De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy.
BACKGROUND
Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia. For many subjects with an SPG3A mutation, spastic gait begins in early childhood and does not significantly worsen even over many years. Such subjects resemble those with spastic diplegic cerebral palsy. To date, only 9 SPG3A mutations have been reported.


OBJECTIVE
To analyze the SPG3A coding sequence in an individual with childhood-onset spastic gait, who, prior to the birth of her similarly affected child, had no previous family history of hereditary spastic paraplegia.


METHODS
The SPG3A coding sequence was analyzed in DNA samples from the proband, her affected child, her unaffected parents, and control subjects by polymerase-chain-reaction amplification of each exon followed by direct DNA sequencing. Seventeen microsatellite polymorphisms were amplified and analyzed to confirm reported paternity.


RESULTS
We identified a novel SPG3A mutation (L157W) in the proband and her affected child. This mutation was absent in the proband's unaffected parents. Results of microsatellite polymorphism analysis were consistent with paternity as reported. These results indicate that this novel SPG3A mutation arose de novo in the proband.


CONCLUSIONS
We report the de novo occurrence of a novel SPG3A mutation in a subject with childhood-onset, nonprogressive, spastic diplegia who had no previous family history of hereditary spastic paraplegia until the birth of her similarly affected son. Although rare, the occurrence of a de novo hereditary spastic paraplegia gene mutation must be considered in subjects with spastic diplegic cerebral palsy for whom no other cause is identified. This is extremely important for correct genetic counseling because recurrence risk may be as high as 50% when a mutation is detected.
Rainier
Shirley
S
Department of Neurology, University of Michigan, Ann Arbor, USA.
Sher
Carron
C
Reish
Orit
O
Thomas
Donald
D
Fink
John K
JK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002547:Cerebral Palsy / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D019204:GTP-Binding Proteins; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D014364:Tryptophan / Q000235:genetics
D008565:Membrane Proteins; D014364:Tryptophan; C440006:ATL1 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D007930:Leucine