Brain, Vol. 126, No. 1, 134-151,
January 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg012
Demyelinating and axonal features of Charcot–Marie–Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients
1 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, 2 Third Department of Internal Medicine, Kagoshima University Faculty of Medicine, Kagoshima, 3 Department of Neurology, Osaka Kosei-Nenkin Hospital, Osaka, 4 Department of Neurology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 5 Department of Pediatrics, Yamagata University School of Medicine, Yamagata, 6 Department of Neurology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, 7 Department of Neurology, Hirosaki University School of Medicine, Hirosaki, 8 Third Department of Internal Medicine, Shiga University of Medical Science, Otsu, 9 Department of Neurology, Kitasato University School of Medicine, Sagamihara, 10 Department of Neurology, Tottori University Faculty of Medicine, Yonago, 11 Department of Neurology, Kyushu University Graduate School of Medicine, Fukuoka, 12 Division of Advanced Clinical Neuroscience, University of Tokushima School of Medicine, Tokushima and 13 Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
Correspondence to: Gen Sobue, MD, Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku Nagoya 466 8550, Japan E-mail: sobueg{at}tsuru.med.nagoya-u.ac.jp
Three genes commonly causing Charcot–Marie–Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.
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