Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis.
Pyridoxine dependent seizure (PDS) is a disorder of neonates or infants with autosomal recessive inheritance characterized by seizures, which responds to pharmacological dose of pyridoxine. Recently, mutations have been identified in the ALDH7A1 gene in Caucasian families with PDS. To elucidate further the genetic background of PDS, we screened for ALDH7A1 mutations in five PDS families (patients 1-5) that included four Orientals. Diagnosis as having PDS was confirmed by pyridoxine-withdrawal test. Exon sequencing analysis of patients 1-4 revealed eight ALDH7A1 mutations in compound heterozygous forms: five missense mutations, one nonsense mutation, one point mutation at the splicing donor site in intron 1, and a 1937-bp genomic deletion. The deletion included the entire exon 17, which was flanked by two Alu elements in introns 16 and 17. None of the mutations was found in 100 control chromosomes. In patient 5, no mutation was found by the exon sequencing analysis. Furthermore, expression level or nucleotide sequences of ALDH7A1 mRNA in lymphoblasts were normal. Plasma pipecolic acid concentration was not elevated in patient 5. These observations suggest that ALDH7A1 mutation is unlikely to be responsible for patient 5. Abnormal metabolism of GABA/glutamate in brain has long been suggested as the underlying pathophysiology of PDS. CSF glutamate concentration was elevated during the off-pyridoxine period in patient 3, but not in patient 2 or 5. These results suggest allelic and non-allelic heterogeneities of PDS, and that the CSF glutamate elevation does not directly correlate with the presence of ALDH7A1 mutations.
Kanno
Junko
J
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574, Japan.
Kure
Shigeo
S
Narisawa
Ayumi
A
Kamada
Fumiaki
F
Takayanagi
Masaru
M
Yamamoto
Katsuya
K
Hoshino
Hisao
H
Goto
Tomohide
T
Takahashi
Takao
T
Haginoya
Kazuhiro
K
Tsuchiya
Shigeru
S
Baumeister
Fritz A M
FA
Hasegawa
Yuki
Y
Aoki
Yoko
Y
Yamaguchi
Seiji
S
Matsubara
Yoichi
Y
D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D004252:DNA Mutational Analysis; D005808:Genes, Recessive; D018698:Glutamic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011736:Pyridoxine / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics
D012333:RNA, Messenger; D018698:Glutamic Acid; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; D011736:Pyridoxine