Ported in some, severely affected, patients (in 5 [26] and 3.5 [28],…

Ported in some, severely affected, patients (in 5 [26] and 3.5 [28], respectively). CMT may predispose to obstructive sleep apnoea [49]. Only rarely patients have normal reflexes, mostly they are absent (in up to 46-75 of patients) or depressed [26-29]. Hypertrophy of nerves is a feature of CMT1A, rarely clinically present and mostly established by pathology [44] or imaging studies [50-53].van Paassen et al. Orphanet Journal of Rare Diseases 2014, 9:38 http://www.ojrd.com/content/9/1/Page 3 ofThere is large clinical variability between patients, even within the same family [54,55]. Overall, 1-7 of patients become wheelchair dependent [27,28,35]. A walking aid (cane, crutches or walker) is needed by 3-14 of patients [27,28,35,38]. Dejerine-Sottas syndrome (in the past also known as Hereditary Motor and Sensory Neuropathy type III) is a hereditary neuropathy with early onset and severe presentation. PRIMA-1 Currently it is not considered a different entity, but part of the phenotypic spectrum of CMT1, because the underlying genetic defects are known CMT1 genes, like the PMP22 duplication [56,57]. There are case reports on severely affected CMT patients demonstrating the presence of two mutations in two different CMT-related genes ("double trouble") [58,59]. On the other side of the spectrum, patients can be asymptomatic (1.6 PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/12711626 to 17 [26-28]) or only exhibit mild symptoms, like foot deformity, leading to no or only mild problems with walking [26,27]. However the term asymptomatic is questionable, as asymptomatic individuals might not experience complaints but clinical examination may show pes cavus and/or ankle jerk areflexia [27]. Although always considered a disease affecting the peripheral nervous system, a recent report on 15 CMT1A patients described central nervous system involvement [60]. Decreased white matter volume was found in 73 , with minimal, predominantly executive, cognitive disorders in 77 . Electrophysiologically, CMT1A is characterized by a homogeneous and diffuse motor and sensory nerve conduction slowing [6,27,38,54,61,62]. Due to a combined effect of dysmyelination and axonal dysfunction and loss, sensory nerve action potentials (SNAP) are also frequently reduced in the arms and reduced to absent in the legs [27,29,38]. Nerve biopsies show decreased density of myelinated nerve fibres, most pronounced in biopsies taken in the first year of life. The mean g-ratio PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/8627573 (axon diameter versus fibre diameter) is significantly lower than normal [63]. Characteristic onion bulb formation occurs after the age of six [44,63-65]. Axonal loss is also found in childhood [65]. Abnormal myelination probably extends over the whole nerve length. The most severe pathological changes were seen distally in nerves, but there were also changes in the proximal nerves and in the roots [66]. An overview of the key features of CMT1A is presented in Table 1.Aetiologyare reported [69]. Occasionally (<5 ) point mutations in the gene are found (see "PMP22 point mutations"). Mutations in the PMP22 gene had previously been identified as the Trembler mouse mutation. Identification of an identical mutation in a CMT family showed that the PMP22 gene is also responsible for CMT1A [70]. Gene dosage of PMP22 is the proposed mechanism, supported by the finding that increased PMP22 protein [71] and elevated PMP22 messenger RNA (mRNA) was found in CMT1A patients in sural nerve biopsies [72]. The PMP22 gene encodes a 22-kD protein that comprises 2 to 5 of peripheral n.