Long-Term Follow-Up of Taiwanese Chinese Patients Treated Early for 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency

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

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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 reductase,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 deficiency, 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-hydroxytryptophan 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.

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©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 Mutation µmol BW, g Age, wk Percentile BH4 5-HTP LevodopaTest, y VIQ PIQ FIQ 1 P87S/N52S 1381.9 2750 38 33.92 19 372 27 19.0 98 100 99 2 R25G/P87S 539.4a 2775 38 35.84 7 148 15 13.3 87 93 88 3 N52S/N52S 1963.8 2700 37 41.38 27 90 27 11.3 99 99 98 4 N52S/N52S 3436.6 2000 40 0.36 28 43 36 10.5 92 82 86 5 P87S/N52S 3091.1 3300 41 56.5 34 55 48 9.3 105 89 97 6 P87S/N52S 1345.5 2780b 38 63.3 21 21 21 8.5 126 106 119 7 P87S/N52S 2454.7 2030b 36 27.9 18 18 18 9.1 110 111 111 8 N52S/N52S 2145.6 2500 40 6.44 18 18 18 8.9 95 86 90 9 F40L/P87S 1745.6 2500 37 25.68 19 19 19 8.3 105 73 88 10 P87S/N52S 527.3a 2500c 38c 14.67c 1 1 1 7.8 99 86 92 11 P87S/N52S 2042.6 2900 40 27.96 18 18 18 5.11 94 102 96 12 P87S/N52S 2885.0 2600 37 33.16 17 17 17 7.2 100 93 96 Mean 2249.2 2669 38.6 29.0 18.9 68.3 22.1 9.9 100.8 93.3 96.7 SD 708.9 349 1.6 17.1 8.8 104.1 11.7 3.5 10.1 10.9 9.7

Abbreviations: BH4, tetrahydrobiopterin; BW, birth weight; FIQ, full-scale IQ; Phe, phenylalanine; PIQ, performance IQ; PTPS, 6-pyruvoyl-tetrahydropterin synthase; VIQ, verbal IQ; 5-HTP, 5-hydroxytryptophan. a Patients 2 and 10 were excluded because they were detected by prenatal diagnosis. b Patients 6 and 7 were excluded because they are each twins from different families. c Patient 10 was excluded because his mother gave his BW from memory, not proved by document. However, if we included this patient, we would get a more significant statistical correlation (Pearson r=0.651; P = .02).

MEASUREMENTS OF age at diagnosis was 20.0 (6.3) days. Patients 6 and 7 are INTELLECTUAL FUNCTION dizygotic twins from 2 different families. Because twins’ body weights are regularly low at birth, we excluded these IQ was measured by the Leiter International Performance Scale 2 patients from the birth weight analysis. The mean birth or the Binet-Simon test in children 3 to 6 years of age, the Wechs- weight was 2669 (349) g, which is significantly lower than ler Intelligence Scale for Children–III in children between the in Taiwanese patients in whom hyperphenylalaninemia ages of 6 and 15 years, and the Wechsler Adult Intelligence Scale, is caused by phenylalanine hydroxylase deficiency (3447 Revised, or the Wechsler Adult Intelligence Scale–III in pa- Ͻ 14 tients older than 16 years. [492] g; P .001). The allele frequencies were 54.2% Correlations between IQ scores and several variables, in- (13 of 24) for N52S, 35.7% (9 of 24) for P87S, 4.2% (1 of cluding genotype, peak serum concentration of phenylalanine 24) for R25G, and 4.2% (1 of 24) for F40L. and urinary concentrations of pterin at the time of diagnosis, birth weight percentile, and age at initiation of treatment with TREATMENT tetrahydrobiopterin, levodopa, and 5-hydroxytryptophan, were also analyzed in this study. All patients maintained serum concentrations of phenyl- STATISTICAL ANALYSES alanine below 120 µM with a 2 mg/kg/d replacement dosage of tetrahydrobiopterin. Replacement with 10 to 15 All values are expressed as mean (SD). Correlations between mg/kg/d of levodopa was well tolerated by all patients. IQ and several variables were examined using the Mann- Treatment with levodopa caused occasional irritability Ͻ Whitney test and Pearson correlation. P .05 was considered and dyskinesia during the early part of replacement in statistically significant. the neonatal period, though they rarely occurred there- after. In contrast, general hypotonia with ptosis, drool- RESULTS ing, slurred speech, drowsiness, or nausea occurred regularly when replacement with levodopa was delayed or Demographic characteristics, results of biochemical tests omitted. Nausea, vomiting, diarrhea, and abdominal pain and mutation analyses, and IQ outcomes of our study occurred regularly during replacement with 5-hydroxy- population are detailed in Table 1. The mean duration tryptophan. In 1993, a shortage of 5-hydroxytrypto- of follow-up was 11.7 (3.3, range, 7.2-19.0) years. The phan in Taiwan forced the interruption of treatment for mean final full-scale IQ of the 12 patients was 96.7 (9.7). up to 6 months in our patients. Because no significant Patients 2 and 10 had PTPS deficiency diagnosed before neurological change was noted during that interrup- birth, and patients 7 and 10 are siblings. Excluding pa- tion, or because of fear of adverse effects of 5-hydroxy- tients 2 and 10, the mean initial peak serum concentra- tryptophan, some of our patients abandoned this replace- tion of phenylalanine was 2249 (709) µM, which is con- ment or lowered their dosages to less than 2 mg/kg/d siderably higher than in Taiwanese patients in whom without apparent adverse neurological or intellectual con- hyperphenylalaninemia is caused by phenylalanine hy- sequences. Most patients were prescribed levodopa and droxylase deficiency (798 [534] µM; PϽ.05).14 The mean 5-hydroxytryptophan to be taken in 4 divided doses per

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Dosages of Levodopa and 5-Hydroxytryptophan Administered to Patients With 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency by Age

Age

Levodopa, mg/kg/d 5-Hydroxytryptophan, mg/kg/d

Full-scale At Last At Last Patient IQ 2mo 1y Follow-up 2 mo 1 y Follow-up 1 102 5.2 10.0 11.5 0 2.4 None for 8 y 2 88 8.3 13.9 12.0 0 3.3 1.03 3 98 12.6 9.3 10.5 0 3.7 4.1 4 86 11.0 10.0 10.0 2.6 2.4 2.0 5 97 8.5 10.6 12.9 3.9 2.8 3.9 6 119 7.7 14.7 11.0 2.7 5.2 3.6 7 111 9.3 11.8 11.0 0.6 2.4 4.4 8 90 9.2 10.4 10.9 2.0 3.9 None for 4 y 9 88 8.7 13.2 15.0 2.7 4.7 5.8 10 92 9.1 9.4 12.5 3.6 4.0 5.0 11 96 8.3 9.6 15.0 3.3 4.0 4.0 12 95 12.5 9.4 10.8 5.0 4.6 5.1 Mean (SD) 97.0 (9.9) 9.2 (2.0) 11.0 (1.8) 11.9 (1.6) 2.2 (1.6) 3.6 (0.9) 3.2 (1.9)

day. However, some patients changed their schedule to trations and the full-scale IQs of our patients (Pearson doses twice daily to avoid having to take medication while r=−0.421; P=.23). Because PTPS deficiency impairs the at school, without experiencing an on/off phenomenon synthesis of tetrahydrobiopterin and its metabolites, we or adverse neurological manifestations. This is in con- examined the correlation between initial urinary biop- trast with our observations in PTPS-deficient patients terin concentrations and full-scale IQ, though we found whose treatment was delayed in whom the on/off phe- none (Pearson r=0.045, P=.9). nomenon occurred more commonly when they changed their medication schedule to 2 doses per day. The dos- Relationship Between Birth Weight ages of levodopa and 5-hydroxytryptophan adminis- Percentile and IQ tered to our patients at the ages of 2 months, 1 year, and the age at last follow-up are summarized in Table 2. After adjustment of the birth weight to the gestational age to calculate the birth weight percentile compared with FACTORS RELATED TO IQ OUTCOME the standard birth weight curves of healthy babies or twins (for patients 6 and 7) in Taiwan,19 we found a correla- Genotype-Phenotype Correlation tion between the percent birth percentile and full-scale IQ (Pearson r=0.642; P=.03). The 3 mutations identified in this study (N52S, P87S, and R25G) have been observed to cause prominent pheno- Relationship Between Treatment and IQ typical expressions of PTPS deficiency.8 However, their various combinations were associated with variably promi- No correlation was found between age at the time of on- nent expressions of the phenotypes. For example, be- set of treatment with tetrahydrobiopterin, levodopa, or fore treatment, the patients with N52S/N52S or P87S/ 5-hydroxytryptophan and full-scale IQ (tetrahydrobiop- R25G genotypes whose treatments were delayed had the terin, Pearson r=0.170, P=.6; 5-hydroxytryptophan, Pear- most prominent phenotypical disease manifestations. son r=−0.021, P=.95; levodopa, Pearson r=0.069, P=.83). These patients were all bedridden and in a vegetative state Finally, we found no correlation between dosages of le- before treatment initiation. On the other hand, in pa- vodopa or 5-hydroxytryptophan administered at ages 2 tients with N52S/P87S genotypes whose treatments were months, 1 year, or at the last follow-up and full-scale IQ delayed, the disease manifestations before treatment on- (Table 2). set were milder. They could eat, walk (albeit with an un- stable gait), and articulate several single words, such as papa or mama. We also found that the patients with N52S/ COMMENT P87S genotypes who underwent early treatment had higher mean IQ scores (101.4 [9.8]) than patients who Our study indicates that (1) an effective referral system had other genotypes (90.0 [4.7]; P=.03). based on neonatal screening and (2) early appropriate therapy can preserve a normal IQ in PTPS-deficient pa- Correlation Between Biochemical tients. Therefore, similar disorders of neurotransmit- Measurements and IQ ters, such as aromatic L-amino acid decarboxylase deficiency, that are systematically associated with a poor After the exclusion of patients 2 and 10, we found no cor- prognosis might have better outcomes if they were treated relation between the initial peak phenylalanine concen- early.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Unexpectedly, we found no correlation between age On the other hand, some of our patients received at the time of onset of treatment with tetrahydrobiop- 5-hydroxytryptophan late or in very low dosages, and terin, levodopa, or 5-hydroxytryptophan and full-scale some discontinued it for several years. Therefore, the IQ. However, because all our patients were very young absence of correlation between 5-hydroxytryptophan when treatment was initiated, the range of ages at the time dosage and full-scale IQ might indicate that replace- of treatment initiation was narrow. Therefore, we re- ment with this drug was not an important determinant peated the analysis after the addition of data from 10 pa- of full-scale IQ in our PTPS-deficient patients. Conse- tients from another Taiwanese hospital’s report (age range quently, we believe that replacement with 5-hydroxy- at onset, tetrahydrobiopterin, 0.2-7.4 months; le- tryptophan in the recommended daily dosages is not in- vodopa, 0.2-5.8 months; and 5-hydroxytryptophan, 1-57 dispensable, particularly when major adverse effects months).14 This new analysis revealed correlations be- develop. tween age at onset of each medication and full-scale IQ Given that our patients are all Taiwanese Chinese, some (tetrahydrobiopterin, Pearson r=−0.655, P=.001; 5-hy- patients from other populations might have even more droxytryptophan, Pearson r =−0.780, P Ͻ .001; le- severe genotypes. Consequently, their response to treat- vodopa, Pearson r=−0.645, P=.002). This observation ment might be different than that observed in our pa- suggests that the IQ did not vary significantly among tients. Furthermore, because our study did not include PTPS-deficient patients whose treatment was initiated a control group treated with low daily dosages of le- within 1 month of age, whereas persistent encephalopa- vodopa, we cannot prove that replacement with high dos- thy was likely to have developed in patients whose treat- ages of levodopa improved our patients’ clinical out- ment was initiated later. comes. However, all our early-treated patients had While there is little doubt that the early initiation of favorable outcomes, and we observed no adverse effects treatment can improve long-term outcome, there is no caused by the long-term administration of levodopa in consensus with respect to the dosages of neurotrans- high daily dosages. We hope that these observations will mitters to be administered to PTPS-deficient patients. prompt other caregivers to reconsider the dosages of neu- An on/off phenomenon and levodopa-induced dyski- rotransmitters, with the goal of optimizing the clinical nesia often develop during long-term therapy with outcomes of PTPS-deficient patients. levodopa in patients with Parkinson disease,20,21 and The systematically lower mean birth weight of pa- similar fluctuations in motor function and dyskinesia tients presenting with PTPS deficiency than that of nor- have also been observed frequently in PTPS-deficient mal individuals3,8,14 suggests prenatal effects of PTPS patients.10,22 Some caregivers have abandoned the deficiency. The positive correlation between birth administration of high dosages of levodopa in favor of weight and IQ observed in our study also raises the is- low daily replacement dosages because of frequent sue of a possible prenatal effect on the brain develop- dyskinesia.22 In our experience, an insufficient daily ment of PTPS. However, because of the many factors replacement with levodopa facilitates the development confounding IQ, the correlation between birth weight of the on/off phenomenon. Unlike in patients with and IQ in our patients remains uncertain, particularly Parkinson disease, in our patients, dyskinesia regularly in light of (1) the small number of observations and (2) disappeared after a period of accommodation. This the presence of an outlier in this analysis (patient 4) indicates that, in PTPS-deficient patients, dyskinesia whose birth weight percentile was 0.36. We believe that is more likely caused by hypersensitivity of the end more data, contributed by multiple medical centers, are organs than by the peak-dose or diphasic effect needed before a conclusion can be drawn regarding a observed in Parkinson disease.21,22 In Parkinson disease, possible correlation between birth weight and IQ in the synthesis, storage, and reuptake of levodopa in the PTPS-deficient patients. nigrostriatal system is impaired owing to the loss of dopaminergic neurons in contrast with PTPS-deficient patients, in whom only the synthesis of levodopa is Accepted for Publication: December 1, 2007. impaired. This may explain the lower incidence of fluc- Correspondence: Dau-Ming Niu, MD, PhD, Depart- tuations in motor function and levodopa-induced dys- ment of Pediatrics, Taipei Veterans General Hospital, Bldg kinesia in our early-treated patients than in patients 201, Section 2, Shih-Pai Rd, Taipei, Taiwan 112 (dmniu with Parkinson disease undergoing prolonged therapy. @vghtpe.gov.tw). Therefore, we believe that every effort should be made Author Contributions: Study concept and design: T. Liu, to continue neurotransmitter replacement therapy, Hsiao, and Niu. Acquisition of data: K. Liu, Lee, and Cheng. because it is a reliable means of gradually overcoming Analysis and interpretation of data: K. Liu and Niu. Draft- the end-organ hypersensitivity. ing of the manuscript: K. Liu. Critical revision of the manu- While we found no correlation between the dosages script for important intellectual content: T. Liu, Lee, Cheng, of neurotransmitter replacement at different ages and full- Hsiao, and Niu. Statistical analysis: K. Liu. Administra- scale IQ, it is noteworthy that, except for the dosage of tive, technical, and material support: K. Liu, Cheng, and patient 1 at the age of 2 months, the dosages of le- Niu. Study supervision: T. Liu, Hsiao, and Niu. vodopa administered to our patients were consistently Financial Disclosure: None reported. higher than the recommended dosages (Ͻ7 mg/kg/d for Additional Contributions: Chia-Chuen Chang from the patients younger than 2 years of age and 8-10 mg/kg/d Department of Labor and Human Resource Manage- for older patients).1 This absence of correlation might thus ment, Chinese Culture University, assisted with the sta- be limited to the high range of dosages. tistical analyses.

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