Isolated central form of tetrahydrobiopterin deficiency associated with hemizygosity on chromosome 11q and a mutant allele of PTPS

6-Pyruvoyl-tetrahydropterin synthase (PTS or PTPS) is involved in tetrahydr obiopterin (BH4) biosynthesis, the cofactor for various enzymes including t he aromatic amino acid hydroxylases. Inherited PTPS deficiency is a heterog eneous disease with different phenotypes leading to BH4 depletion. The seve re form of PTPS deficiency causes hyperphenylalaninemia and monoamine neuro transmitter deficiency, whereas the mild form gives rise to hyperphenylalan inemia only. From 228 patients with PTPS deficiency at least 32 different m utant alleles have been identified on its corresponding gene, located on ch romosome 11q22.3-q23.3, Here we describe a new allele from a child with PTP S deficiency who exhibited a mild but transient form of hyperphenylalaninem ia, yet was deficient in CSF monoamines. The patient was found to carry, on her genomic DNA and cDNA, a homozygous A>G transition, leading to PTPS cod on alteration Tyr99 to Cys (Y99C). The mother and several members of the ma ternal family were carriers of the Y99C allele, also verified by the reduce d PTPS enzyme activity in erythrocytes. By cytogenetic, molecular, and FISH analyses, a de novo deletion spanning from 11q14 to 11q23.3 on the patient 's paternal chromosome was mapped, establishing hemizygosity of the Y99C al lele. The PTPS mutation observed in this patient generates a novel phenotyp e with an apparently isolated central form of BH4 deficiency. Hum Mutat 16: 54-60, 2000. (C) 2000 Wiley-Liss, Inc.