6-pyruvoyl-tetrahydropterin Synthase Deficiency Research Articles

Inherited Pediatric Neurotransmitter Disorders: Case Studies and Long-Term Outcomes

AbstractPrimary pediatric neurotransmitter disorders include genetic defects of neurotransmitter metabolism that may mimic common neurological conditions in children. Our objective was to evaluate the clinical experience and outcomes of affected patients. Five patients with primary neurotransmitter defects were identified in the neurometabolic database between 2004 and 2022. Two patients with 6-pyruvoyltetrahydropterin synthase deficiency and one with pyridoxine-dependent epilepsy (PDE) presented in the neonatal period. One patient with succinic semialdehyde dehydrogenase (SSADH) deficiency and one with aromatic l-amino acid decarboxylase (AADC) deficiency presented in later life. A diagnosis of cerebral palsy was revised following biochemical confirmation of SSADH deficiency. AADC deficiency was confirmed via exome sequencing and reduced activity on enzyme assay. Late diagnosis in the latter two cases was likely due to a low index of suspicion and lack of access to diagnostic tests in the country of origin. In two children with tetrahydrobiopterin deficiency, newborn screening results and atypical clinical features prompted investigations. An early diagnosis of PDE was established based on presenting features, a high index of suspicion, the presence of an identifiable biochemical marker and molecular genetic testing. Pediatric neurotransmitter disorders can be diagnosed based on a high clinical index of suspicion, availability of biochemical markers, and molecular genetic testing. These disorders, though rare, need to be included in the differential diagnosis of common neurological presentations in children as they may be potentially treatable. Outcomes and influencing factors in the present series are discussed in comparison to published data.

Two Cases of 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Case Report and Literature Review

6-pyruvoyl tetrahydropterin synthase deficiency (PTPSD) is a rare neurometabolic disease that can be diagnosed in newborn screening (NBS) and is part of the family of tetrahydrobiopterin deficiency disorders (BH4Ds). It is essential to diagnose and treat this disease early to prevent permanent neurological damage secondary to this neurotransmitter disorder. We present the first two cases of PTPSD in Romania that were genetically confirmed and treated late. Improving the diagnosis and monitoring procedures in Romania with correct metabolic management will prevent severe neurological impairment from PTPSD or other BH4Ds.

Psychiatric Manifestations in Patients with Biopterin Defects.

Psychiatric manifestations in patients with tetrahydrobiopterin (BH4) defects are common, and may occur even with treatment of the underlying disorder. The neurobiological background of these conditions has been linked to abnormalities of neurotransmitters, such as dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid. Here, we review the psychiatric profile of all patients with BH4 defects followed in the pediatric and adult metabolic clinics at our center. Three patients with autosomal recessive (AR) guanosine triphosphate cyclohydrolase (GTPCH) deficiency and three patients with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency were reviewed.All patients had behavioral disturbances and two had significant psychiatric comorbidities. These included attention deficit/hyperactivity disorder, anxiety, depression, aggression, or oppositional defiant disorder. One patient with PTPS deficiency had a severe psychiatric presentation, requiring inpatient admission and temporary placement into foster care for intensive behavioral therapy. Another with AR GTPCH deficiency was diagnosed with aggressive behavioral dysregulation requiring intensive psychiatric treatment. Management of the psychiatric manifestations of BH4 defects can be challenging, due to lack of information and studies of interactions between psychiatric medications on the deficient neurotransmitters and their receptors in these conditions. Further studies are needed to establish safety and efficacy of these treatments.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth

BackgroundPyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition. MethodsRetrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables. ResultsPatients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8 ± 2.4 weeks) and low birth weight (−1.14 ± 0.97 SD below that predicted for gestational age). With time, weight and height approached normal. Values. All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p < 0.01) and weight (p < 0.05). Most patients with PTPS deficiency had delayed development early in life, improving around school age with IQs mostly in the normal range, with a small decline in older individuals. From a neurological standpoint, most patients had normal brain MRI and minor EEG anomalies, although some had persistent neurological symptoms. DiscussionPatients with PTPS deficiency have not only an increased incidence of prematurity, but also decreased birth weight when corrected for gestational age. Hyperphenylalaninemia can be absent in the first day of life. Therapy with sapropterin dihydrochloride normalizes phenylalanine levels and neurotransmitter precursors can improve CSF neurotransmitter metabolites levels. Insufficient dopaminergic stimulation (as seen from elevated prolactin) might result in decreased height in patients with PTPS deficiency. Despite early delays in development, many patients can achieve independence in adult life, with usually normal neuroimaging and EEG.

Characteristics of gene variants among patients with hyperphenylalaninemia from Quanzhou region of Fujian province

To explore the spectrum of genetic variants among patients with hyperphenylalaninemia (HPA) from Quanzhou area of Fujian province. For 63 children affected with HPA, next generation sequencing was used to identify potential variants in PAH, PTS, PCBD1, QDPR, SPR and GCH1 genes. Fifty two variants underlying phenylalanine hydroxylase deficiency (PAHD) and 13 variants underlying 6-pyruvoyl tetrahydropterin synthase deficiency (PTPSD) were identified. Two patients carried variants of both PAH and PTS genes. The most common variants of the PAH gene were R53H (21.69%), R241C(18.07%), R243Q(12.05%) and EX6-96A to G (7.23%), which were mainly located in exons 7 (32.53%), 2 (21.69%), 6 (9.64%) and 12 (9.64%). The L227M variant of the PAH gene was unreported previously. N52S (35.00%), P87S (25.00%), IVS1-291A to G (10.00%) and T67M (10.00%) variants were the most common variants for the PTS gene and were mainly located in exons 2 (35.00%) and 5 (35.00%). The variant spectrum underlying HPA in Quanzhou area showed a geographical specificity. A novel variant of the PAH gene (L227M) has been detected.

6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects

BackgroundTetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders. MethodWe conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency. ResultsSimilar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?). ConclusionThe deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.

Application of isoxanthopterin as a new pterin marker in the differential diagnosis of hyperphenylalaninemia.

This study aimed to explore the value of applying a new pterin marker (isoxanthopterin) to the traditional urine pterin analysis to reduce the rate of mis-diagnosis of 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD) and improve the accuracy of diagnosis. We compared the urine neopterin (N), biopterin (B), isoxanthopterin (Iso), B% and Iso% levels between patients with phenylalanine hydroxylase deficiency and those with PTPSD, and found the most specific pterin biomarkers by ROC analysis. A positive cut-off value of urine pterins was determined. The effect of combined Iso% + B + B% in reducing PTPSD mis-diagnosis was evaluated, and the different urine pterin levels in PTPSD and false PTPSD (FPTPSD) were compared. The concordance of PTPSD diagnosis by the new pterin scheme and gene mutation analysis was determined. (1) Urinary B, B%, Iso and Iso% were significantly lower in PTPSD than those in phenylalanine hydroxylase-deficiency group (P < 0.01); (2) Iso%, B%, and B were the most specific markers; (3) The positive cut-off values of B, B%, Iso% for PTPSD were < 0.17 mmoL/moLCr, < 5.0%, and < 9.5%, respectively; (4) urinary B + B% + Iso% scheme significantly reduced the false-positive rate of PTPSD compared to traditional ones. The Iso% levels in FPTPSD group were higher than the ones in PTPSD group; (5) an accuracy of diagnosis for PTPSD was increased by 9-19% when Iso% was introduced to urinary pterin scheme. Iso% is helpful to reduce the rate of misdiagnosis of PTPSD in the diagnosis by urinary pterin analysis for hyperphenylalaninemias and improve the accuracy of diagnosis. This approach is worthy of further development and increased utilization.

Analysis of types and metabolic profiles of hyperphenylalaninemia

Objective To study the characteristics of hyperphenylalaninemia (HPA) and the differences in blood and urine metabolic index and their correlation. Methods A total of 137 patients with HPA diagnosed by the Pediatric Inherit Metabolism and Endocrine Department, Guangdong Women and Children′s Hospital, Guangzhou Medical University from January 2014 to June 2017, were enrolled.Tandem mass spectrometry (MS/MS), gas chromatography/mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) were used to analyze the concentration of blood and urine metabolites in children, and the patients were divided into different groups according to the drug load test of tetrahydrobiopterin (BH4) and dihydrobiopterindine reductase (DHPR) deficiency.The HPA metabolite analysis of horizontal concentration by statistical differences and correlation analysis were performed. Results Among the 137 cases of HPA, there were 101 cases (73.7%) of phenylalanine hydroxylase deficiency (PAH), and among them 21 cases (15.3%) were classic phenylketonuria (PKU), 37 cases were mild PKU (27.0%), 43 cases (31.4%) were mild HPA.There were 22 cases (16.1%) with BH4 reaction, and 79 cases (57.7%) of non-reactive type.Besides, there were 36 cases(26.3%) of tetrahydrobiopterin deficiency (BH4D), of which 6-pyruvoyl tetrahydropterin synthase deficiency(PTPS) in 34 cases(24.8%) and dihydrobiopterindine reductase deficiency (DHPR) in 2 cases (1.5%). Urinary phenylacetic acid (r=0.673, P 0.05). Conclusions Through the analysis of the different types of HPA metabolic profiles, it can help to master the incidence and characteristics in the region, within a certain concentration range of blood Phe, the phenylacetic acid, phenyllactic acid, phenylpyruvic acid should not be tested by GC-MS alone.Uterine erythropoietin analysis of BH4D classification and identification of BH4 reaction, non-reactive PKU have a supporting role, so master the metabolic index of various types of concentration and relevance of HPA, it can provide basis for early diagnosis, accurate treatment and follow-up. Key words: Hyperphenylalaninemia; Metabolic profiling; Phenylalanine hydroxylase deficiency; Tetrahydrobiopterin deficiency

Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients

Melatonin is synthesized from serotonin and it is excreted as sulphatoxymelatonin in urine. We aim to evaluate urinary sulphatoxymelatonin as a biomarker of brain serotonin status in a cohort of patients with mutations in genes related to serotonin biosynthesis. We analized urinary sulphatoxymelatonin from 65 healthy subjects and from 28 patients with genetic defects. A total of 18 patients were studied: 14 with autosomal dominant and recessive guanosine triphosphate cyclohydrolase-I deficiency; 3 with sepiapterin reductase deficiency; and 1 with aromatic L-amino acid decarboxylase deficiency. Further 11 patients were studied after receiving serotoninergic treatment (serotonin precursors, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors): 5 with aromatic L-amino acid decarboxylase deficiency; 1 with sepiapterin reductase deficiency; 3 with dihydropteridine reductase deficiency; and 2 with 6-pyruvoyltetrahydropterin synthase deficiency. Among the patients without therapy, 6 presented low urinary sulphatoxymelatonin values, while most of the patients with guanosine triphosphate cyclohydrolase-I deficiency showed normal values. 5 of 11 patients under treatment presented low urine sulphatoxymelatonin values. Thus, decreased excretion of sulphatoxymelatonin is frequently observed in cases with severe genetic disorders affecting serotonin biosynthesis. In conclusion, sulphatoxymelatonin can be a good biomarker to estimate serotonin status in the brain, especially for treatment monitoring purposes.

Long-term safety and effectiveness of pramipexole in tetrahydrobiopterin deficiency.

Tetrahydrobiopterin (BH4) deficiencies are inherited neuro-metabolic disorders leading to monoamine neurotransmitters deficiency. An individualized replacement therapy with neurotransmitters precursors is necessary to restore dopaminergic and serotoninergic homeostasis. The correction of dopaminergic tone is complicated, like in Parkinson disease, by l-dopa short half-life and adverse effects. To improve this picture, since 2009 we introduced the non-ergot dopamine agonist pramipexole as an adjunct to l-dopa therapy in the treatment of the most common causes of BH4 deficiency, 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency and dihydropteridine reductase (DHPR) deficiency. In the short-term period, this approach allowed substantial clinical advantages in affected patients, with amelioration and stabilization of the clinical picture on twice daily treatment administration and no adverse effect. Here we describe the long-term clinical follow-up (83±24 months) of seven patients with BH4 deficiency treated with pramipexole. After a period of good clinical compensation (34±1 months), different impulse control disorders (gambling, compulsive buying, and hypersexuality) were observed in three patients treated with high-dose pramipexole (0.030-0.033mg/kg/day) beyond adolescence. These psychiatric adverse effects promptly disappeared after curtailing pramipexole dose by 50-60%. Low-dose pramipexole therapy has been safe and effective in the long-term period in all treated patients (59±9 months). High-dose pramipexole therapy in BH4 deficiency can be complicated, like in Parkinson disease, by psychiatric adverse effects. Low-dose pramipexole therapy (∼0.010mg/kg/day) has been safe and clinically effective on long-term follow-up, representing a helpful therapeutic option in patients with BH4 deficiency.

AB165. Extended follow-up of Taiwanese Chinese patients treated early for 6-pyruvoyl-tetrahydropterin synthase deficiency

Background The 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most important type of BH4 deficiency related to hyperphenylalaninemia. It is also accompanied by various neurological signs and symptoms due to impaired synthesis of catecholamines and serotonin. In this report, we aimed to report the long-term results of early initiation of treatment PTPS.

Neonatal hyperphenylalaninemia screening from 1985 to 2012 in Nanjing: a retrospective analysis of 27 years

Objective To explore the incidence,classification,treatment and prognosis of neonatal hyperphenylalaninemia(HPA) in Nanjing.Methods Infants born from September 1st,1985 to September 1st,2012 in Nanjing were investigated.Heel blood samples of neonates were collected at 72 hours after birth,and the concentration of blood phenylalanine was determined by fluorescent quantitative method in Nanjing Neonatal Screening Center within 20 days after birth.The deferential diagnosis was performed in all 81 cases diagnosed as HPA by tetrahydrobiopterin loading test,urinary pterin analysis and dihydropteridine reductase activity determination.The blood phenylalanine concentration and mental development were followed up regularly on infants with HPA.Mutations of phenylalanine hydroxylase (PAH) gene were analyzed by gene sequencing in 20 patients with PAH deficiency.The relationship between phenylalanine concentration and mental development was analyzed by variance analysis,LSD and Pearson correlation analysis.Results (1) The incidence of HPA in neonates in Nanjing was 1/8800(81/712 818).Among 81 confirmed cases,78 cases (96.3％) suffered from PAH deficiency,including 37 classical phenylketonurias (PKU),23 mild PKU and 18 mild HPA; the three patients (3.7％) with tetrahydrobiopterin deficiency were all 6-pyruvoyl tetrahydropterin synthase deficiency.(2) Among these 81 cases,eight refused to any treatment (two of them died),six had mental retardation (one with epilepsy),and six were lost in follow-up.For the rest 67 patients who received medical treatment,the ages at the last visit were three months to 26 years old.Among the 55 patients who received mental development evaluation,five of them were abnormal [intelligence quotient (IQ)＜75].(3) Negative correlation was observed between IQ and the average concentration of phenylalanine(r=-0.53,P＜0.05),while no correlation between IQ and the initial concentration of phenylalanine was observed (r =-0.39,P＞0.05).(4)Among the 20 patients with PAH deficiency who were tested for gene sequencing,18 mutations of PAHgenewere detected.The most common mutation were EX6-96A＞G and R241C(34.28％).Conclusions The incidence of HPA in Nanjing was higher than the average national level.With early diagnosis and standard treatment,over 90％ of HPA patients could have normal mental development.The mutation spectrum of PAH gene of Nanjing population is different from other areas,and the most common mutations of PAH gene are EX6-96A＞G and R241C. Key words: Phenylketonurias; phenylalanine hydroxylase; Mutation; Neonatal screening; Retrospective studies

Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan

Tetrahydrobiopterin (BH4) deficiency is a rare, congenital and lethal condition resulting in phenylalanine build-up that can lead to mental retardation and developmental defects, unless properly treated. About 1 million newborn infants in Japan undergo neonatal PKU screening every year, of which about 1 in 2 million are diagnosed with the condition. In this post-marketing surveillance study, 19 patients with BH4 deficiency in whom BH4 supplementation with sapropterin dihydrochloride (Biopten®) (hereafter referred to as ‘BH4 therapy’) was initiated before the age of 4years, were followed up for ⩽28years. Patients who screened positive for BH4 deficiency were treated with supplemental BH4 plus L-dopa and 5-hydroxytryptophan. Data on the patients’ clinical courses were collected once yearly at 10 medical centers in Japan. Seventeen patients were diagnosed with 6-pyruvoyl tetrahydropterin synthase deficiency and two with dihydropteridine reductase deficiency at an average age of 3.6months; the mean age at end of follow-up was 14.6years. Average duration of BH4 therapy (mean dose, 5mg/kg per day) was 13.2years. Serum phenylalanine was reduced from more than 10mg/dL at the start of drug administration to less than 2mg/dL at end of follow-up. No abnormalities in height or weight were observed in any patients, except for one female patient with familial obesity. No unwarranted side effects were reported throughout the long-term course of treatment, even during pregnancy. BH4 therapy can effectively maintain serum phenylalanine levels within the normal range in patients with BH4 deficiency, and demonstrated excellent long-term safety, with no side effects.

Dopamine agonists in dihydropteridine reductase deficiency

The traditional treatment of severe disorders of tetrahydrobiopterin (BH4) metabolism is based on the replacement therapy with BH4, 5-hydroxytryptophan, and l-dopa. Major problems are encountered with l-dopa therapy, especially with increasing age when higher doses are necessary, because of its short half-life and adverse effects. Consequently, different l-dopa-sparing strategies have been successively introduced, with partial reduction of l-dopa dosage and amelioration of the clinical outcome. Recently, we demonstrated that the dopamine agonist pramipexole improves the therapeutic effect of l-dopa in 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency, the most common disorder of BH4 metabolism. Here we report its effectiveness in two patients (males, 7 and 22years) with dihydropteridine reductase (DHPR) deficiency, the second most frequent cause of BH4 deficiency. Both patients experienced residual symptoms of dopamine deficiency, movement and behavioral disability, and complications of l-dopa therapy, associated with fluctuating hyperprolactinemia. They had full clinical and biochemical assessment, by an adapted Unified Parkinson's Disease Rating Scale (UPDRS) and measurement of diurnal plasma prolactin (PRL) profile before and after a trial with pramipexole. Besides allowing the reduction of l-dopa daily dosage (−58%) and administrations (from three to two) in one patient and to stop l-dopa therapy in the other, the introduction of pramipexole markedly improved and stabilized clinical and biochemical picture in both patients, as revealed by reduction of UPDRS scores and normalization of diurnal plasma prolactin profiles. Dopamine agonists can improve or even replace l-dopa therapy in disorders of synthesis and regeneration of BH4.

Analysis of inborn errors of metabolism: disease spectrum for expanded newborn screening in Hong Kong.

Data of classical inborn errors of metabolism (IEM) of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area. The laboratory records of plasma amino acids, plasma acylcarnitines and urine organic acids analyses from year 2005 to 2009 inclusive in three regional chemical pathology laboratories providing biochemical and genetic diagnostic services for IEM were retrospectively reviewed. Among the cohort, 43 patients were diagnosed of IEM, including 30 cases (69%) of amino acidemias (predominantly citrin deficiency, hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency and tyrosinemia type I), 5 cases (12%) of organic acidemias (predominantly holocarboxylase synthetase deficiency) and 8 cases (19%) of fatty acid oxidation defects (predominantly carnitine-acylcarnitine translocase deficiency). The incidence of classical IEM in Hong Kong was roughly estimated to be at least 1 case per 4122 lives births, or 0.243 cases per 1000 live births. This incidence is similar to those reported worldwide, including the mainland of China. The estimated incidence of hyperphenylalaninemia was 1 in 29 542 live births. Our data indicate that it is indisputable for the introduction of expanded newborn screening program in Hong Kong. Since Hong Kong is a metropolitan city, a comprehensive expanded newborn screening program and referral system should be available to serve the neonates born in the area.

Two Filipino Patients with 6-Pyruvoyltetrahydropterin Synthase Deficiency

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Dopamine agonists in 6-pyruvoyl tetrahydropterin synthase deficiency

To report the efficacy, tolerability, and safety of the dopamine agonist pramipexole in a series of 5 patients affected by inherited 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency and needing l-3,4 dihydroxyphenylalanine (l-dopa) therapy. Patients included 4 males and 1 female with ages ranging from 2 to 26 years. Their medication included tetrahydrobiopterin (BH4), 5-hydroxytryptophan, l-dopa, carbidopa, selegiline, and entacapone. All experienced residual symptoms of dopamine deficiency, movement and behavioral disability, and complications of l-dopa therapy, associated with fluctuating hyperprolactinemia. Patients had full assessment of clinical and biochemical condition, including evaluation by an adapted Unified Parkinson's Disease Rating Scale (UPDRS) and measurement of plasma prolactin (PRL) and catecholamines, before and after a 6-week trial with pramipexole. Pramipexole was administered twice daily as an adjunct to l-dopa therapy in dosages upwardly titrated, with a concurrent reduction of l-dopa dosage. Clinical follow-up went on for 1 year. Pramipexole was well tolerated by all patients, with marked improvement and stabilization of their clinical picture. The mean improvement on the total UPDRS score was 43% (range 33.3%-55.6%) from baseline. Diurnal profiles of plasma PRL normalized and plasma catecholamine levels lasted unchanged. The daily administrations of l-dopa were curtailed from 3 or 4 to 2, and the l-dopa dosage was reduced up to 40%. The addition of pramipexole to the treatment of 6-pyruvoyl tetrahydropterin synthase deficiency improves the results of l-3,4 dihydroxyphenylalanine therapy. Similar benefits may be expected in other forms of inherited tetrahydrobiopterin deficiency.

The investigation of differential diagnostic development and incidence of tetrahydrobiopterin deficiency

To investigate the development of differential diagnosis of tetrahydrobiopterin (BH4) deficiency among patients with hyperphenylalaninemia (HPA) in provinces or cities of China and to investigate the incidence of BH4 deficiency. Of the thirteen hundreds and ninety-two patients with HPA received, the differential diagnosis for BH4 deficiency during 1993 - 2007 were enrolled in this study. Of which, 591 patients came from outpatient and 801 patients' samples from other provinces or cities were sent to author's laboratory to investigate the case number of differential diagnosis for BH4 deficiency in provinces or cities of China according to the data from both outpatient case histories and laboratory as to investigating the development of differential diagnosis in the whole country. To discuss the diagnostic criteria for BH4 deficiency was according to the results of urinary pterin analysis, determination of dihydropteridine reductase (DHPR) activity and the tetrahydrobiopterin loading test as well as to get the incidence of BH4 deficiency and find some provinces or cities with higher incidence of BH4 deficiency in China. (1) The number of HPA patients, who were performed by urinary pterin analysis and the determination of DHPR activity, were remarkably increased in last three years (2005 - 2007). The patient numbers of both urinary pterin analysis and DHPR activity determination were 217 and 198 respectively in 2005. And in 2007 they increased to 511 and 458, which was about 2.3 times than that in 2005. The patients came from 29 provinces or cities in 2007. (2) The urinary biopterin and biopterin percent were key marks for diagnosis of 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency. The less than 5% [(1.41 +/- 1.10)%] biopterin percent and very low biopterin level [(0.14 +/- 0.17) mmol/mol Cr] were found in 96.83% (61/63) patients with PTPS deficiency in this study. The blood phenylalanine level was remarkably decreased to normal range at 2 - 6 hours after BH4 loading test. The very low DHPR activity was a final diagnostic mark for DHPR deficiency. The very low DHPR activities of 0.27 nmol/(min x 5 mm disc) (6.11% - 7.00% of normal controls) were found in two patients with DHPR deficiency in this study. (3) The incidences of PTPS deficiency and DHPR deficiency among 1392 patients with hyperphenylalaninemia were 8.41% (117/1392) and 0.18% (2/1108) respectively. About 67.23% (80/119) patients with BH4 deficiency came from the south of Yangtze liver. The 80% (8/10) provinces or cities with higher incidence of BH4 deficiency are located in eastern and southern China. The incidence of PTPS deficiency among patients with HPA and normal newborns was 10.81% (8/74) and 0.007 per thousand (8/1,121,429) respectively in Shanghai, China according to data from neonatal screening. The awareness of differential diagnosis for BH4 deficiency from clinic pediatricians has been increased in most provinces or cities of China in last three years, but it should be more strengthened.

Study on 398 neonates with various types of hyperphenylalaninemia detected by neonatal screening program and 26 year-experiences of diagnosis and treatment for hyperphenylalaninemia

Objective To investigate the incidences of various types of hyperphenylalaninemia (HPA)detected by neonatal screening program from 1981 to 2007,and provide the 26 year-experiences of diagnosis,treatment and prognosis for HPA.Methods The differential diagnosis for all patients with HPA has been performed by BH4 loading test,urinary pterin and dihydropteridine reductase activity determination.Analyze the relationship between mental developments and blood phenylalanine(Phe)levels.PAH gene mutations were tested by DNA analyze also.Results (1)85.9%patients(342/398)were diagnosed as phenylalanine hydroxylase deficiency(PAHD),36.7%(146/398)were diagnosed as BH4 responsive PAHD,and 66.5% patients with BH4 responsive PAHD were found in mild phenyIketonuria(MPKU)and mild HPA(MHPA).14.1%patients(56/398)diagnosed as BH4 deficiency,including 55 patients(98.2%)with 6-pyruvoyl-tetrahydropterin synthase deficiency(PTSD)and one patient with DHPR deficiency.(2)Two hundreds and seventy patients of 398 were followed up.Two hundred and forty-one patients were treated.Thirty-five patients with PTSD were treated with BH4,Levodopa and 5-hydroxytryptophan.Their Phe level were (90±60)mmol/L,the percentage of ideal Phe levels were(97.2±8.1)%.Twenty-one patients with BH4 responsive PAHD received the treatment with single BH4 with average blood Phe levels (180±90)mmol/L.One hundred and eighty-five patients were treated with low/free-phenylalanine formula.their average Phe levels were(336±198)mmol/L,the percentage of ideal Phe levels were only(53±30)%.Twenty seven patients without treatment were had normal mental development with Phe levels(156±42)mmol/L.(3)All 241 treated patients had normal growth development and good nutrition.The positive correlation was found between IQ scores(84±19)and the percentage of ideal Phe levels[(56±33)%](r=0.406,P＜0.01),the negative correlation between IQ and average Phe levels[(348±222)mmol/L]was showed in 62 patients(r=-0.406,P＜0.01).(4)Nineteen kinds of PTS gene mutations were found in 31 patients with PTSD,and the mutations of 259C＞T(48.3%)and 286G＞A(15.5%)were the most common.Seven kinds of PAH gene mutations were found in 13 Datients with BH4 responsive PAHD and R241C(43.8%)was the common mutation.Conclusions All HPA patients should be quickly differential diagnosed before treatment.Phe level control is a very key factor for mental development in treatment. Key words: Hyperphenylalaninemia; phenylalanine hydroxylase; tetrahydrobiopterin; neonatalscreening; intelligence quotient