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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 tetrahydrobiopterin (BH4) biosynthesis, the cofactor for various enzymes including the aromatic amino acid hydroxylases. Inherited PTPS deficiency is a heterogeneous disease with different phenotypes leading to BH4 depletion. The severe form of PTPS deficiency causes hyperphenylalaninemia and monoamine neurotransmitter deficiency, whereas the mild form gives rise to hyperphenylalaninemia only. From 228 patients with PTPS deficiency at least 32 different mutant alleles have been identified on its corresponding gene, located on chromosome 11q22.3‐q23.3. Here we describe a new allele from a child with PTPS deficiency who exhibited a mild but transient form of hyperphenylalaninemia, 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 codon alteration Tyr99 to Cys (Y99C). The mother and several members of the maternal family were carriers of the Y99C allele, also verified by the reduced 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 allele. The PTPS mutation observed in this patient generates a novel phenotype with an apparently isolated central form of BH4 deficiency. Hum Mutat 16:54–60, 2000. © 2000 Wiley‐Liss, Inc.