CMT Mutations Research from Japan

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Research Abstract from Brain 2003 Jan;126(Pt 1):134-151

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.

Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H,

Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima

K, Kira JI, Kaji R, Oka N, Sobue G.

Department of Neurology, Nagoya University Graduate School of Medicine,

Nagoya, Third Department of Internal Medicine, Kagoshima University

Faculty of Medicine, Kagoshima, Department of Neurology, Osaka

Kosei-Nenkin Hospital, Osaka, Department of Neurology, School of

Medicine, University of Occupational and Environmental Health,

Kitakyushu, Department of Pediatrics, Yamagata University School of

Medicine, Yamagata, Department of Neurology, Niigata University Graduate

School of Medicine and Dental Sciences, Niigata, Department of

Neurology, Hirosaki University School of Medicine, Hirosaki, Third

Department of Internal Medicine, Shiga University of Medical Science,

Otsu, Department of Neurology, Kitasato University School of Medicine,

Sagamihara, Department of Neurology, Tottori University Faculty of

Medicine, Yonago, Department of Neurology, Kyushu University Graduate

School of Medicine, Fukuoka, Division of Advanced Clinical Neuroscience,

University of Tokushima School of Medicine, Tokushima

and. Department of Internal Medicine, Hyogo College of

Medicine,Nishinomiya, Japan.

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.