Toshihide Kubo

Serum levels of carboxyterminal propeptide of type I procollagen and pyridinoline crosslinked telopeptide of type I collagen in normal children and children with growth hormone (GH) deiciency during GH therapy

In this study, we investigated age-related changes in serum levels of both the carboxyterminal propeptide of type I procollagen (PICP) and the pyridinoline crosslinked telopeptide of type I collagen (ICTP) to elucidate bone formation and resorption, respectively, in 200 normal Japanese children (141 males and 59 females, age range 0-16 years). Furthermore, to clarify the effect of GH on bone turnover, we measured serum PICP and ICTP in 26 growth hormone (GH)-deficient children (20 males and 6 females, age range 4-15 years) who showed significant bone growth during recombinant human GH therapy. In the normal children, the curves for age-related changes in both serum PICP and ICTP levels almost paralleled that of the standard height velocity curve in both sexes. The serum levels of both peptides were higher than those in adults, and the peak increases corresponded with the timing of the adolescent growth spurt. Furthermore, the serum levels of PICP and ICTP were significantly correlated with the height velocity. In the GH-deficient patients, the serum ICTP levels before GH therapy were lower than those in age- and sex-matched controls. Both PICP and ICTP levels in serum increased significantly at the beginning of GH therapy. Furthermore, the percent increase in PICP after 1 month of GH treatment was positively correlated with the percent increase in height velocity during 1 year of GH treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI

Mucopolysaccharidosis type VI (MPS VI) is a progressive, multisystem autosomal recessive lysosomal disorder resulting from deficient N-acetylgalactosamine-4-sulphatase (ASB) and the consequent accumulation of glycosaminoglycan (GAG). Preclinical and clinical studies had demonstrated clinical benefits of early initiation of systemic therapies in patients with MPS. In this case report, two siblings with MPS VI started enzyme replacement therapy (ERT) with weekly infusions of recombinant human ASB (Galsulfase) at 1mg/kg. Sibling 1 started ERT 5.6 years of age and Sibling 2 was 6 weeks old. The disease status in these two siblings prior to and for no less than 36 months of ERT was followed up and compared. The treatment was well tolerated by both siblings. During 36 months of ERT, symptoms typical of MPS VI including short stature, progressive dysmorphic facial features, hepatosplenomegaly, hearing impairment, corneal clouding, and dysostosis multiplex were largely absent in the younger sibling. Her cardiac functions and joint mobility were well preserved. On the other hand, her affected brother had typical MPS VI phenotypic features described above before commencing ERT at the equivalent age, of 3 years. There was significant improvement in the shoulder range of motion and hearing loss after 36 months of treatment and cardiac function was largely preserved. His skeletal deformity and short stature remained unchanged. The results showed that early ERT initiated at newborn is safe and effective in preventing or slowing down disease progression of MPS VI including bone deformities. These observations indicate that early diagnosis and treatment of MPS VI before development of an irreversible disease is critical for optimal clinical outcome.

An ultrasensitive assay revealed age-related changes in serum oestradiol at low concentrations in both sexes from infancy to puberty

OBJECTIVE Intensive studies of oestrogen receptors have suggested extragonadal functions of oestrogen. However, the in vivo extragonadal functions of oestradiol remain unclear because of the lack of an adequate assay system at low concentrations. In this study, we assessed the usefulness of a new ultrasensitive assay for children.

Growth hormone (GH) treatment in achondroplasia.

Achondroplasia is one of the most commonly known types of skeletal dysplasia in the adult leading to short stature. Before beginning growth hormone (GH) treatment of short stature in patients with achondroplasia, we evaluated their growth pattern and their hypothalamic-pituitary function, including GH secretion. We studied 22 patients with achondroplasia (7 males and 15 females: age range, 3 to 12 years). The z-score of their height at admission was -5.4 +/- 1.2 (mean +/- SD), and that of their annual height gain before admission was -3.1 +/- 1.3 (mean +/- SD). GH response to provocative tests was normal in all patients except five: four showed subnormal (< 10 ng/ml) response to L-Dopa stimuli, and one patient showed subnormal (< 20 ng/ml) response to GRF stimuli. The mean GH concentration during sleep was found to be low (< 5 ng/ml) in three patients. These three patients were suspected to have latent GH deficiency, as they also showed a markedly low IGF-1 level and marked delay of bone age. LH, FSH, TSH, and cortisol response to provocative tests were normal in all the patients. We treated this group of patients with recombinant human GH (1 IU/kg/week). In 18 patients who were treated with GH for more than 6 months, height velocity during GH therapy was significantly increased compared to that before GH therapy (4.1 +/- 0.8 cm/year vs 7.2 +/- 1.4 cm/year). We conclude that parameters reflecting hypothalamic-pituitary function, particularly GH secretion, should be examined in achondroplasia patients, and that GH treatment may be beneficial in the treatment of short stature in achondroplasia.

Effect of growth hormone on fatty liver in panhypopituitarism

A 17 year old boy was admitted because of short stature and hepatomegaly. He was diagnosed with panhypopituitarism and fatty liver. The fatty liver improved, not with hydrocortisone or levothyroxine treatment, but with growth hormone administration. The fatty liver in this patient was attributable to a growth hormone deficient state.

Breastfeeding and behavioral development: a nationwide longitudinal survey in Japan.

OBJECTIVE To prospectively examine the prolonged effect of breastfeeding on behavioral development. STUDY DESIGN We used a large, nationwide Japanese population-based longitudinal survey that began in 2001. We restricted participants to term singletons with birth weight >2500 g (n = 41 188). Infant feeding practice was queried at age 6-7 months. Responses to survey questions about age-appropriate behaviors at age 2.5 and 5.5 years were used as indicators of behavioral development. We conducted logistic regression analyses, controlling for potential child and parental confounding factors, with formula feeding as the reference group. RESULTS We observed a dose-response relationship between breastfeeding status and an inability to perform age-appropriate behaviors at both ages. With a single exception, all ORs for outcomes for exclusive breastfeeding were smaller than those for partial feeding of various durations. The protective associations did not change after adjustment for an extensive list of confounders or in the sensitivity analyses. CONCLUSION We observed prolonged protective effects of breastfeeding on developmental behavior skills surveyed at age 2.5 and 5.5 years. Beneficial effects were most likely in children who were breastfed exclusively, but whether a biological ingredient in breast milk or extensive interactions through breastfeeding, or both, is beneficial is unclear.

Methionine adenosyltransferase I/III deficiency: Neurological manifestations and relevance of S-adenosylmethionine

Methionine adenosyltransferase I/III (MAT I/III) deficiency, caused by mutations in the MAT1A gene, is an inherited metabolic disorder characterized by persistent hypermethioninemia, usually detected by newborn mass screening. There is a wide range of clinical manifestations, from completely asymptomatic to neurological problems associated with brain demyelination. Physiological role of S-adenosylmethionine (SAM), the metabolic product of methionine catalyzed by MAT, in the central nervous system has been investigated in vivo and in vitro, and case reports demonstrated an effectiveness of supplementary treatment of SAM in the improvement of neurological development and myelination. Methionine restriction can be an additional therapeutic strategy because hypermethioninemia alone may be neurotoxic; however, lowering methionine carries a risk to decrease the synthesis of SAM.

Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese population-based study

OBJECTIVE To investigate neurological development in small for gestational age (SGA) infants, with a focus on full-term SGA infants. METHODS We analyzed data from a large, Japanese, nationwide, population-based longitudinal survey started in 2001. We restricted the study to participants born before 42weeks of gestation (n=46,563). Parents were asked questions about motor and language development when the children were 2.5years old, and about behavioral development at 5.5years. We analyzed the relationships between SGA status and development by logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for each outcome for full-term and preterm births, adjusting for potential infant- and parent-related confounding factors. We also calculated the population-attributable fractions to estimate the public impact of SGA births. RESULTS SGA full-term children were more likely to demonstrate developmental delays at 2.5years, e.g., being unable to walk alone (OR 3.0, 95% CI: 1.7, 5.3), compose a two-phrase sentence (OR 1.5, 95% CI: 1.2, 1.8), or use a spoon to eat (OR 1.5, 95% CI: 1.1, 1.9). SGA status also had some degree of negative impacts on behavioral problems at 5.5years among term children, e.g., being unable to listen without fidgeting (OR 1.2, 95% CI: 1.1, 1.3), or remain patient (OR 1.1, 95% CI: 1.0, 1.2). The public health impacts were comparable between full-term and preterm SGA children at 2.5years. CONCLUSION SGA is a risk factor for developmental delay, even in full-term infants, with non-negligible public health impacts.

S-adenosylmethionine treatment in methionine adenosyltransferase deficiency, a case report

Reported is a female patient with methionine adenosyltransferase I/III (MAT I/III) deficiency, who was found to have pronounced hypermethioninemia on newborn mass spectroscopy screening, and had two compound heterozygous missense mutations in the gene encoding human MAT1A protein. Hypermethioninemia persisted and her mental development was deficient. At 4 years and 8 months, we started with the supplementary treatment of S-adenosylmethionine, the metabolic product of methionine catalyzed by MAT, which was effective in her neurological development.

Malignant osteopetrosis treated with high doses of 1α-hydroxyvitamin D3 and interferon gamma

A male infant with malignant osteopetrosis was treated with high doses of 1 α -hydroxyvitamin D 3 and interferon gamma. Therapy with 1 α -hydroxyvitamin D 3 increased the serum calcium level despite the markedly elevated serum level of 1 α ,25-dihydroxyvitamin D before treatment. Recombinant human interferon gamma increased neither the bone mineral nor matrix turnover, and was not tolerated because of bone marrow suppression.