered a rare subtype of CMT1 and estimated to account for 1-5% of CMT1 cases (Bird 2015; Li et al. 2013; van Paassen et al. 2014). Pathogenic variants include missense, nonsense, splicing, and small insertions/deletions (Human Gene Mutation Database).

Very rare autosomal recessive neuropathy (CMT4) caused by homozygosity for sequence variants in PMP22 has been reported.

The PMP22 gene encodes for the peripheral myelin protein-22 which is an integral membrane glycoprotein of the intermodal myelin. It is present in the compact myelin and has four transmembrane domains. Pathogenic variants in PMP22 lead to myelin disorganization and result in the PMP22-related neuropathies. PMP22-related neuropathies have variable expressivity and incomplete penetrance.

It is estimated that ~80% of individuals with clinical HNPP have the common 1.5 Mb deletion, while the remaining 20% have a different sequence variant within the PMP22 gene detectable by sequencing (Bird 2015). In a recent study of 100 Greek patients suspected to have HNPP, 54% were found to be positive for either the common 1.5 Mb deletion or a "micromutation". In the positive patients, 96% had the common deletion, while the other 4% had sequence variants detectable by sequencing (Karadima et al. 2015). Another source cites that 85-90% of patients with clinical HNPP have the 1.5 Mb deletion (van Paassen et al. 2014).

It is estimated that ~70% of all Charcot Marie Tooth Type 1 (CMT1) are due to the PMP22 1.5 Mb duplication, while only around 5% of CMT1 cases are due to point mutations (Bird 2015).

This test provides full coverage of all coding exons of the PMP22 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).