Background

Charcot-Marie-Tooth (CMT) disease is a group of hereditary sensory and motor neuropathies resulting from demyelination, axonal dysfunction, or both
Most common genetic neuropathy and most prevalent neuromuscular disease in children; reported prevalence 1:3,300
70%-80% of cases are caused by inheritance of autosomal dominant (most common), autosomal recessive or X-linked mutations, or de novo mutations in disease-causing genes
Symptoms usually begin in the first to third decade of life and slowly progress
There are 5 main types of CMT disease based on inheritance patterns and molecular genetics
- Charcot-Marie-Tooth type 1 (CMT1), CMT2, CMT3 (or intermediate form), CMT4, and CMTX
Complications of CMT disease may include respiratory and sleep disorders, mobility issues, and extremity weakness.
There is no curative treatment available for CMT^,and focus is on optimizing quality of life
- Impact of symptoms has largest effect during first decade following diagnosis
- Symptoms that affect quality of life include:
  - Poor balance
  - Mobility limitations
  - Difficulty traveling distances
  - Upper and lower extremity weakness
  - Cramping
  - Respiratory and sleep disorders

Pathogenesis

Peripheral nervous system maintains its anatomic structural integrity to propagate electrical impulses between motor neurons and muscles, and sensory receptors and sensory neurons

CMT disease affects peripheral nervous system through mutations in certain genes that prompts either or both of a demyelinating and axonal pathology
- Demyelination (most frequent form of CMT), results from:
  - Defects in myelin-forming Schwann cells
  - Dysregulation of peripheral myelination caused by PMP22, MPZ, GJB1, and EGR2
  - Overexpression of PMP22 in CMT1A, resulting in toxic protein aggregation and protein degradation processes
  - Pathogenic gene variants in MPZ in CMT1B, resulting in abnormalities in major peripheral myelin protein
- Axonal pathology (less common form of CMT) results from:
  - Primary abnormalities in the nerve axon and/or its interactions with Schwann cells, which affects motor and sensory/autonomic nerves
  - Aberrations in axonal structure maintenance and axonal function caused by MFN2, GDAP1, RAB7, TRP4, and GARS

Clinical Presentation & Physical Findings

Symptoms usually begin in first to third decade of life, and slowly progress; common symptoms and physical findings include:
- Foot deformities
  - Pes cavus (high arch) (common)
  - Hammer toes (common)
  - Equinovarus
  - Thinning of ankles (suggests more advanced case)
  - Atrophy of anterior and/or posterior compartments of lower legs (suggests more advanced case)
- Hand involvement such as subtle wasting (flattening) in hypothenar muscles and base of thenar muscles
- Sensory loss and weakness of extremities; assess for loss of:
  - Light touch
  - Proprioception
  - Vibration
  - Hot or cold
- Unsteady gait
  - Flail foot
  - Cavovarus foot
  - Toe walking
- Hip dysplasia
- Hearing loss
- Pain

In children, earliest characteristics are often nonspecific but may include:
- Toe walking, along with tripping/falling
- Hand weakness (leading to trouble dressing, tying shoes, or writing)
- Delayed motor development
- Numbness, tingling, or pain, although children may not complain about these symptoms
- Flat feet or high arches (asymmetry in foot alignment not typical)
- Muscle cramps (may suggest axonal forms of CMT)
Dejerine-Sottas syndrome ― rare infantile form of severe demyelinating CMT that presents with nonspecific clinical signs such as:
- Generalized hypotonia
- Hip dysplasia
- Decreased sucking effort
- Breathing problems (in severe cases)

History of Present Illness & Family History

Ask about
- Pain
- Weakness
- Loss of sensation
- Foot deformities/gait issues
- Problems with shoe wear
- Muscle cramps (often gastrocnemius and are related to decreased ankle range of motion/toe walking)
Ask about family history of CMT disease or other neuropathies

Making the Diagnosis

Suspect diagnosis in patients with distal muscle weakness and atrophy, mild-to-moderate sensory loss, depressed tendon reflexes, high-arched feet, and more than 1 of following:
- Family history of neuropathy
- Other foot abnormalities such as hammer toes or equinovarus
- Gait disturbance, especially flail, cavovarus foot or toe walking
- Balance problems
Diagnosis should be confirmed by
- Electromyography (EMG)
  - EMG is abnormal in nearly all patients with CMT disease
  - May help distinguish between acquired and inherited neuropathy, and exclude other types of neuromuscular diseases
  - Testing is minimally invasive, and can be used in patients of any age
  - Surface electrodes may be used to assess motor and sensory nerves
  - Needle examination may provide evidence of acute/chronic denervation patterns, which helps determine whether neuropathy is axonal or demyelinating
- Nerve conduction velocity (NCV)
  - NCV is abnormal in nearly all patients with CMT disease
  - Conduction velocity of motor nerve fibers can differentiate between demyelinating and axonal CMT
  - Demyelination is confirmed when slowing of motor nerve conduction
    - < 30 meters/second in upper limb
    - < 25 meters/second in lower limb
  - Uniform nerve conduction slowing is a characteristic feature of Charcot-Marie-Tooth type 1A (CMT1A); CMTX is characterized by varying conduction velocities
Consider molecular genetic testing to confirm diagnosis if:
- Electromyography and nerve conduction velocity measurements are equivalent
- Presence of known familial mutation
- Testing may distinguish CMT subtypes that have similar disease presentations through detection of specific pathogenic variants
- Consider first testing for pathogenic variants in single gene that best fits clinical presentation
- Mutations in PMP22, GJB1, MPZ, and MFN2 are very common in CMT and therefore should be sequenced before proceeding with further genetic testing

Sural nerve biopsy not routinely performed, but is occasionally helpful in establishing diagnosis of CMT hereditary neuropathy because characteristic lesions are found as compared with other neuropathies

Management Overview

There is no curative treatment available for CMT
Physical therapy and orthoses are mainstays of supportive care
- Refer patient for regular physical therapy focusing on strength, range of motion, and balance training in order to maintain mobility of patients
- Advise patient to perform daily:
  - Heel cord stretching exercises to prevent Achilles tendon shortening
  - Gripping exercises for hand weakness
- Consider patient’s gait pattern, pain, strength, and stability when selecting orthoses
- Refer patient for gait training and occupational therapy as needed
Medications
- Medications are considered for short term to treat symptoms associated with CMT, however long-term use of certain medications may be problematic
- For musculoskeletal pain, give acetaminophen or nonsteroidal anti-inflammatory (NSAID) medications
- For neuropathic pain, consider tricyclic antidepressants or drugs such as carbamazepine or gabapentin
- For fatigue, consider modafinil
Surgery
- Consider orthopedic surgery to correct:
  - Severe pes cavus deformity
  - Hip dysplasia
- Consider surgical corrections in patients with chronic ankle injuries or pain not helped by orthoses

Complications

Complications may occur in patients with CMT including:
- Obstructive sleep apnea
- Restless legs syndrome
- Vocal cord dysfunction
- Laryngeal neuropathy
- Daytime sleepiness/poor sleep
- Dyspnea
- Esophageal dysphagia or oropharyngeal dysphagia
- Pregnancy complications and sexual dysfunction
- Restrictive pulmonary impairment

Kendra Church MS, PA-C, is a physician assistant at Dana-Farber Cancer Institute/Brigham & Women’s Hospital, and is also a senior clinical editor for DynaMed, an evidence-based, point-of-care database.

Sources

1. Yiu EM, Bray P, Baets J, et al. Clinical practice guideline for the management of paediatric Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2022;93(5):530-538. doi:10.1136/jnnp-2021-328483

2. Bird TD, Charcot-Marie-Tooth hereditary neuropathy overview. In: Adam MP, Mirzaa GM, Pagon RA, et al. Eds. GeneReviews [Internet]. University of Washington, Seattle; September 28, 1998. Updated February 23, 2023.

3. Jani-Acsadi A, Ounpuu S, Piertz K, Ascadi G. Pediatric Charcot-Marie-Tooth disease. Pediatr Clin North Am. 2015;62(3):767-786. doi:10.1016/j.pcl.2015.03.012

4. McCorquodale D, Pucillo EM, Johnson NE. Management of Charcot-Marie-Tooth disease: improving long-term care with a multidisciplinary approach. J Multidiscip Healthc. 2016;9:7-19. doi:10.2147/JMDH.S69979

Stat Consult: Charcot-Marie-Tooth Disease