ORIGINAL CONTRIBUTION Long-term Follow-up of Taiwanese Chinese Patients Treated Early for 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency Kai-Ming Liu, MS; Tze-Tze Liu, PhD; Ni-Chung Lee, MD; Ling-Yee Cheng, MS; Kwang-Jen Hsiao, PhD; Dau-Ming Niu, MD, PhD Objective: To report the long-term results of early ini- Interventions: Treatment with tetrahydrobiopterin, le- tiation of treatment of 6-pyruvoyl-tetrahydropterin syn- vodopa, and 5-hydroxytryptophan. thase (PTPS) deficiency. Main Outcome Measure: IQ score. Design: Between 1988 and 2000, 12 newborns with PTPS deficiency who underwent early treatment at our hospi- Results: The mean (SD) IQ score of our PTPS-deficient tal were identified. All patients received tetrahydrobiop- patients was 96.7 (9.7; range 86-119), which is consid- terin replacement in a daily dosage between approxi- erably higher than previous reports of other popula- mately 2 and 4 mg/kg. The dosages of levodopa tions of PTPS-deficient patients. All patients reached a replacement were 10 to 15 mg/kg/d, which is consider- normal IQ on high daily dosages of levodopa replace- ably higher than the typically recommended dosages of ment, without developing apparent long-term levodopa- less than 7 mg/kg/d for patients aged younger than 2 years induced adverse effects. We also observed a correlation and 8 to 10 mg/kg/d for patients aged 2 years or older. between long-term IQ score and genotype, birth weight, Replacement with 5-hydroxytryptophan varied widely and age at initiation of treatment. among patients. Conclusions: An effective newborn screening referral program and early initiation of appropriate therapy pre- Setting: Taipei Veterans General Hospital. served the IQ scores of PTPS-deficient patients. Patients: Twelve newborns. Arch Neurol. 2008;65(3):387-392 YPERPHENYLALANINEMIA IS 6-Pyruvoyl-tetrahydropterin synthase the most common inher- deficiency in humans may not only pro- ited disorder of amino duce the typical phenylketonuric phe- acid metabolism. It may notype but may also be the source of be caused by a defi- neurological signs and symptoms due to ciency of phenylalanine hydroxylase or tet- impaired syntheses of levodopa and H 5,6 rahydrobiopterin, an important cofactor serotonin. 6-Pyruvoyl-tetrahydropterin involved in the biogenic syntheses of ty- synthase deficiency’s extrapyramidal rosine, levodopa, 5-hydroxytryptophan, ni- manifestations, including, among others, tric oxide, and glycerol (Figure).1 Tetra- truncal hypotonia, increased limb tone, Author Affiliations: Institute of hydrobiopterin deficiency may be caused postural instability, hypokinesia, choreic Clinical Medicine, School of by defects in the enzymes involved in its or dystonic limb movements, gait abnor- Medicine (Mr K.-M. Liu and biosynthesis or in its regeneration. In white malities, hypersalivation, and dysphagia, Dr Niu) and Taipei Veterans individuals, the overall prevalence of may resemble the signs of Parkinson General Hospital and hyperphenylalaninemia attributable to disease.7,8 The disease is treated by tetra- Yang-Ming University Genome tetrahydrobiopterin deficiency is only 1% hydrobiopterin, levodopa, and 5-hy- Research Center (Drs T.-T. Liu to 2% of all cases.2,3 According to the droxytryptophan replacement. How- and Hsiao), National Yang-Ming International Database of Tetrahydrobi- ever, choosing the proper amounts of University; Department of opterin Deficiencies database, which precursors of neurotransmitters for Pediatrics, Taipei Veterans General Hospital (Drs Lee and includes patients of various races, replacement is challenging. While lum- Niu); and Department of 6-pyruvoyl-tetrahydropterin synthase bar puncture is key in the diagnosis and Rehabilitation, Taipei Veterans (PTPS) deficiency (OMIM 261640) rep- monitoring of pediatric neurotransmitter General Hospital (Ms Cheng), resents approximately 60% of all tetrahy- disease,9 the choice of dosages of these Taipei, Taiwan. drobiopterin deficiencies.4 precursors based on the concentrations (REPRINTED) ARCH NEUROL / VOL 65 (NO. 3), MAR 2008 WWW.ARCHNEUROL.COM 387 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 GTP GTPCH Neopterin H2NTP PTPS 6PTP SR Phenylalanine Tyrosine Tryptophan Arginine DHPR BH4 Biopterin qBH2 PAH TH TPH NOS PCD 4 α -OHBH4 Tyrosine Levodopa 5-Hydroxytryptophan NO + Dopamine Serotonin Citrulline Figure. The biochemical pathway of tetrahydrobiopterin (BH4) metabolism (http://www.bh4.org/). Tetrahydrobiopterin is synthesized from guanosine triphosphate by the enzymes guanosine triphosphate cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR) in a 3-step pathway. After reacting with the aromatic amino acid hydroxylase as an active cofactor, BH4 is oxidized to pterin-4␣-carbinolamine (4␣-OHBH4). It is then regenerated by pterin-4␣-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR) to BH4. H2NTP indicates dihydroneopterin triphosphate; GTP, guanosine triphosphate; NO, nitric oxide; NOS, nitric oxide synthase; PAH, phenylalanine hydroxylase; qBH2, quinonoid dihydrobiopterin; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase; and 6-PTP, 6-pyruvoyl-tetrahydropterin. of neurotransmitter metabolites in the cerebrospinal deficiency. A prenatal diagnosis was made in 2 other fetuses fluid might not always be optimal, as the patient’s whose siblings were known to be PTPS deficient. The diagno- metabolism might not systematically reflect the clinical sis of all patients identified by newborn screening was con- 8 10-12 firmed by (1) a tetrahydrobiopterin loading test, (2) analysis status of PTPS-deficient patients. In addition, the 15 invasiveness of lumbar puncture limits its serial use in of urinary pterins, (3) enzyme assay of dihydropteridine re- ductase,16 and (4) mutational analysis of the PTS gene.17,18 routine clinical practice. There are few outcome studies of patients undergoing early treatment for PTPS defi- ciency, particularly over long periods of observation. TREATMENT Several reports have described adverse outcomes in a large percentage of patients with PTPS deficiency, Treatment with (1) tetrahydrobiopterin, (2) levodopa with a de- despite its detection by newborn screening and the carboxylase inhibitor, and (3) 5-hydroxytryptophan was initi- institution of early treatment.13,14 ated after confirmation of the diagnosis of PTPS deficiency. The administration of each neurotransmitter was based on the clini- In Taiwan, where the disease’s prevalence (1 in 132 000) cal response and the development of adverse effects observed dur- is considerably higher than in white individuals (1 in ing ambulatory follow-up. The initial dosage of tetrahydrobiop- 14,15 1 000 000), PTPS deficiency is the cause of approxi- terin was approximately 3 to 4 mg/kg/d and was subsequently mately one-third of all cases of hyperphenylalaninemia. adjusted to keep serum phenylalanine concentrations below 120 A recent study at another Taiwanese medical center re- µM. The initial dosage of levodopa with a decarboxylase inhibi- ported a mean (SD) IQ score of 76 (14) in 10 patients tor was 2 mg/kg/d, then increased every 2 to 5 days in 1-mg in- with PTPS deficiency detected by newborn screening.14 crements to a target dosage of 10 to 15 mg/kg/d. Beginning in In contrast, we found a significantly higher (PϽ.001) 1996, serum prolactin concentration was measured at 1-month mean (SD) IQ score (96.7 ([9.7]) in 12 patients whose intervals in patients younger than 6 months and at 3-month in- disease was detected by similar screening. Because these tervals in older patients to guide the dosage of levodopa. When the concentration of serum prolactin exceeded 888 µg/L, the le- 2 groups of patients were from similar genetic back- vodopa dosage was gradually increased until prolactin returned grounds, we hypothesized that different treatments were to less than 888 µg/L. However, in the absence of clinical mani- major determinants of their different outcomes. Our ar- festations of levodopa insufficiency, a dosage greater than 15 mg/ ticle describes the main characteristics of the early treat- kg/d was never administered, even in the presence of a persis- ment administered to our PTPS-deficient patients and ex- tently elevated prolactin. In the event of irritability or dyskinesia, amines the putative factors related to their outcomes the dosage of levodopa was lowered for several days, then in- ascertained by IQ scores. creased again more slowly to the target dosage. 5-Hydroxytryp- tophan was initially administered in a dosage of 1 mg/kg/d, then increased every 2 to 5 days in 1-mg increments to a 5 mg/kg/d METHODS target dosage. As with levodopa, the dosage of 5-hydroxytryp- tophan was lowered when nausea, vomiting, diarrhea, or ab- Between 1988 and 2001, 10 screened newborns found to have dominal pain developed, then was slowly increased to the tar- elevated serum phenylalanine concentrations were referred to get maintenance dosage. Levodopa and 5-hydroxytryptophan Taipei Veterans General Hospital and confirmed to have PTPS were administered together in 4 divided doses before meals. (REPRINTED) ARCH NEUROL / VOL 65 (NO. 3), MAR 2008 WWW.ARCHNEUROL.COM 388 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Demographic and Biochemical Characteristics and Outcomes of Treated Patients With PTPS Deficiency BW Initial Age at Treatment Onset, d IQ Phe Peak, Gestational BW Age at Patient