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Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype-phenotype correlations in Charcot-Marie-Tooth diseases.

Morphological modifications were investigated in the peripheral nerve of three unrelated patients with CMT1B. In two patients, molecular genetic analysis showed an Arg98His mutation in the extracellular domain of MPZ, associated with irregularly uncompacted lamellae. This observation confirms previous studies of a well-defined correlation between mutations and morphological phenotypes. In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations associated with this morphological phenotype.

It is widely thought that mammalian Schwann cells do not express P 0 , the major glycoprotein in peripheral myelin, unless they are induced to do so by axonal signals that can be mimicked by agents that trigger cAMP signaling pathways. In contrast, we find that cultured Schwann cells make large amounts of P 0 without the addition of any axonal-like signal, provided they have not been exposed to serum during the culture process. We also report that glial growth factor/neuregulin inhibits this constitutive P 0 expression. Myelin basic protein is regulated in a similar way. We suggest that expression of P 0 by Schwann cells before the onset of myelination may be prevented by inhibitory signals within the nerve, rather than by the absence of a positive signal from axons.

Rat spinal cord protein (SCP) from peripheral nerves (RSCP-PN) was not detected in purified rat peripheral nerve myelin by sodium dodecyl sulfate (SDS)-polyacrylamide slab gel electrophoresis or by immunodiffusion analyses using an anti-rat SCP in peripheral nerve (RSCP-PN) serum. The slab gel electrophoretic analyses also revealed that RSCP-PN has an appreciably lower molecular size than the component of rat peripheral myelin that is identified as P2 by its molecular size of 13,600 daltons. Thus, RSCP-PN and rat P2 are unrelated proteins.

Summary This study compares peripheral myelination in a specific subdivision of the sciatic nerve of jp msd and unaffected littermate mice. No significant differences are found in numbers of myelinated and unmyelinated axons, diameters of axons, thickness of myelin sheaths relative to axon diameter, extent of unmyelinated axon segregation by Schwann cell processes, or in the ultrastructure of myelin and Schwann cells. By contrast, jp msd mutant mice show severe CNS hypomyelination. This evidence, that the jp msd mutation affects only oligodendrocytes, distinguishes mutations at this locus from others producing CNS hypomyelination in which PNS myelin is also affected.

An infant female had connatal Pelizaeus-Merzbacher disease with neonatal onset of developmental failure, seizures, nystagmus, visual impairment, abnormal movements, and spasticity. There was nearly complete absence of central myelin with preservation of peripheral myelin. The 17 reported patients with connatal Pelizaeus-Merzbacher disease are summarized. Evidence of autosomal recessive inheritance is provided by our patient, 3 previously described girls, and 1 family with both boys and girls affected equally. This possible form of inheritance is important to consider in genetic counseling.