Clinical Presentation

Mr. C, age 65 and white, presented with a 5-year-history of progressive distal asymmetric leg muscle wasting, weakness, painful muscle cramps, and imbalance. He had no sensory complaints or history of diplopia, dysphagia, dysarthria, autonomic dysfunction, urinary or fecal incontinence, lower back pain, changes in mentation, or trauma. His past medical history includes diabetes mellitus and Meniere’s syndrome secondary to German measles. He has no family history of neuromuscular disorders.

Mr. C’s physical examination, including skin and eye evaluation, was unremarkable. On neurologic examination, he had left foot pes cavus (Figure 1), left calf atrophy (left middle calf circumference was 4.5 cm smaller than the right side), toe and foot dorsiflexion weakness (Medical Research Council muscle strength scale [MRC] score 2 on the left and 4 on the right), and left foot eversion weakness (MRC 4). The findings of other strength tests were normal. Mr. C had mild bilateral postural tremor but no clonus, fasciculation, or increased tone. Minimal vibratory impairment at the ankles and loss of temperature and pinprick sensation in his feet were noted. His reflexes were diffusely hypoactive, and his gait was ataxic with a negative finding of the Romberg test. Mr. C’s evaluations for mentation, cerebellar function, and cranial nerve function were unremarkable, except for right-sided hearing loss.

<p>Figure 1. Left foot pes cavus.</p>

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Figure 1. Left foot pes cavus.

Diagnostic Testing

Laboratory studies showed a hemoglobin A1C level of 6.6, but were otherwise normal including complete metabolic panel, complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein, rheumatoid factor, celiac panel, serum protein electrophoresis (SPEP), antinuclear antibodies (ANA), aldolase, Lyme serology, vitamin E levels, anti-cyclic citrullinated peptide (CCP) antibodies, HIV, angiotensin-converting enzyme (ACE), creatinine kinase (CK), and thyroid-stimulating hormone (TSH). Mr. C did not consent to lumbar puncture. The results of his neurophysiologic studies showed a diffuse uniform demyelinating polyneuropathy, and his MRI findings showed diffuse nerve root enlargement (Figure 2).

<p>Figure 2. Sagittal T2 weighted lumbar MRI diffuse enlargement of the cauda equina nerves (A) and diffuse enlargement of the nerve roots at foramina levels (B). Axial T2 weighted lumbar MRI shows enlargement cauda equina nerve diameters (C).</p>

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Figure 2. Sagittal T2 weighted lumbar MRI diffuse enlargement of the cauda equina nerves (A) and diffuse enlargement of the nerve roots at foramina levels (B). Axial T2 weighted lumbar MRI shows enlargement cauda equina nerve diameters (C).

Challenge Questions

1. What is the most likely diagnosis?

A. Amyloidosis

B. Amyotrophic lateral sclerosis

C. Charcot-Marie-Tooth (CMT) de novo mutation

D. Chronic inflammatory demyelinating polyneuropathy

E. Lymphoma

F. Neurofibromatosis

Click here for the answer

C, The most appropriate diagnosis is Charcot-Marie Tooth (CMT) disease.

2. What is the most appropriate treatment for the most appropriate diagnosis?

A. Gene therapy

B. Management of neuropathic pain

C. Orthopedic foot surgery

D. Orthoses

Click here for the answer

D, The most appropriate treatment for CMT is an orthoses.

Weakness and Wasting of Left Foot With Pes Cavus



Genetic testing was ordered, and Mr. C’s results showed he had a heterozygous duplication of exons 1 through 5 of the peripheral myelin protein 22 (PMP22) gene, confirming the diagnosis of CMT disease type 1A.1 Mr. C received an ankle-foot orthotic that improved his gait, and no further treatment was required over a 2-year follow-up period.


Diagnosis and Differential Diagnosis

Charcot-Marie-Tooth Disease. A hereditary motor and sensory neuropathy (HMSN), CMT most commonly presents in the first 2 decades of life.1 The prevalence of CMT1A is approximately 1 to 5/10,000 people with an incidence of 10.5 persons per 100,000 people.2,3 At least 10% of cases are caused by de novo mutations.4 Presentation of CMT1A at age 60 or more is seldom reported.5,6 A positive family history is common with an autosomal dominant pattern of inheritance. In this case, the lack of family history points to a de novo mutation. Characteristically, CMT1A presents with symmetrical distal leg weakness and wasting. Pes cavus is seen in almost all people with CMT1A, and is the initial finding for one-third of cases. Sensory abnormalities in a sock and glove distribution are less common. Enlargement of the nerve roots, as seen in this case, is associated with CMT1A.7 Prognosis for adult CMT1A is overall very good with slow clinical progression and normal life expectancy.

Chronic Inflammatory Demyelinating Polyneuropathy. A demyelinating polyneuropathy that should be considered in the differential, chronic inflammatory demyelinating polyneuropathy (CIDP) presents with chronic proximal and distal muscle weakness and nerve root enlargement.8 However, neurophysiologic studies in CIDP show conduction nerve block and temporal motor dispersion in some nerves and sparing in others rather than the diffuse demyelinating process seen in this case.

Amyotrophic Lateral Sclerosis. It is important to consider amyotrophic lateral sclerosis (ALS) in any case of asymmetric leg weakness with minimal or absent sensory symptoms. In this case, progression over 5 years without the involvement of other muscles and the absence of upper motor neuron signs (eg, stiffness, hyperreflexia, clonus, and Babinski reflex) make the diagnosis of ALS unlikely.

Amyloidosis. Nerve enlargement is common in amyloidosis, which presents with axonal length-dependent polyneuropathy with early sensory and autonomic symptoms. Pain, burning feet, autonomic dysfunction (eg, orthostatic hypotension or anhidrosis), and systemic organ involvement (eg, nephrotic syndrome, hepatomegaly, congestive heart failure) are often present.9 The absence of these clinical and neurophysiologic findings and long survival (10 years) in this case makes amyloidosis unlikely.

Neurofibromatosis Type 1. An autosomal-dominant disorder, neurofibromatosis type 1 (NFM1) is characterized by spinal root and peripheral nerve neurofibromas that present with sensory and motor symptoms. In this case, the absence of family history and lack of typical dermatologic changes required for diagnosis (café-au-lait patches, axillary or groin freckling, and neurofibromas) of NFM1 make this diagnosis unlikely.

Lymphoma-Related Neuropathy. A minority of people with lymphoma have malignant nerve infiltration, more prominent in proximal nerve that can present as a generalized polyneuropathy or as a CIDP-like neuropathy with or without nerve enlargement.10 Neurophysiologic studies often show a demyelinating pattern. In this case, however, the lack of lymphoma history, absence of common systemic symptoms, and duration of illness make lymphoma related-neuropathy unlikely.


Ankle-foot orthoses are recommended for treating foot drop and gait performance and also stabilize the ankle to prevent tripping and falling—frequent causes of morbidity and mortality in people with CMT. Along with orthotics, physiotherapy (eg, daily heel cord stretching to prevent joint contractures) and mild-to-moderate endurance and strength training may be helpful to prevent complications of joint deformities and falls.11 Some research suggests that a fixed-dose combination of baclofen, naltrexone, and sorbitol is safe and delays neuropathy progression in people with mild-to-moderate CMT1A.12

As yet, no gene therapy is approved for the treatment of CMT1A. Neurotrophin 3 (NT-3) is a potential gene therapy

candidate. A nerve growth factor, NT-3 contributes to neuron growth and survival in the central and peripheral nervous systems. In addition to repairing damaged nerves, NT-3 also repairs damaged muscle by increasing muscle fiber diameter and inducing remodeling of fiber types. For a group of 8 participants with CMT1A, NT-3 treatment for 6 months was associated with significant regeneration compared with placebo, with improvement in hand coordination and dexterity.13 Because of the small cohort size, further research is underway to determine potential benefits.

Although in this case, as in most, CMT1A was not painful, pain can occur. When pain is present in people with CMT, it can be treated with gabapentin, pregabalin, duloxetine, tricyclic antidepressants, or topical analgesics. Orthopedic surgery is reserved only for severe cases with debilitating pes cavus, hammer toes, or stiffness.14

1. van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies. Orphanet J Rare Dis. 2014;94:38

2. Bird TD. Charcot-Marie-Tooth neuropathy type 1. Gene Reviews. Published August 31, 1998. Updated March 26, 2015. Accessed September 4, 2019.

3. Kedlaya D. Charcot-Marie Disease. Emedicine. Medscape. Updated April 1, 2019. Accessed September 4, 2019.

4. Blair IP, Nass J, Gordon MJ, Nicholson GA. Prevalence and origin of the novo duplications in Charcot-Marie-Tooth disease type 1A: a first report of a de novo duplication with maternal origin. Am J Hum Genet. 1996;58(3):472-476.

5. Birouk N, Goudier R, Le Guern E, et al. Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain. 1997;120(Pt. 5):813-823.

6. Abe Y, Ikegami T, Hayasaka K, et al. Pressure palsy as the initial presentation in a case of late-onset Charcot-Marie-Tooth disease type 1A. Intern Med. 1997;36(7):501-503.

7. Liao JP and Waclawik AJ. Nerve root hypertrophy in CMT type 1A. Neurology. 2004;62(5):783

8. Schady W, Goulding PJ, Lecky BR, King RH, Smith CM. Massive nerve root enlargement in chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosug Psychiatry. 1996;61(6):636-640.

9. Antoine JC, Baril A, Guettier C, et. al. Unusual amyloid polyneuropathy with predominant lumbosacral nerve root and plexus involvement. Neurology. 1991;41(2, Pt. 1):206-208.

10. Tomita M, Koike H, Kawagashira Y, et al. Clinicopathological features of neuropathy associated with lymphoma. Brain. 2013;136(Pt. 8):2563-2758.

11. Bird TD. Charcot-Marie-Tooth (CMT) hereditary neuropathy overview. Gene Reviews. Published September 28, 1998. Updated January 24, 2019. Accessed September 4, 2019.

12. Attarian, S, Vallat JM, Magy L, et al. An exploratory randomized double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014;9:199-214.

13. Sahenk Z, Nagaraja HN, McCracken BS, et al. NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology. 2005,65(5):68-689.

14. Maranho1 DA, Volpon JB. Acquired pes cavus in Charcot-Marie-Tooth disease. Rev Bras Ortop. 2009;44(6):479-486.

FHR, WL, LBL, AGE, US, SV, MCF, and NT report no disclosures.