Molecular diagnosis of hereditary peripheral neuropathies

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Hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of disorders which include the most common motor and sensory forms (HMSN) as well as the rarer pure motor (HMN) and pure sensory (HSN) phenotypes. These diseases can be inherited as autosomal dominant (AD), autosomal recessive (AR) or X-linked traits. As a group, Charcot-Marie-Tooth (CMT) disease and related neuropathies (Déjérine-Sottas disease [DSD], congenital hypomyelinating neuropathy [CHN] and hereditary neuropathy with liability topressure palsies [HNPP]) represent the most common inherited peripheral nerve diseases as well as one of the most common human inherited disorders with a prevalence of ∼20-40:100,000. During the last decade, advances in molecular genetics have greatly increased our understanding of these disorders and significantly changed the clinical approach to them by providing powerful molecular tools for diagnosis. The most common form is demyelinating CMT (CMT1, HMSN I). Based on genetic location and the gene involved, CMT1 is further subcategorized into AD CMT1A (PMP22, 17p11.2) and CMT1B (MPZ, 1q21.2), and X-linked dominant CMTX (Cx32, Xq13.1). Approx. 3/4 of CMT1 patients belong to the CMT1A subgroup and carry a common 1.5-Mb duplication on chr. 17p11.2, encompassing the gene encoding the myelin protein PMP22. Given the high duplication rate insporadic cases, the diagnosis of CMT1A should be considered even in the absence of a family history. Furthermore, the reciprocal deletion of the CMT1A 1.5-Mb tract is commonly (∼80%) observed in HNPP patients. Altogether, detection of these relatively common molecular abnormalities allows diagnosis in the vast majority of CMT1 or HNPP patients. Patients who do not have the CMT1A duplication should be screened initially for Cx32 mutations which are the next most frequent cause of CMT1, accounting for ∼10% of patients. Approx. 4% of cases belong to the CMT1B subgroup, harboring mutations, in the gene (MPZ) encoding the myelin protein P0. Of the remaining cases, some have been demonstrated to carry mutations in the EGR2 gene. Interestingly, mutations in the PMP22, MPZ and EGR2 genes can also cause the more severe early-onset variants DSD and CHN. A number of loci have been linked to the rare autosomal recessive forms of CMT1. Very recently, mutations in the MTMR2 and NDRG1 genes have been associated with two distinct phenotypes, AR-CMT1 with myelin outfoldings (CMT4B) and HMSN-Lom, respectively. Approx. 20-30% of CMT patients exhibit the axonal type CMT2. For the majority of these patients, no molecular test is currently available. Although several loci have been associated with this form, only one disease gene, NF-L on chr. 8p21, has been identified thus far. However, Cx32 mutationshould always be excluded in female patients diagnosed with CMT2. Finally, recent evidence has indicated that mutations in the MPZ gene can be found in ∼5% of AD-CMT2 families.

Original languageEnglish
JournalNeurological Sciences
Issue number4 SUPPL.
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)


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