Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients.
OBJECTIVE
Pyridoxine-dependent seizure (PDS) is a rare disorder characterized by seizures that are resistant to common anticonvulsants, and that are ultimately controlled by daily pharmacologic doses of pyridoxine (vitamin B6). Mutations of the antiquitin gene (ALDH7A1) are now recognized as the molecular basis of cases of neonatal-onset PDS.


METHODS
Bidirectional DNA sequence analysis of ALDH7A1 was undertaken along with plasma pipecolic acid (PA) measurements to determine the prevalence of ALDH7A1 mutations in a cohort of 18 North American patients with PDS.


RESULTS
In patients with neonatal-onset PDS, compound heterozygous or homozygous ALDH7A1 mutations were detected in 10 of 12 cases, and a single mutation was found in the remaining 2. In later-onset cases, mutations in ALDH7A1 were detected in three of six cases. In two patients with infantile spasms responsive to pyridoxine treatment and with good clinical outcomes, no mutations were found and PA levels were normal. In total, 13 novel mutations were identified.


CONCLUSIONS
Our study advances previous findings that defects of ALDH7A1 are almost always the cause of neonatal-onset PDS and that defects in this gene are also responsible for some but not all later-onset cases. Later-onset cases of infantile spasms with good outcomes lacked evidence for antiquitin dysfunction, suggesting that this phenotype is less compelling for PDS.
Bennett
Craig L
CL
Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, and Children's Hospital and Regional Medical Center, Seattle, Washington 98195-6320, USA. cbenet@u.washington.edu
Chen
Yingzhang
Y
Hahn
Sihoun
S
Glass
Ian A
IA
Gospe
Sidney M
SM
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D049690:History, Ancient; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009656:North America / Q000453:epidemiology; D010875:Pipecolic Acids / Q000097:blood / Q000652:urine; D015995:Prevalence; D011736:Pyridoxine / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D020539:Sequence Analysis, Protein; D014803:Vitamin B Complex / Q000627:therapeutic use
D010875:Pipecolic Acids; D014803:Vitamin B Complex; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; C031345:pipecolic acid; D011736:Pyridoxine