Yohei Ogawa

Usefulness of Serum Adiponectin Level as a Diagnostic Marker of Metabolic Syndrome in Obese Japanese Children

This study aimed 1) to investigate the relationship between serum adiponectin levels and metabolic disorders and 2) to clarify the usefulness of serum adiponectin level as a diagnostic marker of metabolic syndrome in obese Japanese children. One hundred obese boys aged 8 to 13 years were examined. Serum adiponectin levels were measured by radioimmunoassay using a commercial kit. Abdominal fat thickness (maximum preperitoneal fat thickness: Pmax; minimum subcutaneous fat thickness: Smin) was measured by ultrasonography. The relationships between adiponectin and clinical characteristics were analyzed by simple regression. The relationships between anthropometric measurements and metabolic disorders were analyzed among three groups divided according to adiponectin percentile. The prevalence of metabolic syndrome was also analyzed, with metabolic syndrome defined as the presence of three or more complications of obesity. The criteria for metabolic syndrome by adiponectin were subjected to a receiver operating characteristic (ROC) analysis. Body weight, waist circumference, Pmax, alanine aminotransferase and fasting serum insulin were all inversely correlated with adiponectin. There were significant differences in the prevalence of severe obesity, the accumulation of visceral adipose tissue, hyperinsulinemia, high serum low density lipoprotein-cholesterol, the number of complications of obesity and the prevalence of metabolic syndrome among the three groups. The area under the ROC curve for adiponectin was 0.672±0.055 and the cut-off value was 6.65 μg/ml. Hypoadiponectinemia was associated with visceral fat accumulation and metabolic syndrome in obese Japanese boys. Evaluation of adiponectin might contribute to an early intervention for obese children with metabolic syndrome.

PRKAR1A Mutation Affecting cAMP-Mediated G Protein-Coupled Receptor Signaling in a Patient with Acrodysostosis and Hormone Resistance

CONTEXT Acrodysostosis is a rare autosomal dominant disorder characterized by short stature, peculiar facial appearance with nasal hypoplasia, and short metacarpotarsals and phalanges with cone-shaped epiphyses. Recently, mutations of PRKAR1A and PDE4D downstream of GNAS on the cAMP-mediated G protein-coupled receptor (GPCR) signaling cascade have been identified in acrodysostosis with and without hormone resistance, although functional studies have been performed only for p.R368X of PRKAR1A. OBJECTIVE Our objective was to report a novel PRKAR1A mutation and its functional consequence in a Japanese female patient with acrodysostosis and hormone resistance. PATIENT This patient had acrodysostosis-compatible clinical features such as short stature and brachydactyly and mildly elevated serum PTH and TSH values. RESULTS Although no abnormality was detected in GNAS and PDE4D, a novel de novo heterozygous missense mutation (p.T239A) was identified at the cAMP-binding domain A of PRKAR1A. Western blot analysis using primary antibodies for the phosphorylated cAMP-responsive element (CRE)-binding protein showed markedly reduced CRE-binding protein phosphorylation in the forskolin-stimulated lymphoblastoid cell lines of this patient. CRE-luciferase reporter assays indicated significantly impaired response of protein kinase A to cAMP in the HEK293 cells expressing the mutant p.T239A protein. CONCLUSIONS The results indicate that acrodysostosis with hormone resistance is caused by a heterozygous mutation at the cAMP-binding domain A of PRKAR1A because of impaired cAMP-mediated GPCR signaling. Because GNAS, PRKAR1A, and PDE4D are involved in the GPCR signal transduction cascade and have some different characters, this would explain the phenotypic similarity and difference in patients with GNAS, PRKAR1A, and PDE4D mutations.

Lower Birth Weight and Visceral Fat Accumulation Are Related to Hyperinsulinemia and Insulin Resistance in Obese Japanese Children

This study aimed to reveal the relation of birth weight (or the birth weight standard deviation score [BWSDS]) and visceral fat accumulation to hyperinsulinemia and insulin resistance. We examined obese Japanese children (650 boys and 317 girls) with a mean age of 10.3 years (range, 6–15 years). The mean percentage of overweight to the standard body weight of Japanese children was 52.1% in boys and 51.4% in girls. Abdominal fat thickness (maximum preperitoneal fat thickness; Pmax) was measured using ultrasonography. The fasting serum insulin and plasma glucose levels were measured, and the homeostasis model assessment-insulin resistance (HOMA-R) and quantitative insulin sensitivity check index (QUICKI) were calculated. We divided the subjects into four groups according to their birth weight or BWSDS, and compared anthropometric measurements, Pmax, blood pressure, serum insulin levels, HOMA-R and QUICKI among the quartiles. The relationships of both birth weight (or BWSDS) and Pmax to serum insulin levels (or HOMA-R, QUICKI) were examined with multiple regression analyses. The fasting serum insulin level and HOMA-R were highest in the quartile with the lowest birth weight or BWSDS. The birth weight and BWSDS were inversely related to the serum insulin levels and HOMA-R, positively related to QUICKI, and independent of Pmax. Our findings suggest that both lower birth weight and visceral fat accumulation may be independently related to hyperinsulinemia and insulin resistance in obese Japanese children.

Lower Birth Weight Associated with Current Overweight Status Is Related with the Metabolic Syndrome in Obese Japanese Children

The purpose of this study was to clarify the relationship between lower birth weight and current overweight status and to examine the involvement of these factors in the development of the metabolic syndrome (MS) in obese Japanese children. We examined 97 obese boys (mean age 11.3 years; mean percentage overweight [POW] 52.4%) and 29 obese girls (mean age 11.1 years; mean POW 58.3%). The anthropometric measurements, blood pressure, fasting serum insulin and blood glucose, liver enzymes, lipids and lipoproteins were measured. Birth weight and gestational weeks were also recorded. The subjects were divided into either an MS group or a Non-MS group using criteria proposed for Japanese children. We compared the weight parameters (birth weight, current weight and current weight–to−birth weight ratio [WBWR]) between the two groups and analyzed the relationships between the weight parameters and metabolic derangements. There were no significant differences in age or anthropometric measurements between the two groups. However, birth weight in the MS group was lower than that in the Non-MS group, while WBWR of the MS group was higher than that in the Non-MS group. Blood pressure and serum insulin correlated positively with WBWR. These findings suggested that lower birth weight with current overweight status was associated with the MS in obese Japanese children. We were unable to clarify whether subjects with lower birth weight who achieved proper weight gains had the same risk as subjects with appropriate birth weight. However, they should be assisted to grow adequately to prevent future metabolic derangements.

Association of Urinary Type IV Collagen With GFR Decline in Young Patients With Type 1 Diabetes

BACKGROUND Some patients with diabetes have advanced diabetic glomerular lesions and progressive kidney function decline even if urinary albumin levels are in the normal range. Therefore, another prognostic marker for diabetic kidney disease needs to be identified. We aimed to clarify whether urinary type IV collagen is associated with the progression of kidney function decline in patients with type 1 diabetes. STUDY DESIGN Hospital-based observational cohort study. SETTING & PARTICIPANTS 231 normo- and microalbuminuric patients with type 1 diabetes who were younger than 40 years at the start of the study. PREDICTOR & MEASUREMENTS: Urinary type IV collagen, determined using a 1-step sandwich enzyme immunoassay. OUTCOME The primary outcome measurement was rate of change in estimated glomerular filtration rate (eGFR). RESULTS Mean follow-up was 7.4 ± 1.3 (standard deviation) years. Urinary type IV collagen-creatinine ratio (T4C) was associated significantly with rate of change in eGFR in both univariate (r = -0.169; P = 0.01) and multivariate regression analyses (standardized estimate = -0.131; P = 0.03). In the sensitivity analysis limited to patients with normoalbuminuria (n = 213), T4C, but not urinary albumin-creatinine ratio (ACR), was associated significantly with rate of change in eGFR (standardized estimate = -0.12; P = 0.03). The interaction between logarithmically transformed ACR and logarithmically transformed T4C on eGFR decline was not significant (P for interaction = 0.2). We compared the adjusted rate of change in eGFR among 4 groups classified according to normal or increased T4C and ACR values and found that the rate of decline in eGFR in patients with increased T4C and normal ACR values was significantly faster than that in patients with normal T4C and ACR values (-4.3 and -3.0 mL/min/1.73 m(2)/y; P = 0.004, analysis of covariance). LIMITATIONS Study size was relatively small. CONCLUSIONS T4C is associated with progression of kidney function decline in young patients with type 1 diabetes.

A Study of the Etiology of Congenital Hypothyroidism in the Niigata Prefecture of Japan in Patients Born Between 1989 and 2005 and Evaluated at Ages 5–19

BACKGROUND The prevalence of congenital hypothyroidism (CH) increased during the period 1994-2002 in Japan. The reasons for these recently described increases in the prevalence of CH remain unclear. Moreover, the proportion of patients with different etiologies CH in the more recently diagnosed patients has not been established. In this study, we determined the etiologies of CH that were detected by neonatal screening in Niigata refecture, Japan. METHODS A total of 100 patients having a diagnosis of CH (41 men and 59 women, aged 5-19 years old) were evaluated. To determine the etiology of CH, the patients underwent a ¹²³I thyroidal radioiodine uptake test, a scintigram, a saliva to plasma radioiodine ratio analysis, a perchlorate discharge test, thyroid ultrasonography, measurements of thyroidal function and thyroglobulin, and a thyrotropin (TSH)-releasing hormone tolerance test. RESULTS Patients with overt CH (n=34, elevated TSH levels with low free thyroxine levels) made up 34% of the total group, 56% of the patients had subclinical CH (n=56, elevated TSH levels with normal free thyroxinelevels), and 10% had normal thyroid function. These were patients who were considered to have transient hypothyroidism or hyperthyrotropinemia. Thyroid dysgenesis was the diagnosis in 73% of patients with overt CH, and the most of these had ectopic thyroid tissue. In contrast, thyroid dysgenesis was the diagnosis in only 36% of the patients with subclinical CH. CONCLUSIONS Only 50% of our patients with CH detected by neonatal screening had thyroid dysgenesis. With an increase in the percentage of patients with subclinical hypothyroidism, the prevalence of thyroid dyshormogenesis has increased. Studies of the frequency and etiology of CH should consider overt and subclinical CH separately.

Mitochondrial trifunctional protein deficiency in a lethal neonate

Mitochondrial fatty acid β -oxidation provides the primary source of energy for the heart and other high energyrequiring tissue. Mitochondrial trifunctional protein (MTP), an enzyme involved in fatty acid β -oxidation with specificity to the long carbon chain, is a multienzyme complex composed of four molecules of the α -subunit containing 3-hydroxyacyl-CoA dehydrogenase, the enoyl-CoA hydratase domains and four molecules of the β -subunit containing the 3-ketoacyl-CoA thiolase domain. MTP deficiency is characterized by deficiency of all three enzyme activities. 1 Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency in man was first described in 1989. 2 Recently, it was found that LCHAD deficiency is caused by an abnormality in MTP. 3

Long-term follow-up study for a patient with Floating-Harbor syndrome due to a hotspot SRCAP mutation.

Floating–Harbor syndrome (FHS) is a rare autosomal dominant disorder characterized by short stature, skeletal malformations, speech delay, and dysmorphic facial appearance. Recently, mutations in SRCAP encoding a coactivator for cAMP‐response element binding protein (CREB)‐binding protein have been identified in small number of patients with FHS. Here, we report on long‐term follow‐up data of a male patient with a SRCAP mutation. The patient presented with mild hypothyroidism and renal hypouricemia, in addition to several FHS‐compatible features including growth impairment, cognitive disability, facial dysmorphisms, and hypertension. He showed delayed bone age from infancy to 9 years of age and markedly accelerated bone age with the formation of cone‐shaped epiphyses and early epiphysial fusions after the onset of puberty. His pubertal sexual development was almost age appropriate. Two‐year treatment with growth hormone (GH) did not significantly improve the growth velocity. Molecular analysis identified a de novo heterozygous nonsense mutation (p.R2444X) in the last exon of SRCAP, which has been most common mutation detected in patients from other ethnic groups. These results indicate that perturbed skeletal maturation from infancy through adolescence is a characteristic feature in patients with SRCAP mutations. Furthermore, our data imply that GH therapy exerted only a marginal effect on the growth of this patient, and that renal hypouricemia may be a novel complication of FHS.

Evaluation of Parathyroid Gland Function Using Sodium Bicarbonate Infusion Test for 22q11.2 Deletion Syndrome

Background/Aims: 22q11.2 deletion syndrome is a congenital malformation syndrome with hypoparathyroidism. The spectrum of parathyroid gland dysfunction ranges from severe neonatal hypocalcemia to subclinical hypoparathyroidism. The parathyroid hormone (PTH) secretory reserve is reduced in a significant number of 22q11.2 deletion syndrome patients with normocalcemia. The aim of this study was to investigate hypoparathyroid function using the bicarbonate infusion test for 22q11.2 deletion syndrome with normocalcemia. Methods: Sodium bicarbonate solution [7% (w/v); 40 ml/m2 body surface area] was infused for 2 min, and blood samples for the determination of plasma ionized calcium and plasma intact PTH were serially obtained. The test was conducted on five 22q11.2 deletion syndrome patients with normocalcemia. Results: Two patients presented increments of intact PTH levels (peak value – basal value) of 70 pg/ml or higher during the test, whereas the remaining 3 showed PTH level increments of <30 pg/ml. The former 2 patients were diagnosed as having normal parathyroid gland function, and the latter 3 patients as having subclinical hypoparathyroidism. Conclusion: The bicarbonate infusion test may be a valuable method for the evaluation of residual parathyroid gland function in patients with 22q11.2 deletion syndrome. Screening of subclinical hypoparathyroidism should be considered in the regular follow-up of patients with 22q11.2 deletion syndrome, even in cases with normocalcemia.

H62L Mutation of CYP21A2 Identified in the Non-classical Form of 21-Hydroxylase Deficiency

Neonatal mass screening for congenital adrenal hyperplasia (CAH) has been performed in Japan since 1989. Steroid 21-hydroxylase deficiency (21-OHD) represents about 95% of CAH patients and is traditionally divided into three forms, severe classical salt-wasting (SW), simple virilizing (SV) and the milder non-classical (NC) form. Very rare cases of the NC form have been detected because of elevated 17-hydroxyprogesterone (17-OHP) levels at neonatal mass screening in Japan (1). The estimated rate of detection of the NC form by mass screening seems to be low (1:1,100,000) (1). This disease is caused by deletions or mutations of CYP21A2. In Japan, the P30L mutation appears more likely to be associated with Japanese NC patients (1). Here, we report a rare H62L mutation with the NC form in a Japanese 21-OHD patient.