Refinement of the "Silver syndrome locus" on chromosome 11q12-q14 in four families and exclusion of eight candidate genes

Abstract

Silver syndrome is a rare variant of autosomal dominant complicated hereditary spastic paraparesis (HSP), in which spasticity of the lower limbs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. The disease locus has been mapped to chromosome 11q12-q14. We report four Austrian families presenting with the typical clinical features of Silver syndrome. Sixteen individuals were affected upon clinical and/or electrophysiological examination. Ten persons showed mild to severe spasticity of the lower limbs. Wasting of the small hand muscles was present in nine affected family members of whom three had also gait disturbance. Three further individuals were asymptomatic. Electrophysiological studies showed normal or slightly to moderately slowed motor nerve conduction velocities, reduced amplitudes and occasionally chronodispersion of compound motor action potentials. In one patient, conduction block was observed. Sensory nerve action potentials were usually normal. Molecular genetic studies demonstrate linkage to chromosome 11q12-q14. Haplotype analysis in affected individuals indicates a common ancestor in the four families. By recombination analysis in affected individuals the Silver syndrome candidate gene interval can be reduced from 13 to 5.9 cM and can now be placed between the markers D11S1765 and D11S987. By sequence analysis of affected individuals eight functional and positional candidate genes could be excluded. Our study confirms the existence of the Silver syndrome locus on chromosome 11q12-q14 and provides the first report of nerve conduction velocity studies in Silver syndrome, which demonstrate the presence of a peripheral predominantly motor neuropathy.

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

“…Our findings may be relevant as well to other complex neurodegenerative processes in which lipofuscin accumulates (36). A number of unexplained adult onset peripheral neuropathies are linked to the region from 11q12 to 11q14 region containing the cat F gene (18,42). However, some of these have recently been shown to be caused by mutations in BSCL2 and are inherited in an autosomal dominant manner (12).…”

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome

“…A whole-genome scan established linkage to chromosome 11q12-q14, and several candidate genes were excluded by sequence analysis 6 . This chromosomal region overlaps the region involved in Silver syndrome 3 .…”

“…To investigate this possibility, we recruited the following additional families: four Austrian families 6 with spastic paraparesis and amyotrophy of the hands (F01-F04), one Italian family with pure motor neuropathy sometimes starting in the hands (F16), seven Austrian families with dHMN-V (F08-F15), one Belgian family with spastic paraparesis and with distal amyotrophy always starting and predominating in the legs (F05), one Brazilian family (F06) and the original English family described by Silver 2 (F07) and one English family (F17) with dHMN-V. Fine mapping indicated that the disease in all families could be linked to SPG17 and reduced the candidate gene interval from 13 cM to 2.5 cM, placing the critical region between the markers D11S1765 and D11S1883 (ref. 6).…”

“…6). Haplotype analysis further refined the critical region to an interval of ∼1 Mb between the markers WP7 and D11S4205 ( Table 1) containing 31 genes.…”

Hereditary spastic paraplegias

“…Neuropathy is a well-recognised association in complicated HSP, but is commonly asymptomatic, usually sensory, and is largely limited to descriptions of axonal degeneration [4,5,10]. Distal sensorimotor neuropathy and mixed demyelinating-axonal changes on neurophysiological studies have been occasionally reported with complicated HSP [11,12].…”