Search

Tetrahydrobiopterin (BH(4)) deficiency comprises heterogeneous disorders resulting in hyperphenylalaninaemia (HPA) and lack of monoamine neurotransmitters. Among these, 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most common disorder. We report a female Thai patient with PTPS deficiency who was initially detected by newborn screening for HPA, and later treated by supplements of BH(4), L-dopa/carbidopa, and 5-hydroxytryptophan. Monitoring of serum prolactin representing dopamine sufficiency is used for optimizing the dosage of L-dopa. She showed a remarkable progress of development despite delayed treatment at 5 months of age. Mutation analysis revealed two heterozygous missense mutations of the PTS gene: c.259C>T (p.P87S) inherited from the father; and c.147T>G (p.H49Q) inherited from the mother. The latter is a novel mutation that affects the pterin-binding site of the PTPS enzyme. This novel mutation expands the mutation spectrum of PTPS deficiency. Notably, some PTS mutations have been reported in both Thai and Chinese patients. Whether these common mutations are the result of a founder effect with common ancestors of Thai and Chinese people or intermarriage between Thai and Chinese descents in Thailand remain unclear. In conclusion, severe neurological impairment from BH(4) deficiency could be prevented by newborn screening for HPA and proper metabolic management. However, pterin analysis for early diagnosis of BH(4) deficiency is still not available in most developing countries.

Molecular defects in the gene encoding the enzyme iduronate-2-sulfatase (IDS) result in Hunter disease (mucopolysaccharidosis type II, MPS II). To determine the molecular basis of MPS II in Thailand, the IDS gene was analysed in 20 Thai patients with Hunter syndrome from 18 unrelated families. A total of 19 different mutations, including 9 missense mutations, 3 nonsense mutations, 3 splice site alterations, 1 deletion, 2 indels, and 1 rearrangement were identified, 8 of which were novel (p.R101C, p.D148V, p.G224A, p.K227E, p.E254X, p.W337X, c.440_442delinsTT and c.720_731delinsTTTCAGATGTTCTCCCCAG). Evaluation of the IDS activity of two hemizygous variants identified in the same patient, p.R101C and p.R468Q, by expression of IDS with the individual mutations in COS 7 cells indicated that only the p.R468Q mutation affected IDS protein activity. Two exonic mutations, c.257C>T (p.P86L) and c.418G>A, were found to activate multiple cryptic splice sites, resulting in aberrantly spliced transcripts. Thus, MPS II in Thailand is caused by a diverse set of defects affecting both IDS protein production and activity.