Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia.
BACKGROUND
Mutations in a novel GTPase gene SPG3A cause an autosomal dominant hereditary spastic paraplegia linked to chromosome 14q (SPG3), which accounts for approximately 10% to 15% of all autosomal dominant hereditary spastic paraplegia cases. The mutational spectrum of the SPG3A gene and the phenotype/genotype correlations have not yet been established.


OBJECTIVE
To describe a kindred with an infantile onset of hereditary spastic paraplegia caused by a novel mutation in the SPG3A gene.


METHODS
Complete neurological examination and genetic analysis were performed on 6 affected members of a small African American kindred. Linkage analysis to genetic markers near autosomal dominant hereditary spastic paraplegia loci on chromosomes 2p and 14q was performed. The coding sequence of the SPG3A gene was analyzed, and the identified change in the sequence was tested for being a benign polymorphism by sequencing 200 chromosomes from normal controls.


RESULTS
Every affected individual had signs of uncomplicated spastic paraparesis without additional neurological abnormalities. None of the affected family members had ever walked normally. The history was consistent with an infantile onset, despite the normal acquisition of motor milestones. Genetic analysis suggested linkage to the SPG3A locus on chromosome 14q. Analysis of the SPG3A gene revealed a missense mutation C635T, predicted to result in a threonine to isoleucine substitution at codon 156. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects.


CONCLUSIONS
We report a novel mutation in the SPG3A gene in an African American family with an infantile onset of autosomal dominant hereditary spastic paraplegia.
Hedera
Peter
P
Department of Neurology, Vanderbilt University, Nashville, TN 37232-8552, USA. peter.hedera@vanderbilt.edu
Fenichel
Gerald M
GM
Blair
Marcia
M
Haines
Jonathan L
JL
D000293:Adolescent; D000328:Adult; D001741:Black or African American; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D019204:GTP-Binding Proteins; D005838:Genotype; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D013912:Threonine / Q000235:genetics
D008565:Membrane Proteins; D007532:Isoleucine; D013912:Threonine; C440006:ATL1 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins