Long-Term Neurological Outcomes of Adult Patients with Phenylketonuria before and after Newborn Screening in Japan.

Japanese newborn screening (NBS) for phenylketonuria (PKU) was initiated in 1977. We surveyed the neurological outcomes of Japanese adult patients with PKU to investigate the long-term effects and of and issues with NBS. Eighty-five patients with PKU aged over 19 years who continued to be treated with a phenylalanine-free amino acid formula were investigated by administering questionnaires regarding clinical characteristics, such as mental ability, education status, and therapeutic condition. Of the 85 subjects, 68 patients were detected by NBS (NBS group), while the other 17 were clinically diagnosed before the initiation of NBS (pre-NBS group). Further, 10 of the 68 NBS patients presented intellectual and/or psychiatric disabilities, 5 of whom had a history of treatment discontinuation; in contrast, 12 of the 17 pre-NBS patients presented with neuropsychiatric symptoms. Regarding social outcomes, almost all patients in the NBS group could live an independent life, while over half of the patients in the pre-NBS group were not employed or lived in nursing-care facilities. Neurological outcomes are obviously improved by NBS in Japan. However, some patients, even those detected by NBS, developed neuropsychiatric symptoms due to treatment disruption. Lifelong and strict management is essential to maintain good neurological and social prognoses for patients with PKU.

Long-Term Outcomes of Adult Patients with Homocystinuria before and after Newborn Screening.

BACKGROUND: Homocystinuria (HCU) is a rare inherited metabolic disease. In Japan, newborn screening (NBS) for HCU (cystathionine ß-synthase deficiency) was initiated in 1977. We compared the outcomes between patients detected by NBS (NBS group) and clinically detected patients (non-NBS group). METHODS: We administered questionnaires about clinical symptoms and social conditions to 16 attending physicians of 19 adult HCU patients treated with methionine-free formula. RESULTS: Eighteen patients (nine patients each in the NBS and non-NBS groups) participated. The frequency of patients with ocular, vascular, central nervous system, and skeletal symptoms in the NBS group was lower than that in the non-NBS group. Intellectual disability was observed in one and eight patients in the NBS and non-NBS groups, respectively. Concerning their social conditions, all patients in the NBS group were employed or still attending school, while only two patients in the non-NBS group were employed. Three of the four patients who discontinued treatment presented some symptoms, even in the NBS group. CONCLUSION: The social and intellectual outcomes of adult Japanese patients with HCU detected by NBS were favorable. However, even in the patients in the NBS group, some symptoms might not be preventable without continuous treatment.

Time trend and geographic distribution of treated patients with congenital hypothyroidism relative to the number of available endocrinologists in Japan.

OBJECTIVE: To investigate the time trend and geographic distribution of treated patients with congenital hypothyroidism (CH) and explore their possible relationship to the availability of endocrinologists in Japan. STUDY DESIGN: The 2-source capture-recapture method was used to estimate the total number of patients. The ratio of the total estimated number of patients with CH to the number of endocrinologists and Spearman correlation coefficients were calculated. Curve fitting for changes in incidence or prevalence was estimated. RESULTS: The incidence and prevalence of CH exhibited upward trends, with linear slopes of increase during the period 1994-2002. A statistically significant positive correlation was observed between the prevalence of CH and the ratio of the number of patients with CH to the number of endocrinologists in the 10 regions studied. The prevalence of CH was significantly higher in the regions with a higher ratio of patients with CH to endocrinologists, and also in younger patients. CONCLUSIONS: A shortage of endocrinologists may be one reason for the upward trend in the incidence and prevalence of treated patients with CH.

Increased incidence of extrathyroidal congenital malformations in Japanese patients with congenital hypothyroidism and their relationship with Down syndrome and other factors.

BACKGROUND: Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with primary congenital hypothyroidism (PCH) and Down syndrome (DS). Here, we investigated the frequency of ECMs in patients with PCH, particularly among patients with or without DS. METHODS: In a retrospective review of questionnaires based on medical records, ECMs were identified in 1520 patients with PCH and were compared with congenital malformations among nationwide live births or liveborn infants with DS. The ECMs in PCH patients with or without DS were then analyzed. The statistical analysis was based on the Poisson distribution. Ethnicity, sex, and familial and seasonal factors were also observed in relation to the ECMs. RESULTS: The incidences of ECMs (222/1520, 14.6%) and DS (86/1520, 5.7%) were significantly higher among the PCH patients than among the general population. Among the 127 PCH patients without chromosomal abnormalities, 101 had a single ECM and 26 had multiple ECMs. Unlike previously reported American and Egyptian patients with PCH, a significantly higher incidence of cardiovascular malformations was observed in the Japanese PCH patients, and a female predominance was also observed, except in patients with multiple ECMs. Regarding the PCH patients with DS, a significantly higher, male-predominant incidence of duodenal atresia was observed, compared with data for liveborn infants with DS, whereas a male-predominant, significantly higher incidence of gastrointestinal malformations and a female-predominant, significantly higher incidence of cardiovascular malformations were found compared with data among PCH patients without DS. Moreover, urogenital and orofacial ECMs were absent among the PCH patients with DS. Regarding PCH patients without DS, a male-predominant, significantly higher incidence of urogenital malformations and a female-predominant, significantly higher incidence of cardiovascular and nervous malformations were found, compared with data for nationwide live births. In PCH patients with DS and in PCH patients with a single ECM, both familial and seasonal factors existed, while in PCH patients with multiple ECMs, only familial factors were observed. CONCLUSION: The incidence of ECMs in PCH patients was significantly higher than in the normal population, and ethnic-, sex-, and DS-related differences were observed. Genetic and environmental factors were also identified in PCH patients with ECMs.

Diagnosis of tetrahydrobiopterin (BH4) responsive mild phenylketonuria in Japan over the past 10 years.

BACKGROUND: A novel therapeutic strategy for phenylketonuria (PKU) has been initiated in Japan. Hyperphenylalaninemia (HPA) results from a phenylalanine hydroxylase (PAH) enzyme deficiency or a deficiency of its cofactor, tetrahydrobiopterin (BH4). BH4 can normalize blood phenylalanine levels in BH4 deficiency, but typically not in PKU. However, since 1999 it has been reported that many HPA patients (serum phenylalanine <20 mg/dL) showed a gradual decrease of serum phenylalanine levels after 24 hours from BH4 loading. The BH4 responsiveness seems to be regulated in mild PKU by PAH mutations, and affected by the BH4 dose and administration period. METHODS AND RESULTS: In 2002 we formulated a provisional diagnostic criteria for patients with BH4-responsive PAH deficiency, and newly diagnosed 19 patients in 100 HPA cases between 2002 and 2006. The incidence in the recent 5 years for BH4-responsive mild PKU among patients with PAH deficiency was 25 %. CONCLUSION: A total of 31 patients was detected in the past 10 years, and the incidence detected using the provisional diagnostic criteria had increased to 25% among PAH deficient patients. BH4 treatment for BH4-responsive mild PKU is a new and effective pharmacotherapy, which replaces or liberalises the phenylalanine-restricted diets for a considerable number of mild PKU patients.

Seasonality in the incidence of congenital hypothyroidism in Japan: gender-specific patterns and correlation with temperature.

OBJECTIVE: Seasonality in the incidence of congenital hypothyroidism (CH) has been reported in several countries. The objective of this study was to examine whether seasonality was also observable in Japan and whether this seasonality affected genders differently. METHODS: Confirmed primary CH cases (n = 1586) occurring between 1994 and 2003 were examined through a retrospective review of the nationwide follow-up system at the Aiiku Maternal and Child Health Center, Tokyo, Japan. The number of live births in Japan was obtained from the country's vital statistics. Monthly incidence of CH was analyzed using time series analysis. The relationship between monthly incidence and ambient temperature was also investigated. MAIN OUTCOME: The sex ratio (female/male) was 1.25 for CH, against a background ratio of 0.95 for overall live births in Japan. Monthly CH incidence showed an upward time trend and clear seasonality among both males and females, but with different patterns between the two genders: from January to December, males had one peak while females had two peaks, which continued for a longer period than males had. A significant statistical correlation was found between the incidence and temperature (p < 0.001). CONCLUSION: In Japan, the monthly incidence of primary CH cases exhibits temperature-associated seasonality, gender-specific patterns, and an upward time trend.

Growth of patients with congenital hypothyroidism detected by neonatal screening in Japan.

BACKGROUND: The growth of patients with congenital hypothyroidism detected by neonatal screening in Japan was investigated. The data investigated were obtained from Medical Aid Program for Chronic Pediatric Diseases of Specified Categories registered in 2002. METHOD: The present study included 2341 patients (1030 male, 1311 female) registered as having congenital hypothyroidism. To investigate the growth of these patients, their heights plotted on cross-sectional growth charts for boys and girls, their bodyweights expressed as percentage of bodyweight for height and the frequency distribution of percentage of bodyweight for height were assessed. RESULTS: Cross-sectional growth charts of both male and female patients showed that the heights of the majority of the patients with congenital hypothyroidism were within +/-2SD. Approximately half of the patients with heights below -2SD, had some complications. The mean percentages of ideal bodyweights for height were 103.0 +/- 12.9% for both sexes (+/-SD, n = 2033), 103.3 +/- 12.7% for boys, and 102.7 +/- 12.9% for girls. The frequency distribution of percentage of bodyweight showed no tendency of shifting to either ends in comparison with normal distribution curve. CONCLUSION: Patients with congenital hypothyroidism detected by neonatal screening had normal growth in general, suggesting that the neonatal screening system is being performed efficiently from detection to treatment of the disease in Japan. However, it remains unclear whether some uncomplicated patients with a height below -2 SD are sufficiently treated or not. Close observation of these patients may be needed.

Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene.

A novel therapeutic strategy for phenylketonuria (PKU) has been initiated in Japan. A total of 12 patients who met the criteria for tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) (EC 1.14.16.1) gene were recruited at 12 medical centers in Japan between June 1995 and July 2001. Therapeutic efficacy of BH(4) was evaluated in single-dose, four-dose, and 1-wk BH(4) loading tests followed by long-term BH(4) treatment, and also examined in relation to the PAH gene mutations. The endpoints were determined as the percentage decline in serum phenylalanine from initial values after single-dose (>20%), four-dose (>30%), and 1-wk BH(4) (>50%) loading tests. Patients with mild PKU exhibiting decreases in blood phenylalanine concentrations of >20% in the single-dose test also demonstrated decreases of >30% in the four-dose test. The 1-wk test elicited BH(4) responsiveness even in patients with poor responses in the shorter tests. Patients with mild HPA, many of whom carry the R241C allele, responded to BH(4) administration. No clear correlation was noted between the degree of decrease in serum phenylalanine concentrations in the single- or four-dose tests and specific PAH mutations. The 1-wk test (20 mg/kg of BH(4) per day) is the most sensitive test for the diagnosis of BH(4)-responsive PAH deficiency. Responsiveness apparently depends on mutations in the PAH gene causing mild PKU, such as R241C. BH(4) proved to be an effective therapy that may be able to replace or liberalize the phenylalanine-restricted diets for a considerable number of patients with mild PKU.

Long term follow-up of patients with inborn errors of metabolism detected by the newborn screening program in Japan.

A newborn mass-screening program for the early detection of phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia, congenital hypothyroidism, congenital adrenal hyperplasia, using filter paper blood specimens, was started throughout Japan in 1977. The total number of newborns screened by March 2000 reached 29,657,738; this represents 95% of the newborns during this period. A collaborative study group has performed a follow-up study of the cases detected by this program since the start of this screening program. The results we have obtained through this study to date include: hyperphenylalaninemia, 1:70,000; congenital hypothyroidism, 1:5,000; and, congenital adrenal hyperplasia, 1:20,000. The cases of maple syrup urine disease, homocystinuria, and galactosemia type 1 were too few for a reliable incidence. Accumulated data for PKU show that IQ is inversely related to blood phenylalanine level and stricter dietary control guidelines have resulted. We now have a number of adolescents with PKU and long-term follow-up data are being obtained.

Newborn screening in Japan.

In the 1970's, the government began to take steps for the treatment of congenital diseases. Mass newborn screening was started in October 1977 throughout Japan in order to detect five inborn errors of metabolism including phenylketonuria, maple syrup urine disease, homocystinuria, histidinemia, and galactosemia. In 1979, mass screening for congenital hypothyroidism was added to the original program. In 1989, screening for congenital adrenal hyperplasia was added and in 1992, screening of histidinemia was discontinued. Currently, screening covers six diseases. The government paid half the cost of screening tests initially and in 2001 this was raised to the full cost (approximately 3000 yen). Parents pay for sample collection. The program is carried out according to law. A new activity involving screening for Wilson disease now necessitates taking dried blood specimens from children 1-3 years old.