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Central nervous system involvement in axonal Charcot–Marie–Tooth disease

Charcot–Marie–Tooth (CMT) disease is the most common inherited peripheral neuropathy, with an estimated prevalence of 1 in 2,500. The disease is phenotypically and genetically heterogeneous, and various classification schemes have focused on clinical presentation, inheritance pattern, and specific genetic mutations. The pathophysiology of peripheral nerve dysfunction in CMT has been extensively characterized by electrophysiological and pathological studies. Central nervous system involvement is considered unusual and has been occasionally reported in X-linked CMT and postmortem studies. We report a patient with CMT II in whom spinal cord atrophy was observed in vivo by means of magnetic resonance imaging (MRI). The patient is a 67-year-old man with a long history of CMT. He first noticed symptoms including bilateral foot drop, frequent ankle sprains, and falls in his early teens. Gradually he developed symmetric progressive distal numbness, weakness, and muscle atrophy in both legs. The upper extremities were involved in a similar pattern but at a later time. Electrodiagnostic tests (EDX) done when he was in his early 30s were said to be consistent with CMT disease. His symptoms progressed slowly over the next 30 years, but there was relatively rapid functional decompensation within the past year. There is a strong family history. His son has similar symptoms and has electrophysiological features of CMT. His father and grandfather both had high arches and ‘‘leg weakness,’’ but they were not evaluated by physicians. On examination, he had high arches, striking distal muscle atrophy especially in the lower extremities, profound distal muscle weakness, length-dependent sensory loss, and absent deep tendon reflexes throughout. No palpable nerve hypertrophy was found. Cranial nerves were intact. He had diminished muscle tone. His plantar reflexes were mute, however upon plantar stimulation, triple flexion was observed bilaterally. He otherwise had no clinical symptoms or findings suggesting central involvement. MRI of the spine performed to evaluate the cause for the triple flexion reflex revealed diffuse, severe spinal cord atrophy without signal abnormality (Fig. 1). Axial images suggested uniform involvement of the spinal cord. Postcontrast imaging was only done of the lower thoracic cord and lumbar spine and showed no abnormal enhancement. A repeat EDX revealed absent sensory nerve action potentials, absent right peroneal compound muscle action potential (CMAP), and low CMAP amplitudes and slow conduction velocities in other motor nerves (right ulnar 0.2 mV and 42 m/s, right median 0.2 mV and 54 m/s, right tibial 0.1 mV and 33 m/s); concentric needle examination demonstrated enlarged motor unit potentials and reduced recruitment. These findings suggest a chronic, severe, widespread sensorimotor peripheral polyneuropathy, with prominent features of axonal involvement. We consider the clinical features of our patient to be most consistent with CMT II given the prominent axonal loss. Hereditary motor and sensory neuropathy type V (HMSN V) can have similar electrophysiological findings but is associated with prominent spasticity, which was not present in our patient. Genetic testing was not performed due to the patient’s preference. We failed to find any reports of radiographic studies of spinal cord pathology in patients with CMT. We report here in vivo evidence of central nervous system involvement in a patient with CMT II disease. The MRI findings in our patient are consistent with several autopsy observations of CMT patients. Postmortem study of a 73-year-old with CMT II reported anterior horn cell and dendritic degeneration at the cervical and lumbar levels. Yoshimura et al. reported severe posterior column degeneration and atrophy of anterior horn cells in a 41-year-old with CMT II. A similar finding was observed in an autopsy of a 92-year-old with CMT 1B. CMT is primarily a peripheral nerve disease; however, our observations complement postmortem studies that suggest the pathology may extend to involve the central nervous system at least to the level of the spinal cord affecting both the anterior and posterior portions. It is unclear whether this is a primary process or VC 2009 Wiley Periodicals, Inc.