Takahiko Saijo

Dynamic Changes in Serum Leptin Concentrations during the Fetal and Neonatal Periods

We investigated the dynamics of the leptin concentration throughout the perinatal period. Serum leptin concentrations in venous cord blood at different gestational ages were measured in 20 preterm and 139 term newborns, as well as in 143 pregnant women and 24 term newborns at approximately 6 d of life. Leptin concentrations in preterm newborns (mean 4.6 ± 6.9 ng/mL) were lower than those in term newborns (mean 19.6 ± 14.3 ng/mL) and tended to increase according to gestational age and birth weight, especially from the late stage of gestation. Leptin concentrations in pregnant women increased from the first trimester and then remained higher than those in non-pregnant women throughout the remainder of pregnancy even after controlling for body mass index. The leptin concentrations of newborns declined rapidly and were extremely low by approximately 6 d of life (mean 1.9 ± 1.1 ng/mL). These results suggest that fetuses might produce a part of circulating leptin in their own adipocytes and that the relatively high leptin concentrations at birth and their rapid decline in the early neonatal period might reflect the dramatic changes of the hormonal and nutritional state during the perinatal period.

Thiamine-responsive lactic acidaemia: role of pyruvate dehydrogenase complex

Abstract Lactic acidaemia is sometimes associated with a defect of the pyruvate dehydrogenase complex (PDHC), catalysing the thiamine-dependent decarboxylation of pyruvate. The activity of PDHC for different thiamine pyrophosphate (TPP) concentrations was determined in 13 patients with lactic acidaemia, clinically responsive to thiamine treatment in order to assess the role of PDHC in the aetiology of thiamine-responsive lactic acidaemia. Culture of lymphoblastoid cells and skin fibroblasts and muscle biopsies were performed in these 13 patients. The activity of PDHC to sodium dichloroacetate (DCA), known as the activator of PDHC, was also examined. Three groups were identified according to PDHC activity. Group 1 (two patients) displayed very low PDHC activity, which was not increased by DCA. This PDHC activity increased at high TPP concentrations. Group 2 (five patients) displayed below normal PDHC activity at low TPP concentrations, increased by DCA. This PDHC activity became normal at high TPP concentrations. PDHC deficiency in these patients of groups 1 and 2 was due to a decreased affinity of PDHC for TPP. Group 3 included six patients with normal PDHC activity at low as well as high TPP concentrations. This PDHC activity was increased by DCA. Conclusion High concentrations of TPP may be required for maximal activity of PDHC in some patients with lactic acidaemia. The assay of PDHC activity, performed at a low concentration of TPP (1 × 10−4 mM) allows selection of patients with thiamine-responsive lactic acidaemia.

Short‐latency somatosensory evoked potentials in infantile autism: evidence of hyperactivity in the right primary somatosensory area

Children with infantile autism sometimes show hyperesthesia or hypoesthesia to touch, pain, and/or temperature. To clarify the pathophysiology, we examined short‐latency somatosensory evoked potentials (S‐SEPs), elicited by median nerve stimulation, in 24 children with infantile autism (17 males, seven females; age range 2y 2mo–9y; mean age 4y 2mo [SD 1y 7mo]). We also evaluated relationships between S‐SEP findings and clinical manifestations. Of the 24 children, 10 showed abnormal S‐SEPs as follows: prolonged peak latency of N20 (n=2), extended interpeak latency of P13/14–N20 (n=7), appearance of a giant SEP (n=1), and a more than twofold right hemispheric peak‐to‐peak amplitude predominance of N20–P25 (n=5). In addition, a peak‐to‐peak amplitude of N20–P25 elicited by left median nerve stimuli was significantly higher than that obtained with right median nerve stimuli, which indicated right hemispheric hyperactivity relative to the left (p=0.008). Infantile autism is frequently associated with somatosensory abnormalities and right hemispheric hyperactivity relative to the left, especially in the primary somatosensory area. This is believed to contribute to the pathophysiology of infantile autism, especially the idiopathic form.

Type II citrullinaemia (citrin deficiency) in a neonate with hypergalactosaemia detected by mass screening

Type II citrullinaemia (CTLN2) is an adult- or late childhood-onset liver disease characterized by a liver-specific defect in argininosuccinate synthetase protein. The enzyme abnormality is caused by deficiency of the protein citrin, which is encoded by the SLC25A13 gene. Until now, however, few cases with SLC25A13 mutations have been reported in children with liver disease. We describe an infant who presented with neonatal hepatitis in association with hypergalactosaemia detected by neonatal mass screening. DNA analysis of SLC25A13 revealed that the patient was homozygous for a IVS11+1G>A mutation. This case suggests that SLC25A13 mutant should be suspected in neonatal patients with hypergalactosaemia of unknown cause.

Effect of growth hormone on the translocation of GLUT4 and its relation to insulin-like and anti-insulin action.

To elucidate the effect of growth hormone (GH) on the insulin signal transduction pathway leading to the translocation of glucose transporter-4 (GLUT4), we constructed Chinese hamster ovary cells that overexpressed GH receptor and GLUT4. Treatment with GH triggered GLUT4 translocation, and this translocation was completely inhibited by wortmannin. GH-induced GLUT4 translocation reached a maximum level after 30 min, and then gradually decreased and returned to the basal level after 2 h. Tyrosine phosphorylation of JAK2 also became maximal after 30 min and then gradually decreased. In contrast, GLUT4 translocation remained unchanged for 2 h after insulin treatment, and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) also remained constant for up to 2 h. Chronic GH treatment had almost no effect on insulin-stimulated Akt kinase activation and GLUT4 translocation. These results suggest that GH and insulin translocate GLUT4 in a similar manner, at least in part, and the difference in translocation depends on the difference in the tyrosine phosphorylation of JAK2 and IRS-1. The anti-insulin action of GH after chronic GH treatment does not appear to be mainly due to the inhibition of GLUT4 translocation.

Concomitant administration of sodium dichloroacetate and vitamin B1 for lactic acidemia in children with MELAS syndrome

Myoclonic seizures, intractable abdominal pain, and headaches resolved during the concomitant administration of sodium dichloroacetate and vita min B1 in two Japanese siblings with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike syndrome).

Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency.

We report molecular analysis of thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency in a patient with an X-linked form of Leigh syndrome. PDHC activity in cultured lymphoblastoid cells of this patient and his asymptomatic mother were normal in the presence of a high thiamin pyrophosphate (TPP) concentration (0.4 mmol/L). However, in the presence of a low concentration (1 X 10-4 mmol/L) of TPP, the activity was significantly decreased, indicating that PDHC deficiency in this patient was due to decreased affinity of PDHC for TPP. The patients older brother also was diagnosed as PDHC deficiency with Leigh syndrome, suggesting that PDHC deficiency in these two brothers was not a de novo mutation. Sequencing of the X-linked PDHC E1 α subunit revealed a C → G point mutation at nucleotide 787, resulting in a substitution of glycine for arginine 263. Restriction enzyme analysis of the E1α gene revealed that the mother was a heterozygote, indicating that thiamin-responsive PDHC deficiency associated with Leigh syndrome due to this mutation is transmitted by X-linked inheritance.

Rapid diagnosis of vitamin D-dependent rickets type II by use of phytohemagglutinin-stimulated lymphocytes

The interactions of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] with phytohemagglutinin (PHA)-stimulated lymphocytes from normal subjects and three patients with vitamin D-dependent rickets (DDR) type II were investigated. Impaired nuclear uptake and normal cytosol binding of [3H]1,25-(OH)2D3 were observed with PHA-stimulated lymphocytes of these patients as with their cultured skin fibroblasts. Furthermore, the incorporation of [14C]thymidine into PHA-stimulated lymphocytes of the patients was not reduced by 1,25-(OH)2D3, which is known to inhibit proliferation of various cells. These findings suggest that 1,25-(OH)2D3 receptors are reduced or absent in patients with DDR type II. Thus, the capacities of cytosol binding and nuclear uptake of 1,25-(OH)2D3 in PHA-stimulated lymphocytes seem to reflect those of endo-organs such as the intestine and bone. These findings show that a test of the effect of 1,25-(OH)2D3 on thymidine incorporation into PHA-stimulated lymphocytes is useful for rapid diagnosis of DDR type II.

Favorable response of ADHD with giant SEP to extended-release valproate.

We treated three boys with attention deficit/hyperactivity disorder (ADHD) associated with giant somatosensory evoked potentials (SEP). All responded well to extended-release valproate (EVA), a gamma-aminobutyric acid (GABA) enhancer. Improvement particularly involved hyperactivity and impulsivity. When methylphenidate previously was administered to two patients, symptoms worsened. EVA therefore may be preferable for ADHD with giant SEP.

Diagnosis of Atlantoaxial Subluxation in Morquio's Syndrome and Spondyloepiphyseal Dysplasia Congenita

Compression of the spinal cord due to atlantoaxial subluxation was diagnosed in a patient with Morquios syndrome and in another with spondyloepiphyseal dysplasia (SED) congenita by cervical radiography and magnetic resonance imaging (MRI). The patient with Morquios syndrome, a 15 year old boy, had no neurologic symptoms and his somatosensory evoked potential (SSEP) was normal. However, MRI demonstrated spinal cord compression at C1‐C2. In contrast, the patient with SED congenita, an 11 year old girl, had neck pain, hyperreflexia and loss of vibration sense in both legs. These findings were explained by the absence of P3 and later waves in SSEP and by compression of the spinal cord observed on MRI. Both SSEP and MRI should be used for evaluating disorders in which atlantoaxial subluxation might be present.