Analysis of gene mutations in Chinese patients with maple syrup urine disease.
OBJECTIVE
Maple syrup urine disease (MSUD) is predominantly caused by mutations in the BCKDHA, BCKDHB and DBT genes, which encode for the E1α, E1β and E2 subunits of the branched-chain α-keto acid dehydrogenase complex, respectively. The aim of this study was to screen DNA samples from 16 Chinese MSUD patients and assess a potential correlation between genotype and phenotype.


METHODS
BCKDHA, BCKDHB and DBT genes were analyzed by polymerase chain reaction (PCR) and direct sequencing. Segments bearing novel mutations were identified by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis.


RESULTS
Within the variant alleles, 28 mutations (28/32, 87.5%), were detected in 15 patients, while one patient displayed no mutations. Mutations were comprised of 20 different: 6 BCKDHA gene mutations in 4 cases, 10 BCKDHB gene mutations in 8 cases and 4 DBT gene mutations in 3 cases. From these, 14 were novel, which included 3 mutations in the BCKDHA gene, 7 in the BCKDHB gene and 4 in the DBT gene. Only two patients with mutations in the BCKDHB and DBT genes were thiamine-responsive and presented a better clinical outcome.


CONCLUSIONS
We identified 20 different mutations within the BCKDHA, BCKDHB and DBT genes among 16 Chinese MSUD patients, including 14 novel mutations. The majority were non-responsive to thiamine, associating with a worse clinical outcome. Our data provide the basis for further genotype-phenotype correlation studies in these patients, which will be beneficial for early diagnosis and in directing the approach to clinical intervention.
Department of Pediatric Endocrinology, Genetic and Metabolic Disease, Shanghai Institute of Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
Nan
N
Yang
Lianshu
L
Han
Xuefan
X
Gu
Jun
J
Ye
Wenjuan
W
Qiu
Huiwen
H
Zhang
Zhuwen
Z
Gong
Yafen
Y
Zhang
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000737:chemistry / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D002681:China; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008375:Maple Syrup Urine Disease / Q000201:enzymology / Q000235:genetics*; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary
D050505:Mutant Proteins; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)