Laboratory Studies

The workup should be primarily geared toward the identification or exclusion of a treatable neuropathy, including tests that address the causes of neuropathy. If a clear family history is identified and CMT has not been confirmed genetically, genotyping is warranted. Ascertaining the presence of a demyelinating or axonal form with nerve conduction studies, and establishing inheritance pattern with a pedigree can narrow the differential diagnosis and reduce the number of needed tests. De novo mutations are not rare, and genetic counseling can be pursued even in the absence of a family history of neuropathy.

Despite the lack of available treatments, genotyping is useful in providing information for prognosis and genetic counseling.^[84]

A negative genetic test does not exclude the diagnosis, especially in axonal forms. Beinfait and colleagues found mutations in only 3 out of 18 families (61 patients) with CMT2, and Bennett and colleagues found no mutations in 6 families with late-onset (median age 57), predominantly axonal neuropathies.^{[71, 83]}

Imaging Studies

Nerve root hypertrophy can be directly imaged with an MRI of the spine, which may help in distinguishing hereditary from acquired demyelinating neuropathy.^[85]Sonography of peripheral nerves can play a similar role.^[86]

Other Tests

Examination of the CSF is usually normal except for an elevated CSF protein. More marked elevations of protein are routinely seen in Dejerine-Sottas syndrome and may be more common in forms of CMT with MPZ mutations.^{[4, 87, 43]}

Procedures

Electrodiagnostic studies are critical to narrow the differential diagnosis.

Harding and Thomas found median nerve conduction velocities below 38 m/s in patients with CMT1 and above 38 m/s in patients with CMT2.^[66]Thomas and colleagues found median nerve conduction velocities averaged 19.9 m/s and ranged from 5-34 m/s in patients with CMT1. Values in the lower limb nerves were more difficult to obtain because of denervation of small foot muscles, but peroneal and tibial nerve conduction velocity averaged 17 m/sec and ranged between 10-22 m/sec. Sensory nerve action potentials were usually absent or severely reduced in amplitude, but when present, showed similar reductions in velocity (mean 22.9 m/sec).^[65]Dyck and Lambert had previously shown that ulnar nerve conduction velocities were even more severely affected in patients with Dejerine-Sottas syndrome, consistently measuring less than 10 m/s.^{[4, 87]}

Lewis and Sumner compared 18 patients with CMT1 to 40 patients with chronic acquired demyelinating neuropathies, and found that slowing was uniform both along individual nerves and between different nerves in an individual patient with CMT1. There was no evidence of dispersion or conduction block in any of these patients. They concluded that this pattern serves to distinguish patients with CMT1 from patients with CIDP or AIDP, who demonstrate more multifocality. These findings were confirmed in a larger study of 129 patients with CMT1.^{[88, 89]}

Female carriers with CMTX often demonstrate intermediate nerve conduction velocities, averaging 45 m/sec (ranging from 26-61 m/sec), which is significantly faster than CMT1A. Affected men, by comparison, have slower conduction velocities, averaging 31 m/sec, also significantly higher than those found in CMT1. The combination of intermediate conduction velocities and more rapid velocities in affected females suggests CMTX.^[78]Interestingly, Dubourg and colleagues found that the difference between the median and ulnar motor nerve conduction velocities in affected female patients differed significantly when compared to the uniform velocities found in CMT1 and healthy subjects. Men with CMTX also demonstrated uniform slowing.^[48]

CMT1

Dyck and Lambert observed an abnormally large transverse fascicular area in biopsied nerves, but a reduction in the number of myelinated fibers both per unit of fascicular area and per nerve. Large onion bulbs were seen, and there was marked variation in length and diameter of myelinated fiber internodes on teased fiber preparations, indicating chronic demyelination and remyelination. There was additional evidence of Wallerian degeneration in some nerve fibers, indicating concurrent axonal injury.^[4]

CMT1A

Sural nerve biopsies in patients with confirmed PMP22 duplications show nerve thickening and a reduction in myelinated fiber density even in the first year of life. As the first few years pass, active demyelination is prominent and onion bulbs are infrequent. By late childhood, active demyelination subsides and well-formed onion bulbs appear. There is loss of large fibers and a relative increase in small fibers as a result of regeneration of damaged axons.^[90]

CMT2

Behse and Buchthal demonstrated endoneurial areas to be normal. Onion bulbs were absent, and segmental demyelination was absent or rare on teased fiber analysis. The main abnormality was a reduction in the number of large fibers.^[91]

CMTX

Pathology of CMTX is mixed, as would be expected from electrophysiologic data. Hahn and colleagues found mild to moderate degeneration and loss of myelinated nerve fibers. Remaining fibers were surrounded by the thin myelin sheaths that would be expected with either repaired demyelination or regenerated nerve fibers. There were clusters of small fibers, indicating attempts at sprouting as part of the regenerative process. Teased fibers showed evidence of myelin instability in paranodal regions.^[47]

Treatment & Management

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Author

Timothy C Parsons, MD Fellow in EMG and Neuromuscular Disease, Department of Neurology, Columbia University Medical Center, New York

Timothy C Parsons, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Thomas H Brannagan III, MD Associate Professor of Clinical Neurology and Director, Peripheral Neuropathy Center, Columbia University Vagelos College of Physicians and Surgeons; Co-Director, EMG Laboratory, New York-Presbyterian Hospital, Columbia Campus

Thomas H Brannagan III, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Peripheral Nerve Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Neil A Busis, MD Chief of Neurology and Director of Neurodiagnostic Laboratory, UPMC Shadyside; Clinical Professor of Neurology and Director of Community Neurology, Department of Neurology, University of Pittsburgh Physicians

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Academy of Neurology<br/>Serve(d) as a speaker or a member of a speakers bureau for: American Academy of Neurology<br/>Received income in an amount equal to or greater than $250 from: American Academy of Neurology.

Chief Editor

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Former Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for Physician Leadership

Disclosure: Nothing to disclose.

Additional Contributors

Dianna Quan, MD Professor of Neurology, Director of Electromyography Laboratory, University of Colorado School of Medicine

Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Association of Neuromuscular and Electrodiagnostic Medicine<br/>Received research grant from: Alnylam; Pfizer; Ionis; Cytokinetics; Momenta; Viela Bio; .