TY - JOUR
T1 - Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1
AU - Mushimoto, Yuichi
AU - Fukuda, Seiji
AU - Hasegawa, Yuki
AU - Kobayashi, Hironori
AU - Purevsuren, Jamiyan
AU - Li, Hong
AU - Taketani, Takeshi
AU - Yamaguchi, Seiji
N1 - Funding Information:
We thank the attending physicians in charge of the present cases for providing clinical information regarding each patient. We are also grateful to Nana Tomita, Mayumi Nagase, Mayumi Naito, Midori Furui, Rie Eda, Toyomi Esumi, Yuka Ito, and Shine Mushimoto for their technical assistance. This study was partly supported by grants from The Ministry of Health, Labor, and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science, and Technology .
PY - 2011/3
Y1 - 2011/3
N2 - Glutaric acidemia type 1 (GA1) is a metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Untreated patients mostly develop severe striatal degeneration. More than 200 mutations have been reported in the GCDH gene, and common R402W and IVS10-2A>C were found in Caucasian and Chinese/Taiwanese, respectively. However, in Japan, genetic mutations have only been reported in a few cases. Herein, we report the clinical and molecular basis of GA1 in 19 Japanese patients, including six previously reported patients. All cases showed high urinary glutaric acid excretion. Eleven patients were severely impaired (three patients died), three had mild impairment, and five showed normal development. Four of 5 patients that developed normally were detected in the presymptomatic stage by neonatal or sibling screening. Nineteen mutations in 26 alleles were identified, and eight of them (89 or 90delC, Y155C, IVS4+2T C, G244S, Q352X, G354A, K361E, and 1144-1145delGC) were novel. S305L (12.1%, 4/34 alleles) was found in several cases, suggesting that this mutation is a common mutation. In contrast, R402W was not identified and IVS10-2A>C was only found in one allele, suggesting that Japanese patients with GA1 show allelic heterogeneity and have a different genetic background to patients from other countries. One of a pair of sisters with the same mutations (M339V/S305L) lacking residual activity was severely retarded, whereas the older girl remains asymptomatic at 22. years of age, indicating that genotype does not necessarily predict GA1 phenotype. We consistently found that there was no association between genotype and phenotype. However, children with mild impairment were diagnosed and treated earlier than severely impaired cases {4.7 ± 2.5. months (range: 2-8. months) vs. 11.6 ± 12.7. months (range: 4-51. months)}. Our results suggest that early detection and treatment but not genotype are associated with better patient outcome, reinforcing the importance of neonatal screening.
AB - Glutaric acidemia type 1 (GA1) is a metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Untreated patients mostly develop severe striatal degeneration. More than 200 mutations have been reported in the GCDH gene, and common R402W and IVS10-2A>C were found in Caucasian and Chinese/Taiwanese, respectively. However, in Japan, genetic mutations have only been reported in a few cases. Herein, we report the clinical and molecular basis of GA1 in 19 Japanese patients, including six previously reported patients. All cases showed high urinary glutaric acid excretion. Eleven patients were severely impaired (three patients died), three had mild impairment, and five showed normal development. Four of 5 patients that developed normally were detected in the presymptomatic stage by neonatal or sibling screening. Nineteen mutations in 26 alleles were identified, and eight of them (89 or 90delC, Y155C, IVS4+2T C, G244S, Q352X, G354A, K361E, and 1144-1145delGC) were novel. S305L (12.1%, 4/34 alleles) was found in several cases, suggesting that this mutation is a common mutation. In contrast, R402W was not identified and IVS10-2A>C was only found in one allele, suggesting that Japanese patients with GA1 show allelic heterogeneity and have a different genetic background to patients from other countries. One of a pair of sisters with the same mutations (M339V/S305L) lacking residual activity was severely retarded, whereas the older girl remains asymptomatic at 22. years of age, indicating that genotype does not necessarily predict GA1 phenotype. We consistently found that there was no association between genotype and phenotype. However, children with mild impairment were diagnosed and treated earlier than severely impaired cases {4.7 ± 2.5. months (range: 2-8. months) vs. 11.6 ± 12.7. months (range: 4-51. months)}. Our results suggest that early detection and treatment but not genotype are associated with better patient outcome, reinforcing the importance of neonatal screening.
UR - http://www.scopus.com/inward/record.url?scp=79851489228&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79851489228&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2010.11.159
DO - 10.1016/j.ymgme.2010.11.159
M3 - Article
C2 - 21176883
AN - SCOPUS:79851489228
VL - 102
SP - 343
EP - 348
JO - Biochemical Medicine and Metabolic Biology
JF - Biochemical Medicine and Metabolic Biology
SN - 1096-7192
IS - 3
ER -