Newly Identified CMT Type 1 Mutations Linked to Milder Disease, Clinical Variability, Study Reports

Two new mutations causing Charcot-Marie-Tooth disease type 1 (CMT1) were identified in the gene PMP2, and associated with variable clinical severity, including slow progression of disease and mild symptoms, according to a study.

The study, “Peripheral myelin protein 2 – a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy,” was published in the Orphanet Journal of Rare Diseases.

Charcot-Marie-Tooth (CMT) includes a varied group of genetic disorders affecting the peripheral nervous system, the network of nerves that supply movement and sensation to the limbs.

Mutations in more than 80 different genes have been described as the cause of several types of the disease.

Recently, the PMP2 gene was identified as a novel cause of CMT1, the most common type of the disease. CMT1 is marked by demyelination or loss of myelin — a fat-rich coating essential for the insulation and rapid conduction of electrical impulses across nerve fibers — and consequent slowing of nerve conduction velocities.

PMP2 provides instructions for making the peripheral myelin protein 2 (PMP2), one of the major constituents of the myelin coatings of peripheral nerve fibers.

Recently, three mutations in PMP2 (p.Ile43Asn, p.Thr51Pro, and p.Ile52Thr) were reported in five families with CMT1 of European descent.

Here, researchers describe two new mutations that were the cause of CMT1 in a Bulgarian and German family.

The mutations were identified during genetic screenings in people in whom CMT was suspected, but the genetic cause of which was unknown. The screenings were done using whole-exome sequencing (WES), a technique that enables researchers to sequence large amounts of DNA, in particular, the regions in an individual’s genome that provide instructions for making proteins, known as exons.

One of the mutations (p.Met114Thr, c.341C > T) was found in a 37-year-old Bulgarian female, with disease onset during childhood. She had a family history of CMT, with both a parent and grandparent affected.

She developed foot deformities (high arched feet, thin calves) and muscle weakness in her legs when she was a child, which evolved to hand muscle weakness and trouble in fine movements. Electrophysiological tests — nerve conduction tests that measured the electrical activity of nerves — revealed severe demyelination and nerve fiber degeneration, as well as deficits in sensory perception.

The second mutation (p.Val115Ala, c.344 T > C) was identified in a German adult who, as a child, started having difficulty walking and developed foot deformities. These problems worsened slightly as he got older, and nerve conduction tests were consistent with primarily demyelinating disease.

The patient’s older sibling also developed milder signs and symptoms of CMT1, including foot deformities, sensory deficits, and some difficulty walking. Nerve tests showed only slight abnormalities.

Both mutations affected close regions of the PMP2 protein, revealing a new mutation site within the gene. Using computational models, both changes were predicted to significantly destabilize protein structure and cause disease.

Considering the previously reported cases, the researchers conclude that CMT1 caused by PMP2 mutations can have a variable clinical course, with initial complaints between the first years of life — related to delayed motor milestones — and adolescence. Demyelination seen by electrophysiology tests is of variable severity and location. Foot deformities and lower limb weakness are always present.

“Our findings contribute to an improved clinical and genetic diagnosis of patients and families with inherited peripheral neuropathies [nerve disease],” the researchers wrote.

“Importantly, we expand the clinical and electrophysiological spectrum of PMP2-related neuropathy with the identification of very mildly affected individuals who have only subtle proximal demyelination and focal pattern of distribution along peripheral nerves,” they added.