Spotlight on Charcot-Marie-Tooth disease

charcot-marie-tooth disease

 

Charcot-Marie-Tooth (CMT), also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy (PMA), is a group of inherited disorders that affect the peripheral nervous system – the nerves outside of the brain and spinal cord that control the muscles and sensory organs in the limbs. Charcot-Marie-Tooth is part of the hereditary motor and sensory neuropathy subset of peripheral neuropathies and is the most common of all hereditary neuropathies, affecting approximately 1 in 2,500 individuals.

Due to the common onset of symptoms in adolescence or early adulthood and gradual progression, patients are often diagnosed outside of childhood. Due to great variance in severity of symptoms from patient to patient, it is not uncommon for individuals with Charcot-Marie-Tooth to go undiagnosed and to be unaware that they carry the genetic disorder.

Symptoms of Charcot-Marie-Tooth include:

  • Foot and lower leg muscle weakness
  • Foot drop and high-stepped gait, due to above muscle weakness
  • Frequent tripping and falls, due to above muscle weakness
  • Foot deformities, including high arches, hammertoes, inverted heel or flat feet
  • Hand muscle weakness and atrophy, later in the disease
  • Difficulty with fine motor skills involving fingers, hands, wrists, feet and tongue

An initial diagnosis is most often the result of neurological examination followed by electrodiagnostic testing. Nerve conduction studies use a small electrical shock to stimulate sensory and motor nerves and quantify conduction while electromyography (EMG) studies measure the bioelectrical activity of muscles looking for evidence of axon degeneration. Genetic testing is used to molecularly confirm a suspected diagnosis.

There are many different forms of the disease, each typically caused by mutations that result in myelin sheath abnormalities or axonal abnormalities.

The CMT1 form has three major subtypes: CMT1A, HNPP and CMT1B. This autosomal dominant form accounts for the majority of all Charcot-Marie-Tooth cases, with each subtype characterized by distinct mutation types. CMT1B is caused by mutations in the MPZ gene. CMT1A is caused by duplication of the PMP22 gene while HNPP is caused by deletion of the PMP22 gene. Traditionally, a molecular diagnosis of CMT1 employs separate tests based on separate technologies, screening first for point mutations and then for deletions/duplications (or vice versa) if the initial test yields no results. Based on whole genome sequencing (WGS), the Variantyx Unity™ test is able to detect both mutation types, across all relevant genes, in a single assay.

The CMT2 form also has multiple subtypes, with the most common being CMT2A. This sometimes autosomal dominant and sometimes autosomal recessive form is usually caused by mutation of the MFN2 gene, although some studies have linked it to mutations in the KIF1B gene.

When all forms of Charcot-Marie-Tooth are considered, the number of associated genes to be screened grows significantly as shown in the following, partially representative table:

With its ability to simultaneously identify small sequence changes, deletions and duplications for all genes, Variantyx Unity™ is able to distinguish between the different forms via a single assay.

Form Subtype Associated gene(s)
CMT1 CMT1A PMP22 duplication
HNPP PMP22 deletion
CMT1B MPZ
CMT1C LITAF
CMT1D EGR2
CMT1E NEFL
CMT2 CMT2A MFN2, KIF1B
  CMT2B RAB7
  CMT2D GARS
  CMT2E NEFL
  CMT2H HSP27
  CMT2I HSP22
CMT3 MFZ, PMP22
CMT4 CMT4A GDAP1
  CMT4B1 MTMR13
  CMT4B2 MTMR2
  CMT4C SH3TC2
  CMT4D NDG1
  CMT4E EGR2
  CMT4F PRX
Form Subtype Associated gene(s)
CMT1 CMT1A PMP22 duplication
HNPP PMP22 deletion
CMT1B MPZ
CMT1C LITF
CMT1D EGR2
CMT1E NEFL
CMT2 CMT2A MFN2, KIF1B
  CMT2B RAB7
  CMT2D GARS
  CMT2E NEFL
  CMT2H HSP27
  CMT2I HSP22
CMT3 MFZ, PMP22
CMT4 CMT4A GDAP1
  CMT4B1 MTMR13
  CMT4B2 MTMR2
  CMT4C SH3TC2
  CMT4D NDG1
  CMT4E EGR2
  CMT4F PRX

Charcot-Marie-Tooth is not generally fatal, and most affected individuals have a normal life expectancy. There is no cure, but symptoms can be treated through physical therapy, occupational therapy, orthopedic devices and in some cases orthopedic surgery. A molecular diagnosis is an important determinant of eligibility for a number of clinical trials that are planned or currently in progress. A molecular diagnosis also plays an important role in making family members aware of the presence of the disease within the family. Such knowledge reduces the unknowing treatment of undiagnosed Charcot-Marie-Tooth individuals with contraindicated neurotoxic chemotherapy agents in the event of a cancer diagnosis. Such chemotherapeutic treatment of individuals with Charcot-Marie-Tooth can cause irreversible, disabling sudden onset of peripheral neuropathy symptoms.

 

References
1. NINDS Charcot-Marie-Tooth fact sheet

2. Hereditary Neuropathy Foundation

2. Ibanez-Julia et al. Acta Oncol. 2018 Mar;57(3):403-411. PMID 29243538.

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