BASICS
DESCRIPTION
- Hereditary neuropathies are a genetically heterogeneous group of disorders primarily affecting peripheral nerves in a length-dependent pattern with symmetrical motor > sensory manifestations in most cases.
- Onset is typically in childhood, adolescence, or young adulthood.
- Catagorized by pathophysiology, inheritance pattern, and geneotype; type 1 is characterized by a disruption in myelin formation.
- Type 2 is due to disruption of axonal integrity.
- OMIM has 64 entries in its phenotypic series for Charcot-Marie-Tooth (CMT) disease.
- Autosomal dominant
- CMT1 subtypes A to F
- CMT2 subtypes A to L
- CMT3/Dejerine-Sottas disease (severe congenital)
- X-linked dominant: CMTX
- Autosomal recessive (rare): CMT4
- Mitochondrial disorders with neuropathy
- NARP (neuropathy, ataxia, and retinitis pigmentosa)
- MNGIE (mitochondrial neurogastrointestinal encephalomyopathy)
- Hereditary neuropathy with liability to pressure palsies (HNPP)
- Axonal neuropathies
- Giant axonal neuropathy (GAN)
- Hereditary neuralgic amyotrophy (HNA with predilection for the brachial plexus)
- Hereditary sensory and autonomic neuropathies (HSAN; rare): HSAN1; HSAN2 (Morvan disease); HSAN3 (familial dysautonomia); HSAN4 (anhidrotic sensory neuropathy)
EPIDEMIOLOGY
Prevalence
CMT: 1/2,500 to 1/3,300
- CMT1: 70% of all CMT disorders, CMT1A is the most common making up 80% followed by type 1B, which accounts for 10%.
- 20% of patients with undiagnosed polyneuropathy presenting to a neurologist have CMT1A.
- CMTX is 10% of all CMT.
- CMT2 is 30% of all CMT. CMT2A2 is the most common subtype (20%).
ETIOLOGY AND PATHOPHYSIOLOGY
- CMT is a spectrum of disorders caused by ~1,000 different genetic mutations in >80 different genes (1).
- Peripheral myelin protein 22 (PMP22) is responsible for the formation of compact myelin.
- Duplication of the gene (increased PMP dosage) results in the CMT1A phenotype
- Deletion results in the HNPP phenotype
- Mitofusin 2 (MFN2) determines structure and morphology of mitochondria.
- Mutation present in 20% of CMT2.
- Myelin protein zero (MPZ or P0) compacts myelin; mutations present as different phenotypes (CMT1B, DSD, CHN, and CMT2).
- Gap junction protein, β-1 gene (GJB1, connexin 32)
- Gap junction protein found in noncompact myelin, forms a gap junction to facilitate the movement of metabolites and ions through myelin.
- Mutation present in 90% of CMTX.
Genetics
- Vast majority are autosomal dominant inheritance.
- X-linked dominant (codominant) is second most common inheritance pattern: females less severely affected than male family members
- Autosomal recessive inheritance is rare and occurs typically in isolated populations with consanguinity. Mitochondrial or maternal inheritance is rare, usually associated with involvement of other organ systems.
RISK FACTORS
- Positive family history of neuropathy
- Foot and hand deformities (e.g., pes cavus, hammer toes, claw hand)
- Frequent ankle sprain, tripping, gait difficulties, distal weakness and sensory loss
GENERAL PREVENTION
Most inherited neuropathies are highly penetrant; treatment is supportive.
COMMONLY ASSOCIATED CONDITIONS
- Foot deformities, heel-cord shortening, contractures, muscle wasting, osteoarthritis, scoliosis
- Hearing loss
- Optic atrophy (CMT2A, CMTX5), retinopathy
- Vocal cord and phrenic nerve involvement (CMT2C)
- Restrictive airway disease and sleep apnea with phrenic nerve involvement
DIAGNOSIS
- Classic presentation: motor > sensory polyneuropathy
- Family history
- Nerve conduction studies/electromyography
- Accurate genetic diagnosis may be difficult due to the genetic heterogeneity.
- Gene discovery has been revolutionized by high-throughput technology.
- Phenotypic diversity is increasingly recognized.
HISTORY
- Symptoms usually begin in the first 2 decades of life.
- Delayed motor milestones in early-onset CMT only
- Clumsiness, weakness, frequent falls, and loss of fine motor control
- Foot drop is often the initial symptom.
- Progressive length-dependent weakness (stocking-glove distribution). Occasionally associated with sensory loss, paresthesias, or pain
- Later onset can be seen in subtypes of CMT2.
- Severe motor impairment early in life is seen in CMT2A and some cases of CMT2B.
- Infantile onset is most suggestive of CMT4, DSD, and CHN.
PHYSICAL EXAM
- Distal muscle atrophy and weakness with pes cavus, ankle equinus, hammer toes, and claw hand deformity
- Slowly progressive weakness and atrophy initially involving the foreleg muscles and intrinsic hand muscles, later progressing to the thighs and forearms
- Diminished deep tendon reflexes (diffusely hypoactive in demyelinating and length dependent in axonal)
- Motor > sensory loss
- Difficulty heel walking, steppage gait
- Shortened Achilles' tendons
- Abnormalities of vibration sense, proprioception, and 2-point discrimination
- Kyphosis or scoliosis
- Postural tremor develops in some patients.
DIFFERENTIAL DIAGNOSIS
- In early-onset motor > sensory polyneuropathy with associated foot and hand deformities-consider CMT.
- Acquired polyneuropathy-extensive differential diagnosis includes primary inflammatory/autoimmune conditions (e.g., CIDP, MMN, Lewis-Sumner syndrome), secondary toxic (medication), metabolic (diabetes mellitus), vitamin deficiency, collagen vascular disease, renal failure, paraneoplastic
- Nerve conduction studies (NCS)
- Hereditary: Uniform conduction slowing (forearm conduction velocity of <38 m/s) with exception of HNPP, in which conduction slowing is limited to common sites of compression or entrapment.
- Inflammatory: nonuniform or segmental conduction slowing with abnormal temporal dispersion and conduction block
- Predominantly motor neuropathy: chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barr © syndrome, lead toxicity, porphyria
- Predominantly sensory neuropathy: diabetes, alcoholism, amyloidosis, paraproteinemic neuropathy, leprosy, Lyme, malignancy, vitamin B12 deficiency
- Painful neuropathy: diabetes, Lyme, vasculitis
- Other causes of acquired neuropathy include thyroid disease, HIV infection, vasculitis, neurosyphilis, occult neoplasm, heavy metal intoxication.
- Autosomal recessive disorders with neuropathy: Refsum disease; metachromatic leukodystrophy; Krabbe disease; Friedreich ataxia-progressive ataxia that may present with high-arched feet, sensory loss, and depressed tendon reflexes.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Guided by family history and findings
- If family history is negative and/or findings are sensory > motor abnormalities, consider an acquired polyneuropathy (e.g., secondary to diabetes mellitus, renal failure, collagen vascular disease, paraproteinemia).
- Initial screening tests should include the following: serum blood glucose, serum B12 with metabolites (methylmalonic acid or homocysteine), serum protein immunofixation, electrophoresis (2)[C]
- Genetic testing is warranted in most cases of inherited neuropathy (3)[A] with consideration of phenotype and mode of inheritance.
- PMP22, GJB1, MPZ, MFN2 account for 95% of CMT (4).
- If CMT is suspected, based on presentation with or without a family history, then NCS and electromyography (EMG) testing should be performed to differentiate demyelinating and axonal forms of CMT.
- If demyelinating (forearm conduction velocity <38 m/s), then targeted DNA testing is recommended.
- The first DNA test is for PMP22 duplication, which is present in 80% of patients with CMT.
- If X-linked inheritance cannot be excluded (no male-to-male transmission, and males more severely affected than females), GJB1 sequencing should be considered.
- If NCS/EMG is intermediate or if PMP22 duplication is negative
- Consider MPZ sequencing (which will detect another 10%).
- If X-linkage is a possibility, GJB1 sequencing
- If NCS/EMG is consistent with an axonal polyneuropathy (normal or slightly slow conduction), then the differential diagnosis is broad, and genetic testing is much more limited. If axonal, consider testing for MFN2 mutation, which causes the most common axonal CMT.
- If PMP22, GJB1, MPZ, and MFN2 are not revealing, consider whole exome sequencing (5).
Follow-Up Tests & Special Considerations
- 2-hour oral glucose tolerance test in cases of distal symmetric polyneuropathy
- Nerve biopsy is rarely indicated. May be helpful when coupled with muscle biopsy for vasculitis or amyloid
- The diagnosis of small fiber suspected based on history and normal EMG study is supported by skin biopsy to determine epidermal nerve fiber density.
Diagnostic Procedures/Other
- EMG/NCS: demyelinating and axonal forms distinguished by motor nerve conduction velocities
- Demyelinating (CMT1)
- Slowed motor nerve conduction, <38 m/s in the upper limbs (usually ~20 m/s)
- Focal slowing at common nerve entrapment sites is indicative of HNPP.
- Axonal (CMT2) degeneration manifests as a reduction in compound muscle action potential amplitude with normal or mildly slowed motor nerve conduction velocity, >38 m/s in upper limbs.
- Intermediate nerve conduction velocities
- Nerve conduction velocities 35 to 45 m/s
- Intermediate nerve conduction velocities can be seen in CMT1X and late-onset CMT1B.
Test Interpretation
- Sural nerve biopsy is not necessary for diagnosis of hereditary polyneuropathy, reserved primarily for acquired neuropathies (e.g., vasculitis, amyloid).
- Demyelinating (CMT1), loss of large myelinated fibers with "onion bulb" formation from demyelination and remyelination
- Axonal (CNT2) shows axon loss.
- Leprosy, vasculitis, and amyloid neuropathy have characteristic findings.
TREATMENT
No current treatments significantly alter the clinical course of patients with CMT (8)[A]. An important goal is to maintain mobility, flexibility, and muscular strength.
GENERAL MEASURES
- Pain, contracture, and weakness are the principal reasons for decreased motion in patients with neuropathies.
- Pain may be neuropathic or orthopedic and may result from joint deformities or compensatory overuse of certain muscle groups.
- Contracture and weakness (6)[C]
- Exercises to preserve strength, range of motion
- Strengthening hip flexors may improve walking.
- Prevent contractures: daily passive ROM, optimal positioning, splinting in a functional position
- Orthotic devices to compensate for weak dorsiflexion and plantar flexion, subtalar instability, and knee instability
MEDICATION
- There are no approved medications to treat CMT specifically.
- Nonsteroidal anti-inflammatory agents or acetaminophen for musculoskeletal pain
- Tricyclic antidepressants, carbamazepine, or gabapentin for neuropathic pain
- Avoid drugs and medications that are known to cause nerve damage, such as vincristine, taxol, cisplatin, isoniazid, and nitrofurantoin.
- Therapies under investigation include the following:
- Ascorbic acid: High dose of vitamin C is helpful in CMT1A animal model, but 1.5 g/day ascorbic acid supplementation showed no improvement in neuropathy score at 24 months in CMT (7)[B].
- Neurotrophin 3 (NT-3; nerve growth factor) is helpful in mouse models of CMT1A. A pilot trial of NT-3 showed improved sensory and reflex scores on the neuropathy impairment scale but no significant change in motor scores (8)[B].
ISSUES FOR REFERRAL
- CMT: Referral to neuromuscular/MDA clinic that provides a multidisciplinary approach.
- Muscular dystrophy association (MDA) provides support for clinic visits and durable medical equipment.
- Neurologist/neuromuscular physician for diagnostic support and to direct supportive therapy
- Orthopedic/foot-and-ankle surgeon for management of progressive severe pes cavus deformities. Tendon transfer, arthrodesis if indicated
- Genetic counseling prior to genetic testing. Mode of inheritance important to ascertain. Prenatal diagnosis may be possible for known mutations.
- Physical therapy: exercise, mobility, stretching (9)[C]
- Occupational therapy for hand weakness
ADDITIONAL THERAPIES
- Thick-handled tools and cutlery facilitate ADL.
- High-top shoes or boots can provide support for weak ankles. Ankle braces to limit ankle sprains and falls
- Orthotist provides custom fittings of ankle/foot orthoses (AFO) to improve gait and prevent foot drop.
- Custom shoes may be necessary, but truly custom shoes made on a custom last are difficult to find.
- Thumb splints can help with hand weakness and loss of fine motor skills.
SURGERY/OTHER PROCEDURES
- Patients may benefit from the release of plantar fascia, hammer toe correction, tendon transfer, Achilles' tendon lengthening, and foot or ankle arthrodesis in severe cases.
- Early osteoarthritis of the hip from reduced hip rotation may lead to early hip replacement.
COMPLEMENTARY & ALTERNATIVE MEDICINE
Adjunctive treatment with osteopathic manipulative medicine (OMM) theoretically could assist with improving gait, optimizing the patient's postural balance, and addressing any compensatory postural deviations, although there is no published evidence.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Daily low-impact exercise. The goal is muscle strength training, muscle and ligament stretching, stamina training, and moderate aerobic exercise.
PATIENT EDUCATION
www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001741/
PROGNOSIS
- With rare exceptions, the patient's lifespan is generally not altered. The degree of disability is highly variable and difficult to predict.
- Disability in 44% and depression in 18%
COMPLICATIONS
- Loss of mobility
- Kyphosis and scoliosis
- Early degenerative joint disease
- Pain
- Foot ulcers
REFERENCES
11 Timmerman V, Strickland AV, Z ¼chner S. Genetics of Charcot-Marie-Tooth (CMT) disease within the frame of the Human Genome Project success. Genes. 2014;5(1):13-32.22 Patzk ³ A, Shy ME. Update on Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep. 2011;11(1):78-88.33 England JD, Gronseth GS, Franklin G, et al. Practice parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72(2):185-192.44 Ekins S, Litterman NK, Arnold RJ, et al. A brief review of recent Charcot-Marie-Tooth research and priorities. F1000Res. 2015;4:53.55 DiVincenzo C, Elzinga CD, Medeiros AC, et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014;2(6):522-529.66 Ramdharry GM, Day BL, Reilly MM, et al. Hip flexor fatigue limits walking in Charcot-Marie-Tooth disease. Muscle Nerve. 2009;40(1):103-111.77 Pareyson D, Reilly MM, Schenone A, et al. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. 2011;10(4):320-328.88 Young P, De Jonghe P, St ¶auer F, et al. Treatment for Charcot-Marie-Tooth disease. Cochrane Database Syst Rev. 2008;(1):CD006052.99 Jani-Acsadi A, Krajewski K, Shy ME. Charcot-Marie-Tooth neuropathies: diagnosis and management. Semin Neurol. 2008;28(2):185-194.
CODES
ICD10
- G60.0 Hereditary motor and sensory neuropathy
- G60.8 Other hereditary and idiopathic neuropathies
- G60.9 Hereditary and idiopathic neuropathy, unspecified
- G54.5 Neuralgic amyotrophy
ICD9
- 356.1 Peroneal muscular atrophy
- 356.2 Hereditary sensory neuropathy
- 356.0 Hereditary peripheral neuropathy
- 353.5 Neuralgic amyotrophy
SNOMED
- Hereditary motor and sensory neuropathy
- Charcot-Marie-Tooth disease, type I (disorder)
- Charcot-Marie-Tooth disease, type II (disorder)
- Neuralgic amyotrophy (disorder)
- Giant axonal neuropathy (disorder)
- Djrine-Sottas disease
- Congenital hypomyelinating neuropathy (disorder)
CLINICAL PEARLS
- CMT presents in youth, adolescence, or early adult and with progressive distal muscle weakness and wasting, foot deformities, and areflexia.
- Inheritance varies; most patients without a family history of CMT will have a sporadic mutation of an autosomal dominant form.
- Consider genetic counseling.
- If family history is lacking, rule out treatable causes of acquired neuropathy.
- Treatment is supportive.