Kikumaro Aoki

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 (BH4)-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 BH4 was evaluated in single-dose, four-dose, and 1-wk BH4 loading tests followed by long-term BH4 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 BH4 (>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 BH4 responsiveness even in patients with poor responses in the shorter tests. Patients with mild HPA, many of whom carry the R241C allele, responded to BH4 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 BH4 per day) is the most sensitive test for the diagnosis of BH4-responsive PAH deficiency. Responsiveness apparently depends on mutations in the PAH gene causing mild PKU, such as R241C. BH4 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.

Follow-up study of a nation-wide neonatal metabolic screening program in Japan

A nationwide neonatal sreening program for phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, histidinemia and galactosemia was started in Japan in 1977. The total number of infants screened had reached 6,311,754 by March, 1982. A follow-up study revealed the incidence of the disease in Japan: 1/108,823 for PKU; 1/450,840 for hyperphenylalaninemia (HPA); 1/1,577,939 for biopterin deficiency; 1/525,980 for MSUD; 1/1,051,959 for homocystinuria; 1/8,371 for histidinemia, and 1/788,969 for galactosemia type 1. The incidences of PKU, HPA, homocystinuria, and galactosemia (type 1) were found to be markedly low in Japan as compared with those in Caucasian countries. There was no great difference in the incidence of MSUD between both. On the other hand, the incidence of histidinemia was higher in Japan.It was found that most of the patients with PKU, HPA, MSUD, homocystinuria, or galactosemia are developing normally due to the early initiation of dietary treatment. These results clearly indicate that the neonatal mass screening program plays a great role in preventing the occurrence of handicapped children.

Management of acute metabolic decompensation in maple syrup urine disease: A multi‐center study

Abstract Background: Therapeutic modalities in acute metabolic decompensation in maple syrup urine disease (MSUD) are variable, and outcomes of each therapeutic measure have been known only individually. Factors that affect neurological outcome are not clear.

Taste preferences and feeding behaviour in children with phenylketonuria on a semisynthetic diet

Abstract Low-phenylalanine formula for phenylketonuria (PKU) made from free amino acids as a protein source (AAM formula) has a poor taste and smell. We developed a more palatable formula using low-phenylalanine peptide (LPP) as a protein source. Palatability tests performed by 41 healthy adults confirmed that the palatability of LPP formula was significantly better than that of AAM formula. A group of 48 patients with PKU who had been administered AAM formula since the newborn period were assessed for their preference between the AAM and LPP formulae and their feeding behaviour was compared to that in healthy children. Of patients, 90.9% and 66.6% of healthy infants less than 18 months of age took both formulae without apparent preference, suggesting that sensitivity to taste and smell is more immature in infancy than in later life. Of patients with PKU aged between 18 months and 11 years, 29.1% liked AAM formula rather than the LPP formula, while 66.7% took both formulae without apparent preference. Most healthy children in the same age group who had never previously tasted therapeutic formulae disliked it, although they tended to prefer the LPP formula. Of patients aged between 11 and 17 years, 84.6% preferred the LPP formula while 15.4% preferred the AAM formula. In the controls of this age group, 33% disliked therapeutic formulae, but they tended to prefer the LPP formula. Conclusion In some young children with phenylketonuria the characteristic taste of amino acid mixture formula encountered in early life is considered to be imprinted and remains as a preference for a long time. Since school children with phenylketonuria usually obtain about 50% of their energy intake from natural food containing small amounts of protein, these patients are considered to have come to have similar preferences as healthy people which result from a waning of the imprinted taste of amino acid mixture formula.

Treatment of phenylketonuria with a formula consisting of low-phenylalanine peptide

A method of preparation of a more palatable therapeutic formula for phenylketonuria (PKU), consisting of low-phenylalanine peptide (LPP), was reported. There were no adverse effects and, in fact, there was a reduced frequency of diarrhea in patients who received LPP formula for more than 6 months. The LPP formula can be used not only as a more palatable therapeutic milk for PKU, but also as an ingredient to make more palatable foods of low-phenylalanine content.

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.

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.

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.