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Abstract
Objective: To perform a clinical and genetic study of two large Italian families (RM-36 and RM-51) showing the cardinal clinical features of Silver syndrome (SS), a rare dominantly inherited form of hereditary spastic paraplegia (HSP) complicated by amyotrophy of the small hand muscles.
Methods: Clinical assessment including neurophysiologic, neuropsychological, and neuroimaging evaluations. Genetic studies included linkage and sequence analyses.
Results: Using a genome-wide survey in the RM-36 family, a novel locus (SPG38) has been identified and mapped within the 13.1-cM region on chromosome 4p16-p15 between markers D4S432 and D4S1599. The RM-51 family was linked to the SPG4 locus at 2p21-p24 and sequence analysis of SPG4 showed a novel frameshift mutation p.Asp321GlyfsX6. Clinical examination of the affected members carrying the mutation showed high frequency of additional clinical features including decreased vibration sense, pes cavus, temporal lobe epilepsy, and cognitive impairment.
Conclusions: This study demonstrates evidence of a novel locus SPG38 for Silver syndrome (SS) and suggests that genetic defects in SPG4 might lead to broad clinical features overlapped with those of SS.
Glossary
- AD=
- autosomal dominant;
- ALS=
- amyotrophic lateral sclerosis;
- AR=
- autosomal recessive;
- CAMCOG=
- Cambridge Cognitive Examination;
- CMAP=
- compound muscle action potential;
- CMCT=
- central motor conduction time;
- dHMN V=
- distal hereditary motor neuropathy type V;
- FDI=
- first dorsal interosseus;
- HS=
- hippocampal sclerosis;
- HSP=
- hereditary spastic paraplegia;
- LMN=
- lower motor neuron;
- MCI=
- mild cognitive impairment;
- MEP=
- motor evoked potential;
- MN=
- median nerve;
- mNCS=
- motor nerve conduction studies;
- MT=
- microtubule;
- PN=
- peroneal nerve;
- RFLP=
- restriction fragment length polymorphism;
- SCM=
- sternocleidomastoid muscle;
- sNCS=
- sensory nerve conduction studies;
- SS=
- Silver syndrome;
- SSEP=
- somatosensory evoked potential;
- TA=
- tibialis anterior;
- TLE=
- temporal lobe epilepsy;
- TN=
- tibial nerve;
- UMN=
- upper motor neuron;
- UN=
- ulnar nerve.
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