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Vol. 10 Supplement 1

October 2012


Newborn Screening for Inborn Errors of Metabolism in Japan A History of the Development of Newborn Screening

Teruo Kitagawa, MD


In 1977, the Ministry of Health and Welfare (MHW) directed prefectural officials in charge of maternal and child health to start publicly funded newborn mass-screening (NBS) for phenylketonuria (PKU), maple syrup urine disease (MSUD), histidinemia, homocystinuria and galactosemia and a study group of MHW formulated the treatment guideline for the target diseases. In 1980, MHW launched the Japan Cooperative Project on Special Formula (JCPSF) to ensure a stable supply of special formula and also organized the committee for JCPSF. From 1977 to 2003, a study group of MHW conducted a follow-up study of the patients detected by the screening. From the follow-up it was concluded that dietary therapy was unnecessary for histidinemia and the screening for the disease was discontinued. In 1995, the guideline for the treatment of PKU was revised to keep lower blood phenylalanine levels. The guideline committee for the treatment of BH4 deficiency was establish in 1996 to obtain better prognosis. In 2012, the MHW decided to initiate publicly funded NBS using MS/MS for inborn errors of amino acid, organic acid, and fatty acid metabolism. The Japanese nationwide NBS has been performed for 35 years. This paper reviews the Japanese history of the development of NBS which has enabled more IEM patients to lead active and productive lives today.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):8-25

Keywords: Newborn screening, Treatment guidelines, Outcome surveys, Inborn errors of metabolism, Amino acid metabolism, Organic acid metabolism, Fatty acid metabolism, Tandem mass spectrometry


Enzyme Replacement Therapy for Lysosomal Storage Diseases

Toya Ohashi, MD, PhD


Enzyme replacement therapy (ERT) has been approved for 6 lysosomal storage diseases (LSDs) worldwide including Japan. These diseases include Gaucher disease (GD), Fabry disease, mucopolysaccharidosis (MPS) types I, II, and VI, and Pompe disease (PD). The efficacy and safety of ERT for LSDs has been confirmed by extensive clinical trials. However, there are still obstacles to successful ERT, such as immune reactions against the infused enzyme, mistargeting of enzymes rather than lysosomes, and intractable tissues. Regarding immune reactions, a negative impact of antibody formation on therapeutic effect has been reported for GD, Fabry disease, MPS type I, and PD. In PD, mistargeting of the enzyme was reported in a mouse model due to autophagic build up. Another challenge is intractable tissues, such as the brain and bone, which are key tissues in LSDs. Thus, control of immune reactions against therapeutic enzymes and control of autophagic build up are key issues to maximize the efficacy of ERT. Finally, the development of a new enzyme that effectively targets the brain and bone is very important to improve the quality of life of patients with LSDs.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):26-34

Key words: Enzyme replacement therapy, Lysosomal storage disease, Antibody, Autophagy


Pediatric Aspects of Skeletal Dysplasia

Keiichi Ozono1, MD, PhD, Noriyuki Namba1, MD, PhD, Takuo Kubota1, MD, PhD, Taichi Kitaoka1, MD, PhD, Kohji Miura1, MD, Yasuhisa Ohata1, MD, Makoto Fujiwara1, MD, Yoko Miyoshi1, MD, PhD, Toshimi Michigami2, MD, PhD


Skeletal dysplasia is a disorder of skeletal development characterized by abnormality in shape, length, a number and mineral density of the bone. Skeletal dysplasia is often associated with manifestation of other organs such as lung, brain and sensory systems. Skeletal dysplasias or dysostosis are classified with more than 400 different names. Enchondral bone formation is a coordinated event of chondrocyte proliferation, differentiation and exchange of terminally maturated chondrocyte with bone. Impaired enchondral bone formation will lead to skeletal dysplasia, especially associated with short long bones. Appropriate bone volume and mineral density are achieved by balance of bone formation and bone resorption and mineralization. The gene encoding fibroblast growth factor receptor 3 is responsible for achondroplasia, representative skeletal dysplasia with short stature. The treatment with growth hormone is approved for achondroplasia in Japan. Osteogenesis imperfecta is characterized by low bone mineral density and fragile bone. Data on the beneficial effect of bisphosphonate for osteogenesis imperfecta are accumulating. Osteopetrosis has high bone mineral density, but sometimes show bone fragility. In Japan as well as other countries, pediatrician treat larger numbers of patients with skeletal dysplasia with short stature and fragile bones compared to 20 years ago.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):35-43

Key words: Achondroplasia, Hypochondroplasia, Osteogenesis imperfecta, Osteopetrosis, Short stature, Fracture, Bone mineral density, Bisphosphonate


Epidemiology of Childhood Diabetes Mellitus in Japan

Naoko Tajima1, MD, PhD, Aya Morimoto2, MD


The incidence of type 1 diabetes mellitus (T1DM) in Japan among those below 15 years of age is reportedly 1.5–2.5 per 100,000; however, population-based data have not been available in recent years. Although the incidence of T1DM in Japan is extremely low compared with that in Caucasians, the vast majority of Japanese children who are diagnosed with diabetes before the age of 10 years have T1DM. The incidence of type 2 diabetes mellitus (T2DM) in childhood is approximately 3.0 per 100,000, with the figure among junior high school children being 3–6 times higher than that among primary school children. The most common type of diabetes in children appears to shift from T1DM to T2DM with advancing age, especially after puberty. The mortality risk of patients with childhood-onset T1DM diagnosed between 1965 and 1979 is 12.9-fold higher than that of the general population. However, due to efforts aimed at improving medical care and ameliorating the effects of diabetes among children and adolescents, the standardized mortality ratio (SMR) has declined markedly over the past 30 years. The progression of complications in T2DM appears to be more rapid than that in T1DM, primarily due to the number of drop-out cases. Therefore, appropriate education and treatment programs are necessary to protect against diabetic complications in the younger generation. The establishment of an ongoing population-based national T1DM and T2DM registry system is critical for identifying risk factors associated with diabetes and its complications.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):44-50

Keywords: Type 1 diabetes mellitus, Type 2 diabetes mellitus, Incidence, Prevalence, Prognosis, Mortality rate, Standardized mortality ratio


Screening and Treatment of Childhood Type 1 and Type 2 Diabetes Mellitus in Japan

Tatsuhiko Urakami1, MD, Junichi Suzuki1, MD, Hideo Mugishima1, MD, Shin Amemiya2, MD, Shigetaka Sugihara3, MD, PhD, Tomoyuki Kawamura4, MD, Toru Kikuchi5, MD, Nozomu Sasaki2, MD, Nobuo Matsuura6, MD, Teruo Kitagawa1, 7,MD


A large number of children with type 2 diabetes mellitus (T2DM) and a small number with a slowly progressive form of type 1 diabetes mellitus (SPT1DM) have been detected by a urine glucose screening program conducted at Japanese schools since 1974. The incidence of T2DM in children has increased over the last 3 decades and is estimated to be approximately 3.0/100,000/year, which is twice as that of T1DM. In contrast, SPT1DM in children is more prevalent in Asians, particularly Japanese, and exhibits unique clinical features that differ from those of the rapid onset form of T1DM, usually seen in Caucasians. In the first part of this review, we summarize the urine glucose screening program conducted at Japanese schools and clinical characteristics of the 2 diabetic subtypes in Japanese children. In recent years, concerns regarding childhood diabetes in Asian countries, including Japan, have risen, and medical care for the same is exceedingly developing. Intensive insulin therapy such as basal–bolus therapy by multiple daily insulin injections and pump therapy, both using insulin analogs, has been increasing in pediatric patients with T1DM. In addition, various antidiabetic medications have been introduced for children with T2DM. In the second part of this review, we describe treatment of Japanese children with T1DM and T2DM and changes in glycemic control as a result of development of the treatment.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):51-61

Keywords: Type 1 diabetes mellitus, Type 2 diabetes mellitus, Urine glucose screening, Obesity, Glycemic control, Intensified insulin therapy, CSII, Antihyperglycemic drug


Genetic Susceptibility of Childhood Type 1 Diabetes Mellitus in Japan

Shigetaka Sugihara, MD, PhD


Most cases of type 1 diabetes mellitus(T1DM) are caused by an autoimmune reaction, involving genetic and environmental factors, which ultimately disrupt insulin-producing pancreatic 􀁠cells. Several genes, including those encoding human leukocyte antigen (HLA) class II (IDDM1 locus), insulin (IDDM2 locus), and cytotoxic T lymphocyte antigen (CTLA) 4 (IDDM12 locus), are involved in this process. In this paper, I review the studies of Japanese patients with childhood type 1A diabetes mellitus(T1ADM), including the results of the multicenter study conducted by The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). The JSGIT study analyzed the HLA-DRB1, DQB1, DPB1, A, C, and B genes in Japanese patients with childhood T1ADM to identify candidate genes specific for Japanese individuals. Some of the genes were also involved in diabetes in Caucasian. A comparison of parents and siblings showed that several susceptible DRB1-DQB1 haplotypes and resistant alleles were involved in the development of T1ADM . However, results of transmission disequilibrium tests demonstrated no genomic imprinting of HLA Class I or II genes in Japanese patients. The frequency of the DRB1*09:01 allele was significantly higher in patients who developed the disease at 2–5 years old than in other patients. Identifying HLA gene polymorphisms may help to examine the relationship between antigen-presenting molecule structures and autoantigenic peptides. The JSGIT study also identified single nucleotide polymorphisms in genes other than HLA. Understanding the genetic factors associated with T1ADM that help explain the lower incidence of this disease in Japanese than in Caucasian individuals, will help us to elucidate its pathogenesis.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):62-71

Keywords: HLA class II gene, HLA class I gene, Type 1A diabetes mellitus, Japanese children, Transmission disequilibrium test


Neonatal Screening for Congenital Adrenal Hyperplasia in Japan

Toshihiro Tajima1, MD, PhD, Kaori Fujikura2, MS, Masaru Fukushi3, PhD, Tomoyuki Hotsubo4, MD, Yu Mitsuhashi2, MD, PhD


A nationwide screening test for congenital adrenal hyperplasia (CAH) was first initiated in Japan in 1989, over 20 years ago, and it is now 30 years since a pilot study was initiated in Sapporo in 1982. The incidence of 21-hydroxylase deficiency in Japan is about 1/18,000 persons, which is similar to that in other countries. The effectiveness of early detection and treatment of CAH in Japan has been demonstrated by costbenefit analyses. However, the false-positive rate of CAH screening in preterm infants remains high compared to screening tests for term infants. To improve the positive predictive value, we have employed 21-hydroxylase gene (CYP21A2) analysis on dried blood spots and high performance liquid chromatography (HPLC) to measure 17-hydroxyprogesterone, and currently use tandem mass spectrometry (LC-MS/MS) as a screening technique. We suggest that LC-MS/MS should be used in the future to improve the accuracy of CAH screening in Japan.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):72-78

Key words: Congenital adrenal hyperplasia (CAH), 21-hydroxylase deficiency, 17-hydroxyprogesterone (17- OHP), False positive rate, Positive predictive value, Tandem mass screening


Neonatal Screening for Congenital Hypothyroidism in Japan

Kanshi Minamitani1, MD, PhD, Hiroaki Inomata2, MD, PhD


Congenital hypothyroidism may cause irreversible intellectual disability or failure to thrive if left untreated. Because this disorder can be prevented by early identification and early treatment, newborn mass screening started in 1979 in Japan. A guideline for mass screening for this disease was prepared in 1998. Currently, approximately 100% of newborns undergo this mass screening. The screening results show significant improvement of the intellectual outcome of patients with this disease, with almost no patients having irreversible intellectual disturbance or failure to thrive. However, there are issues of a delayed increase in thyroid stimulating hormone, management of latent hypothyroidism, and detection of central hypothyroidism. In recent years, as studies on this disease have advanced at the molecular level, many causative genes have been reported, clarification of the etiology, pathology, and clinical features has progressed, and new findings have been obtained.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):79-88

Keywords: Intellectual disability, Failure to thrive, Early identification, Dried blood spot filter paper, Thyroid dysgenesis, Hormone biosynthesis, Nationwide survey, Gene abnormality


Growth Hormone Treatment in Japan: Past, Present, and Future

Toshiaki Tanaka, MD


Growth hormone (GH) treatment was approved for growth hormone deficiency (GHD) in Japan in 1975. Since then, GH treatment has been approved for treating five other diseases with short stature. However, available data on adult height after long-term GH treatment is limited to patients with GHD and Turner syndrome. Although adult height of patients with GHD has improved with early diagnosis and early initiation of treatment, the adult height after long-term GH treatment is still not so satisfactory because the therapeutic dose used in Japan is smaller than that used in US and Europe. With early diagnosis, early high-dose treatment, and low-dose estrogen replacement therapy, both adult height and quality of life (QOL) of the patients with Turner syndrome have been improved.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):89-97

Key words: Growth hormone deficiency, Growth hormone treatment, Adult height, Turner syndrome


Genetic Defects in Pregnenolone Synthesis

Noriyuki Katsumata, MD, PhD


The pregnenolone synthesis is the first step in the biosynthesis of all steroid hormones. The disruption of this step is known to result in congenital lipoid adrenal hyperplasia (CLAH), a most severe form of congenital adrenal hyperplasia. CLAH was first demonstrated to be caused by mutations in the STAR gene encoding steroidogenic acute regulatory protein (StAR). Now genetic and phenotypic variations have been elucidated in pregnenolone synthesis defects; mutations in the CYP11A1 gene encoding cholesterol side-chain cleavage enzyme (SCC) also cause disordered pregnenolone synthesis, and STAR mutations do not necessarily results in typical CLAH. To define these conditions precisely, pathophysiological diagnoses, such as StAR deficiency and SCC deficiency, are more likely to be appropriate than the histopathological diagnosis like CLAH.

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):98-109

Keywords: Congenital lipoid adrenal hyperplasia, STAR, Steroidogenic acute regulatory protein, CYP11A1, Cholesterol side-chain cleavage enzyme, Pregnenolone


Genetics of Male Hypogonadotropic Hypogonadism

Naoko Sato, MD

Ref: Ped. Endocrinol. Rev. 2012;10(suppl 1):110-125

Keywords: Hypogonadotropic hypogonadism, Kallmann syndrome, Oligogenicity



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