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Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1
- Source :
- Molecular Genetics and Metabolism. 102:343-348
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- 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 22years 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±2.5months (range: 2–8months) vs. 11.6±12.7months (range: 4–51months)}. Our results suggest that early detection and treatment but not genotype are associated with better patient outcome, reinforcing the importance of neonatal screening.
- Subjects :
- Male
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Biology
Biochemistry
Asymptomatic
Gastroenterology
Fatty-acid metabolism disorder
Glutarates
Endocrinology
Genotype-phenotype distinction
Japan
Internal medicine
Gene Order
Genotype
Genetics
medicine
Humans
Multiple Acyl-CoA Dehydrogenase Deficiency
Amino Acid Metabolism, Inborn Errors
Molecular Biology
Glutaryl-CoA Dehydrogenase
Brain Diseases, Metabolic
Infant, Newborn
Infant
medicine.disease
Pedigree
Child, Preschool
Organic acidemia
Mutation
Female
Allelic heterogeneity
medicine.symptom
Glutaric Acidemia Type 1
Subjects
Details
- ISSN :
- 10967192
- Volume :
- 102
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics and Metabolism
- Accession number :
- edsair.doi.dedup.....ffe40c5acab82d331914b24965b19248
- Full Text :
- https://doi.org/10.1016/j.ymgme.2010.11.159