Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4.
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.
Orlacchio
A
A
Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, 64 Via del Fosso di Fiorano, Rome 00143, Italy. a.orlacchio@hsantalucia.it
Patrono
C
C
Gaudiello
F
F
Rocchi
C
C
Moschella
V
V
Floris
R
R
Bernardi
G
G
Kawarai
T
T
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology; D004576:Electromyography; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000473:pathology; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D023281:Genomics; D006801:Humans; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D009431:Neural Conduction; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000074181:Spastin
D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human