This Article  • Full text  • PDF  • Correction  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (2)  • Contact me when this article is cited  Related Content  • Related articles  • Similar articles in this journal  Topic Collections  • Neurogenetics  • Neuropathology  • Neurology, Other  • Genetic Disorders  • Alert me on articles by topic

Jun Li, MD, PhD; Khaled Ghandour, BS; Danijela Radovanovic, MS; Rosemary R. Shy, MD; Karen M. Krajewski, MS; Michael E. Shy, MD; Garth A. Nicholson, PhD

Arch Neurol. 2007;64(7):974-978.

Background  Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by a 1.4-megabase deletion at chromosome 17p11.2, which bears the PMP22 gene and other genes. However, whether other genes besides PMP22 contribute to the phenotype is unknown. Whether any mutation within the coding region of the PMP22 gene ultimately causes HNPP by reducing the amount of peripheral myelin protein 22 (PMP22) expressed in myelin is also unknown.

Objective  To determine whether affected patients develop a phenotype identical to that found in HNPP and whether the leucine 7 frameshift (Leu7fs) mutation reduces PMP22 levels in myelin.

Design  We evaluated affected family members by neurological examination, electrophysiology, and skin biopsies. We identified a large family with a Leu7fs mutation of PMP22 (11 affected members across 3 generations) that predicts truncation of the protein prematurely and eliminates PMP22 expression from the mutant allele.

Results  We found that PMP22 levels were reduced in peripheral nerve myelin in dermal skin biopsies in patients with an Leu7fs mutation. Through clinical and electrophysiological evaluation, we also found that patients with the Leu7fs mutation were indistinguishable from patients with HNPP caused by deletion. We also found that a length-dependent axonal loss became pronounced in elderly patients with Leu7fs mutations, similar to what has been described in heterozygous knockout mice (pmp22 +/–).

Conclusions  Taken together, these results confirm that the phenotypic expression is identical in patients with Leu7fs mutation and patients with HNPP caused by chromosome 17p11.2 deletion. They also demonstrate that reduction of PMP22 is sufficient to cause the full HNPP phenotype.

Author Affiliations: John D. Dingell VA Medical Center, Detroit, Michigan (Dr Li); Department of Neurology (Drs Li and M. E. Shy, Mr Ghandour, and Ms Krajewski), and Children's Hospital of Michigan (Dr R. R. Shy), Wayne State University School of Medicine, Detroit; and Department of Medicine, Molecular Medicine Laboratory, University of Sydney, Sydney, Australia (Ms Radovanovic and Dr Nicholson).

RELATED ARTICLES

Dwindling Indications for Sural Nerve Biopsy
David E. Pleasure
Arch Neurol. 2007;64(7):935-936.
EXTRACT | FULL TEXT  

Skin Denervation and Cutaneous Vasculitis in Eosinophilia-Associated Neuropathy
Chi-Chao Chao, Sung-Tsang Hsieh, Chia-Tung Shun, and Song-Chou Hsieh
Arch Neurol. 2007;64(7):959-965.
ABSTRACT | FULL TEXT  

Clinical and Electrophysiological Features in Charcot-Marie-Tooth Disease With Mutations in the NEFL Gene
Gabriel Miltenberger-Miltenyi, Andreas R. Janecke, Julia V. Wanschitz, Vincent Timmerman, Christian Windpassinger, Michaela Auer-Grumbach, and Wolfgang N. Löscher
Arch Neurol. 2007;64(7):966-970.
ABSTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Dwindling Indications for Sural Nerve Biopsy
Pleasure
Arch Neurol 2007;64:935-936.
FULL TEXT