Hereditary motor and sensory neuropathy‐russe: New autosomal recessive neuropathy in balkan gypsies

Abstract

A novel peripheral neuropathy of autosomal recessive inheritance has been identified in Balkan Gypsies and termed hereditary motor and sensory neuropathy-Russe (HMSN-R). We investigated 21 affected individuals from 10 families. Distal lower limb weakness began between the ages of 8 and 16 years, upper limb involvement beginning between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in two instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve. HMSN-R is a new form of autosomal recessive inherited HMSN caused by a single founder mutation in a 1 Mb interval on chromosome 10q.

A mutation in an alternative untranslated exon of hexokinase 1 associated with Hereditary Motor and Sensory Neuropathy – Russe (HMSNR)

“…The phenotype is limited to the PNS, nerve biopsy immunohistochemistry showed no abnormalities in the expression levels or distribution of PBD-containing isoforms, and total Hexokinase activity measurement in cultured Scs showed no deficit in HMSNR samples (one should note however the possibility that neurons, rather than Scs, may be the primary target of the disease process). An intriguing possibility of increased anti-apoptotic activity is raised by the unusual profuse regenerative activity in HMSNR nerve, 8,9 contrary to the inhibited outgrowth expected under reduced HK1 activity or OMM binding. 24 Impaired apoptosis is increasingly recognised as a mechanism in CMT disease, and a role in its regulation has been proposed for a number of proteins mutated in different CMT forms, such as PMP22 (CMT1A), 32 EGR2/Krox20 (CMT1D/ CMT4E), 33 MFN2 (CMT2A) 34 and HSP27 (CMT2F).…”

“…The same distribution pattern and staining intensity were found in HMSNR (Figure 3b), with the difference in appearance due to the disease-related paucity of large fibres. 8,9 Next, we compared total Hexokinase catalytic activity in cultured Scs from an HMSNR patient and a normal control. We obtained no evidence of enzyme deficiency -the results were 55.3 nmol/min*mg protein in HMSNR (average of the three dilutions: 53.7, 66.7 and 45.5 nmol/min*mg) and 42.5 nmol/min*mg protein in control cells (average of the three dilutions: 42.2, 48.2 and 37.3 nmol/min*mg protein).…”

“…A peculiar electrophysiological feature is an increase in the threshold for electrical nerve stimulation, that could be due to muscle re-innervation by abundant small-calibre, hypomyelinated fibres. 8,9 Sensory action potentials are absent. Neuropathological studies show a marked reduction in the large myelinated fibre population, but no evidence of active demyelination or fibre degeneration and lack of hypertrophic changes.…”

“…The most characteristic feature of HMSNR neuropathology is the profuse regenerative activity, with numerous clusters of thinly myelinated regenerating fibres leading to an abnormally increased density of non-myelinated axons. 8,9 The findings do not provide a straightforward indication of the localisation of the primary defect -in the Schwann cell(SC) or the axon.…”

“…10 Further analysis reduced the region to B70 kb. 8,9,11 Here we report on the detailed study of this interval and the identification of a G4C substitution in a highly conserved novel alternative untranslated exon of Hexokinase 1 (HK1), implicating this unexpected candidate gene in the pathogenesis of PNS disorders.…”