The phenotypic manifestations of chromosome 17p11.2 duplication

Abstract

Clinical and electrophysiological investigations and nerve biopsies were carried out on 61 patients shown to have a chromosome 17p11.2 duplication (hereditary motor and sensory neuropathy-HMSN Ia). Of these, 50 showed a Charcot-Marie-Tooth (CMT) phenotype and eight could be classified as having the Roussy-Lévy syndrome. Of the patients with a CMT phenotype, three had associated pyramidal signs and of these one had 'complicated' HMSN and also signs of cerebellar and bulbar involvement. Diaphragmatic weakness was present in three severely affected cases, one of whom also had denervation of the anal sphincter associated with faecal incontinence. One unusual case presented in middle life with incapacitating muscle cramps associated with calf hypertrophy and only mild clinical signs of neuropathy. Prominent distal sensory loss was a consistent feature in one family, resulting in acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT and Roussy-Lévy phenotypes, in seven patients. Upper limb motor nerve conduction velocity was 19.9 m/s +/- 1.3 (SEM), range 5-34 m/s. This corresponds to values previously obtained for autosomal dominant HMSN I. This series consisted mainly of older patients with more advanced disease. In contrast to the findings in younger patients, in their nerve biopsies, myelin thickness tended to be relatively reduced for axon size, indicating remyelination and/or hypomyelination; there was also regression of the onion bulbs. It is concluded that the possession of two copies of the peripheral myelin protein 22 gene within the duplicated region on chromosome 17p gives rise to a range of phenotypes and not solely to a CMT syndrome, and that the pattern of histological change in the peripheral nerves alters with advance of the disease.

Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation

“…9 Sensorineural hearing loss may occur in CMT1. 10 Even bulbar muscle weakness has been reported as a rare manifestation of CMT1A 10 or DSD.…”

“…10 The axonal subtype CMT2C is characterized by laryngeal recurrent and frenic nerve involvement 1,2 ; these nerves are rather long and progression of a length-dependent severe neuropathy might explain their involvement. 10 However, this mechanism cannot explain either oculomotor nerve palsy, which does not occur in CMT and DSD, or sensorineural hearing loss. In our patient, involvement of multiple cranial nerves seems to be associated with a specific EGR2 function.…”

Caveats in the Established Understanding of CMT1A

“…It has been hypothesized that this pathology is caused by repetitive demyelination and remyelination. Demyelination has thus been considered to account for the slowed conduction velocity in CMT1A 7, 8…”

Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication

“…Blood from the patient's grand-niece was not available for study. The presence or absence of the chromosome 17p11.2-p12 duplication was determined using fluorescent semiquantitative PCR with the following microsatellite markers contained within the involved segment: D17S122, D17S839, D17S921, D17S955 and D17S1358, as de-scribed by Thomas et al (7). Analysis was carried out with an ABI 373A automatic DNA sequencer and the Genescan software.…”