Hereditary Motor Sensory Neuropathy (HMSN)

Author(s): Vikki A. Stefans, MD

Originally published:

Last updated:11/16/2016

1. DISEASE/DISORDER:

Definition

Hereditary motor sensory neuropathy (HMSN) or Charcot-Marie-Tooth Disease (CMTD), is a group of inherited, progressive, motor and sensory peripheral nerve disorders with demyelination, axonal degeneration, or both. It overlaps with distal hereditary [pure] motor neuropathies (dHMN) but is distinct from hereditary sensory and autonomic neuropathy (HSAN) and motor neuron disease (MND). Peripheral neuropathy is also part of some mitochondrially inherited and other multisystem genetic diseases not under the HMSN umbrella.1

Etiology

50-60 genes which code for proteins involved in nerve structure (myelin, Schwann cells, axons) and function (axonal transport, energy production) have been identified as causing length-dependent neuropathy. Modes of inheritance include autosomal dominant, autosomal recessive, X-linked recessive, and X-linked semi-dominant (milder disease in carrier females).

Epidemiology including risk factors and primary prevention

HMSN is the most common inherited neuromuscular disease with overall prevalence of approximately 1/2500 and incidence 15/100,000 in the general population. Frequency of some subtypes varies with ethnicity. Risk factors are family history for autosomal dominant or X-linked forms, and consanguinity for autosomal recessive ones. Primary prevention is genetic counseling.

CMT1 = primarily demyelinating (nerve conduction velocity 5-30 m/sec), representing nearly half of all CMT cases; CMT1a, due to duplication in PMP22 (peripheral myelin protein 22), accounts for nearly a third of all CMT cases, and for 60-70% of cases within this group. CMT1b, due to MPZ (myelin protein zero) alterations, accounts for another 12% in this group.

CMT2 = primarily axonal (nerve conduction velocity 35-48 m/sec), about one fifth of all CMT cases.

CMTX = X-linked, most with both demyelinating and axonal features. CMTX1, due to GJB1 (gap junction B1, formerly known as connexin 32) alterations, comprises 10-12% of all CMT cases and is by far the most common in this group.

CMT4 = autosomal recessive, typically more severe, early onset, may be demyelinating, intermediate, or axonal.

Classification is complex because both electrophysiology and genetic cause are considered. The above is the system most frequently used today. Some sources include CMTX1 in CMT1, some formerly designated CMT3 as the Dejerine Sottas phenotype with nerve hypertrophy; others use CMT3 for axonal autosomal recessive diseases and CMT4 for demyelinating autosomal recessive diseases. A dominant-intermediate classification (DI-CMT) may also be encountered.

Additionally, hereditary neuropathy with susceptibility to pressure palsy (HNPP), if included as a CMTD, comprises about 2% of cases.

For a frequently updated complete listing, refer to the Charcot-Marie-Tooth Hereditary Neuropathy Overview in NCBI Gene Reviews.2

Patho-anatomy/physiology

CMT1a has overproduction of peripheral myelin protein; other demyelinating forms have myelin compaction or impaired maintenance or development with problems in Schwann cell differentiation, function, or survival. Histologically, onion bulbs, focal folds and/or swelling occur. Axonal forms may have abnormal mitochondrial fusion or fission, or other defects in axonal transport and intracellular membrane trafficking.

Several demyelinating etiologies can produce a “Dejerine-Sottas” phenotype with early onset, palpable nerves, and marked onion-bulb formation. “Roussy-Levy syndrome” describes a clinical picture with tremor and also occurs with a variety of genetic alterations. Additionally, different changes in the same gene may cause different phenotypes; the best-known example is PMP22, for which duplication causes CMT1a, deletion causes hereditary disposition to pressure palsies (HNPP), and point mutations cause CMT1e. Cases of more severe disease with homozygous changes or triplication in that gene, or with additional variations in other CMT-associated genes, have also been reported.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Most forms show progressive loss of strength and sensation distally to proximally, “length-dependent” affecting lower extremities first.

Early Onset: Severe forms may have infant hypotonia with delayed motor milestones, toe walking and even arthrogryposis; most present before age 20, with clumsiness and abnormal gait. Later onset cases may mimic slowly progressive acquired neuropathies.

Later Course: Foot deformity, foot drop, and later quadriceps weakness may further limit unaided mobility. Falls increase with fatigue and proprioceptive loss. Fine motor performance is more affected, with cramping pain in distal extremities, and visible atrophy.

Rare forms may have proximal or predominantly upper extremity involvement.

Specific secondary or associated conditions and complications

Musculoskeletal: pes cavus, hammer or claw toes typical in 1a; some may have pes planus instead. Scoliosis and hip disorders are uncommonly seen with 1a, more notable in some other types. CMT1a is usually otherwise uncomplicated.

Pulmonary: laryngeal dysfunction is characteristic of CMT2c due to alterations in TRPV4 (transient receptor potential cation channel subfamily V member 4, which is also associated with short stature and musculoskeletal anomalies in some cases); sleep apnea, restrictive disease and vocal cord paralysis can also occur in some CMT2 and CMT4. Cardiac function is usually unaffected.

Hearing: Impairment characteristic of some types, varied onset and severity; audiologic screening should always be done in CMTX1.

Vision impairment is uncommon; optic atrophy can occur in CMT 2a and CMTX5, and glaucoma and cataracts in some CMT4.

Intellectual disability: some CMT4, CMTX4 (Cowchock) and CMTX5 (Rosenberg-Chutorian/Arts). Learning differences and cerebral white matter changes may be seen in CMTX1 and others.

Skin ulcers: CMT2b (RAB7)

2. ESSENTIALS OF ASSESSMENT

History

Family history: Ask about others in the family with incoordination, gait, or leg problems, as well as anyone specifically diagnosed. Inquire sensitively about possible consanguinity.

Delayed gross and fine motor milestones, awkward/slow running, frequent falls, recurrent ankle injuries, progressive fatigue/poor endurance, distal extremity pain/cramps. Sensory loss typically less noticeable to patient and family. Neuropathic pain (tingling, burning, aching) less common but may occur.

Associated symptoms: voice, respiratory, hearing or visual impairments, need for educational modifications.

Physical examination

Classic pictures of CMT1a have “inverted champagne bottle” legs due to atrophy around the ankle and preserved proximal muscle. Pes cavovarus, hammer/claw toes are noted with intrinsic atrophy, with later loss of palmar arches. Planovalgus may occur instead with early hypotonia. Spine and hip status should be assessed.

Foot drop (steppage) pattern may progress to waddling gait in more advanced disease.

Neurologic: diminished or absent reflexes, particularly lower extremity, mild proprioceptive deficit with preserved pinprick/light touch in most types, distal weakness in peroneal then other muscle groups, milder weakness of hand intrinsics and eventually abnormal grip. Romberg may be positive, but pure cerebellar (nystagmus, dysmetria) or upper motor neuron signs should not be present.

Findings suggesting less common types include proximal weakness, upper extremity predominance, scapular winging, voice changes, calcaneovalgus, and evidence of decreased protective sensation.

Functional assessment

ADLs and mobility: Specifically ask about the extent of any help provided with daily activities, and about any difficulties in school. Fasteners and shoe-tying may be difficult. Handwriting speed and legibility may be a barrier to academic achievement. Limited ability to participate in sports, recreation and other community activity due to pain and fatigue, and effects on mood and behavior should be addressed.

Laboratory studies

Sometimes needed to rule out other causes of neuropathy (nutritional, toxic, autoimmune.) PMP22 duplication can be tested first if history and exam typical; some sources recommend CMT1b if negative, and/or CMTx1 if X-linked pedigree possible. Panel testing is first line for atypical presentations, and may be narrowed by electrodiagnostic findings.

Imaging

MRI brain may show mild white matter changes in some forms. If there is clinical doubt that incoordination is purely proprioceptive and weakness-related, cerebellar abnormality may be an important clue to alternative diagnosis such Friedreich’s ataxia or spinocerebellar disorders.

Orthopedic imaging of hips or spine is done when clinically indicated.

Muscle ultrasound or MRI could reveal enlarged nerves and pattern of distal atrophy but is not usually essential to diagnosis.

Supplemental assessment tools

Electrodiagnosis is the mainstay of clinical classification into demyelinating (low or very low NCV), axonal (near-normal NCV early, more denervation) or intermediate forms. It can also confirm pre- or questionably symptomatic disease when a family history is known and genetic tests are not covered or available in the situation. Note that Friedreich and other ataxias and hereditary spastic paraparesis may also show abnormal results so that finding a reduced NCV does not always confirm CMTD as the diagnosis.

Sural nerve or neuromuscular biopsy is rarely indicated, but may help to confirm effect of a genetic variation of uncertain pathogenicity. If done, electron microscopy (EM) studies can delineate details of anatomic findings in the nerve or structural defects of mitochondria, and should usually be requested.

Early predictions of outcomes

Most forms are slowly progressive and compatible with normal general health and lifespan, with needs for augmentative mobility later in adult life. In general, early onset and greater severity of onset correlate with faster progression. Research specific mutations via OMIM, PubMed, and Leiden for their spectrum of severity and course.

Environmental

Assess home, school, work and barriers to participation, e.g., uneven terrain, stairs, long distances. Address fall prevention; remove loose rugs, add handrails for stairs and bathroom. Voice dictation and typing facilitate lengthier written communications. Proprioceptive loss may impede driving without hand controls; specialized OT assessment is often warranted.

Social role and social support system

Patients and families need support and information. Encourage affected adults to seek care for themselves also. Advocate for modified recreation, camp and sports participation, accommodations at school and work, consider referral for vocational rehabilitation, and joining registries, MDA affiliations, and/or disease-specific national associations.

Professional Issues

Referral for genetic counseling should be made, with attention to relief of guilt about passing on the condition, and the effects of a diagnosis on employment, non-medical insurance, reproductive decisions, and family relationships. Truly asymptomatic children in an affected family are not typically tested.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

HMSN-specific comprehensive guidelines are not available. There is an AAN

practice parameter for distal symmetric polyneuropathy indicating class A evidence for genetic testing in HMSN3; other sources recommend various diagnostic testing strategies. Reviews of effectiveness of orthotic management including custom, not off-the-shelf, inserts for relief of foot pain and flexible AFOs for foot drop are generally favorable. Some surgeries appear beneficial. Several disease-specific organizations post suggestions for management. Evidence to avoid vincristine in CMT1a is strong. There is a “practice brief” focused on foot care published by the Centre of Research Excellence in Neuromuscular Disorders Murdoch Children’s Research Institute/University of Sydney, Australia at:

https://www.mcri.edu.au/sites/default/files/media/charcot_marie_tooth_-_why_feet_matter_3.pdf

At different disease stages

new onset/acute

  • Review options for diagnosis with family, being aware gene testing for HMSN is specifically considered investigational by some third party payers.
  • Curative treatments are not available; clinical trials of medications, generally specific to genetic diagnosis, are underway though some have been tested and failed to demonstrate benefit.
  • Night splints are generally not helpful, but stretching, serial casting, and therapy for functional improvement of balance and mobility skills have shown benefit.
  • Recommend alternatives to reduce volume of handwritten work, limiting overuse of distal leg muscle, and treating with NSAIDs and acetaminophen for pain.
  • Formal 504 plans address physical accommodation needs including not grading on penmanship; elevator use, extra time or shorter distances due to falls, fatigue and endurance; lunch tray assistance, extra set of books at home. IEPs should usually be reserved for cases where multiple aspects of learning are problematic.
  • Reassure that though progressive, most HMSN is compatible with gainful employment and normal lifespan.

subacute/chronic

  • Screen regularly for scoliosis during growth.
  • Introduce orthotic management and gait aids including cane, walker, and manual or powered wheelchair only as needed to promote safe and efficient mobility. In advanced stages, individuals may need powered mobility because of hand/upper limb weakness.
  • Promote strengthening and use of proximal muscle in exercise and recreation.

Coordination of care

Interdisciplinary approach is ideal; team includes patient and family, primary care physician, physiatrist, neurologist, geneticist and/or genetic counselor, physical therapist, occupational therapist, orthotist, and psychologist, social worker or educational specialist. Routine orthopedist involvement versus screening and selective referral are options. Neuropsychology, speech therapy, ENT, audiology and pulmonology are needed for some forms as well.

Patient & family education

Explain that although HMSN is an MDA-covered condition, it is not “muscular dystrophy” but peripheral neuropathy. Avoid pursuing occupations requiring above-average fine motor skills. Teach self-advocacy for avoiding overwork and obtaining modifications. Encourage using orthotics, adaptive equipment and techniques to avoid limiting participation. Educate about registries, support organizations, and possible clinical trial participation.

Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based

Neuropathy Impairment Score (NIS) and CMT Neuropathy score (CMTNS, CMTNS2) have been validated for CMT1a to monitor progression for clinical and research purposes. In children, the Walk12, CMT examination score (CMTES) and 9-hole peg test have correlated reasonably but they and the CMTNS may not be as sensitive to changes over time. Timed 6-10 meter comfortable walk and Maryland Foot Score have been used for orthopedic purposes.

Usual scales such as WeeFIM, FIM, PEDI, health-related quality-of-life assessments, and CHART or similar measures of participation are not particularly suited for CMT progression but could be used for clinical screening and guidance.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Remember that abnormal electrodiagnostic study without either thorough neurologic examination or genetic confirmation can lead to misdisgnosis of CMT in cases of HSP, SCA, toxic, metabolic, and mitochondrial disorders.

Help patients avoid sedentary, inactive lifestyles.

Many patients and families are ashamed and fearful about diagnosis, and benefit from meeting others with CMT in person or online. MDA resources including MDA camps are available to young people with this condition and can greatly increase self-efficacy and self-confidence. Empowered patients and families raise funds and awareness of “the biggest disease no one has ever heard of,” some after avoiding diagnosis and struggling to manage without aids or modifications for many years.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

A mixture of compounds called PXT3003 and an anti-progestin (ulipristal acetate) are currently being studied for CMT1a; ascorbic acid, creatine, cucurmin, and ubiquinone were helpful in rodent models with no demonstrable benefit in short to mid-term human trials. A trial of mexiletine for CMT-related muscle cramps is underway. Cost-effective routes to specific diagnosis, optimal exercise programs, and pedatric CMT scales are still subjects of study and require individual clinical judgement.

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Avoiding other medicines besides vincristine and in other forms of HMSN besides CMT1a may be advisable, but evidence is less certain for amiodarone, cisplatin, oxaliplatin, dapsone, gold salts, leflunomide, nitrofurantoin, pyridoxine, taxols, thalidomide, and even some antidepressants.   New genes and modifiers of known genes are being sought to explain some variation in severity and possibly open up other avenues for treatment.

REFERENCES

  1. Charcot–Marie–Tooth Diseases: An Update and Some New Proposals for the Classification, Stéphane Mathis et. al. J Med Genet. 2015;52(10):681-690.
  2. Charcot-Marie-Tooth Hereditary Neuropathy Overview, Thomas D Bird, MD Initial Posting: September 28, 1998; Last Revision: May 7, 2015. http://www.ncbi.nlm.nih.gov/books/NBK1358/
  3. England JD et. al., Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Neurology. 2009 Jan 13;72(2):185-92.

Additional Bibliography

Burns, J et. al. Effective orthotic therapy for the painful cavus foot: a randomized controlled trial. Journal of the American Podiatric Medical Association, 2006 96(3), 205-211.

Burns, J et. al. Feasibility of foot and ankle strength training in childhood Charcot-Marie-Tooth disease, Neuromuscul Disord. 2009 Dec;19(12):818-21.

Chetlin, RD et. al. Resistance training effectiveness in patients with Charcot-Marie-Tooth disease: recommendations for exercise prescription. Arch Phys Med Rehabil. 2004; 85(8):1217-23.

Guyton, GP. Current concepts review: orthopaedic aspects of Charcot-Marie-Tooth disease, Foot Ankle Int. 2006 Nov;27(11):1003-10. Review.

Hanemann, CO. Müller HW, Pathogenesis of Charcot-Marie-Tooth 1A (CMT1A) neuropathy, Trends Neurosci. 1998 Jul;21(7):282-6.

Hawke, F et. al. Custom-made foot orthoses for the treatment of foot pain, Cochrane Database of Systematic Reviews(3), 2008.

Leeuwesteijn, AE et. al. Flexible cavovarus feet in Charcot-Marie-Tooth disease treated with first ray proximal dorsiflexion osteotomy combined with soft tissue surgery: a short-term to mid-term outcome study, Foot Ankle Surg. 2010 Sep;16(3):142-7. doi: 10.1016/j.fas.2009.10.002.

Lindeman, E et. al. Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: a randomized clinical trial, Arch Phys Med Rehabil. 1995;76(7):612-20.

Maggi, G, et. al. Outcome measures and rehabilitation treatment in patients affected by Charcot-Marie-Tooth neuropathy: a pilot study, Am J Phys Med Rehabil. 2011 Aug; 90(8):628-37.

Pagliano, E, et.al. Outcome measures for Charcot-Marie-Tooth disease: clinical and neurofunctional assessment in children, J Peripher Nerv Syst. 2011 Sep; 16(3): 237–242.

Original Version of the Topic:  

Joline Skinner, MD. Hereditary Motor Sensory Neuropathy (HMSN). Publication Date: 2011/11/16.

Author Disclosure

Vikki A. Stefans, MD
Nothing to Disclose

Related Articles