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
- Demyelination (most frequent form of CMT), results from:
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
- Foot deformities
- 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
- Electromyography (EMG)
- 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
- Consider orthopedic surgery to correct:
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