Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications.
Propionic acidemia [MIM 606054] is a form of organic acidemia caused by genetic deficiency of propionyl-CoA carboxylase (PCC) and characterized by attacks of severe metabolic acidemia and hyperammonemia beginning in the neonatal period or in early infancy. There are, however, patients who have higher PCC activities and present later with unusual symptoms, such as mild mental retardation or extrapyramidal symptoms, sometimes even without metabolic acidosis. Through the neonatal screening of more than 130,000 Japanese newborns we detected a frequency of patients with propionic acidemia more than ten times higher than previously reported, most of them with milder phenotypes. The mutational spectrum was quite different from that of patients with the severe form and there was a common mutation (Y435C) in the beta subunit of the PCC gene (PCCB). Since patients with the mild form could present with unusual symptoms and therefore could easily remain unrecognized, it is important to identify those patients and clarify their natural history. Molecularly, one of the mutations (A1288C) caused an unusual pattern of multiple exon skipping and another unidentified mutation lead to the absence of mRNA. Taking into consideration previous findings regarding PCCB mutations, it appears that this gene is particularly prone to posttranscriptional modifications such as missense mediated exon skipping, mRNA decay, or rapid product degradation.
Department of Pediatrics, Kyoto University Hospital, 54 Shogoin Sakyo, Kyoto 606-8507, Japan. yorif@kuhp.kyoto-u.ac.jp
Tohru
T
Yorifuji
Masahiko
M
Kawai
Junko
J
Muroi
Mitsukazu
M
Mamada
Keiji
K
Kurokawa
Yosuke
Y
Shigematsu
Satoko
S
Hirano
Nobuo
N
Sakura
Ichiro
I
Yoshida
Tomiko
T
Kuhara
Fumio
F
Endo
Hiroshi
H
Mitsubuchi
Tatsutoshi
T
Nakahata
D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D002262:Carboxy-Lyases / Q000235:genetics* / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood; D002675:Child, Preschool; D002951:Citrates / Q000652:urine; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D043586:Methylmalonyl-CoA Decarboxylase; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D015995:Prevalence; D011422:Propionates / Q000097:blood*; D012333:RNA, Messenger / Q000235:genetics
D002951:Citrates; D017931:DNA Primers; D011422:Propionates; D012333:RNA, Messenger; C003223:propionylcarnitine; D002262:Carboxy-Lyases; D043586:Methylmalonyl-CoA Decarboxylase; C029658:propionic acid; D002331:Carnitine