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Congenital hypomyelination neuropathy (CHN) has been related with mutations of the MPZ gene that codes for P0, the major structural protein of the peripheral myelin and of EGR2/Krox20 gene that codes for a transcription factor essential for the normal development of myelinating Schwann cell. More recently, we reported the association between CHN and a Ser72Leu mutation of the peripheral myelin protein 22 (PMP22), a quantitatively minor component of the compact myelin of peripheral nerves, whose functions are still debated. Here we describe a second patient with CHN associated with a novel mutation of PMP22. The patient is the 4-year-old daughter of healthy nonconsanguineous parents and is affected with early delay of motor development. At seven years she could not walk without support; examination disclosed muscle weakness and atrophy, foot drop, pes cavus, scoliosis, areflexia, and impairment of all sensory modalities. MNCV at the median nerve was 3.6 m/s. Nerve biopsy disclosed marked loss of fibers; residual fibers were devoid of myelin or encircled by extremely thin myelin sheaths and were surrounded by basal laminae onion bulbs. Clinical follow up demonstrated no progression of the disease. Molecular analysis disclosed a novel heterozygous T-to-C transition at nucleotide 374 of PMP22, that is predicted to cause a nonconservative substitution of cysteine109 (a phylogenetically conserved residue) with arginine, in the third transmembrane domain. The duplication of PMP22 causes the common demyelinating form of Charcot-Marie-Tooth neuropathy type 1 (CMT1). Our reports indicate that missense mutations of the same protein may cause dysmyelination rather than demyelination, and prompt to investigate the function of PMP22 in myelinogenesis as well as in Schwann cell differentiation. [ABSTRACT FROM AUTHOR]

Slow channel syndrome, first recognized by Engel in 1982, has distinct phenotypic features, dominant inheritance, selective weakness of cervical scapular and finger extensor weakness, ophtalmoparesis. Histochemical findings show type 1 fibers preponderance, small group of atrophic fibers of either fiber type, increased fiber size variability, tubular aggregates. We examined 3 biopsies in 3 patients (2 males – 55years and 66years, 1 female – 61years) presenting a dominant distal myopathy with variable age at onset (from second to third decade). The patients had ophtalmoparesis, upper limb extensor, forearm and finger weakness and distal myopathy with a progressive slow course. The woman had also some difficulty in anterior tibial flexor muscle but also atrophy of forearms muscles. Electrophysiology on single stimulus of ulnar nerve showed repetitive CMAP. The genomic wide linkage analysis identified 3 regions co-segregating with the disease in chromosome 1, 13, 17. Next generation sequencing showed in all patients a known mutation in epsilon-subunit of AchR receptor and a mutation in phospholipase. Muscle showed mild changes consisting in atrophic fibers, mostly of type 2, some fiber type grouping, central nuclei and ring fibers. Such fibers are consistent with abnormal regeneration.We suggest that the occurrence of mutations involving both AchR receptor and phospholipase might concur in determining a new distal phenotype with permanent weakness. Our family was previously diagnosed as myotonic dystrophy or distal myopathy. The presence of the histochemical findings of both myopathy and neuropathy were present. We suggest the possibility of calcium overload due to prolonged open time of the AChR channel with a presynaptic component might determine a distal neuro-myopathy with slow evolution and muscle rearrangement due to a muscle fiber degeneration and functional denervation. The slow channel mutation should be searched in families with permanent distal weakness. [Copyright &y& Elsevier]

Abstract: X-linked Charcot-Marie-Tooth disease is the second most common variant of CMT. CMTX1 is caused by mutations in the GJB1 gene encoding for connexin 32. We describe an Italian family with an intermediate CMTX phenotype with late onset. Mutation screening of the GJB1 gene revealed a 9-bp duplication leading to the insertion of three aminoacids (Thr-Val-Phe) between the end of the second extracellular domain and the beginning of the fourth transmembrane domain. This is the third in-frame insertion in the GJB1 gene identified so far and, like the previous ones, it consists in the duplication of the flanking sequence which is repeated in tandem in the wild-type gene. [Copyright &y& Elsevier]

This study reports the characterization of a novel human gene, chromosome 3 open reading frame 6 (C3orf6), mapped to chromosome 3q28, within the critical region of hereditary spastic paraplegia SPG14 locus. Based on computational “spliced” EST alignment and RT-PCR, two C3orf6 transcript variants were identified. The longer C3orf6 transcript contains a 1449-nt ORF, encoding a protein of 482 aa, while the shorter variant contains a 921-nt ORF, encoding for a protein of 306 aa. C3orf6 gene is organised on 12 exons and the shorter transcript comes from an alternative splicing event skipping exon 6. The two mRNA are differentially expressed in brain and in several other human tissues with a predominant level for the shorter transcript. By database analysis, EST assembling and RT-PCR, we identified the transcripts of mouse and rat C3orf6 orthologous genes. The involvement of C3orf6 in the spastic paraplegia was investigated by sequencing all coding exons and flanking sequences in the SPG14 family, excluding the presence of causative mutations. [Copyright &y& Elsevier]

Examines the association of hereditary spastic paraplegias (HSPs) associated with mental retardation and distal motor neuropathy, ASPG14. Description of the disorder of lower limbs; Characterization of the HSPs by clinical and genetic heterogeneity; Use of homozygosity mapping for chromosome 3q27-q28.