Hideki Shimomura

Pyruvate therapy for mitochondrial DNA depletion syndrome

BACKGROUND Mitochondrial DNA depletion syndromes are a group of heterogeneous autosomal recessive disorders associated with a severe reduction in mitochondrial DNA in the affected tissues. Sodium pyruvate has been reported to have a therapeutic effect in mitochondrial diseases. METHODS We analyzed the effects of 0.5g/kg of sodium pyruvate administered through a nasogastric tube in a one-year-old patient with myopathic mitochondrial DNA depletion syndrome. To evaluate the improvement, we used the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) and manual muscle testing. As the improvement of motor functions in this severely disabled infant could not be comprehensively detected by NPMDS, we also observed the infants ability to perform several tasks such as pouting, winking, and number of times she could tap a toy xylophone with a stick. Blood lactate and pyruvate levels were also monitored. RESULTS After one months treatment, the NPMDS score in section IV, the domain for the quality of life, improved from 17 to13. The infant became capable of raising her forearm, lower leg and wrist against gravity. The maximum number of times she could repeat each task increased and the movements became brisker and stronger. No significant change of the blood lactate level or lactate-to-pyruvate ratio, both of which were mildly increased at the initiation of the therapy, was observed despite the clinical improvement. CONCLUSION Sodium pyruvate administered at 0.5g/kg improved the muscle strength and the NPMDS score of an infant with myopathic mitochondrial DNA depletion syndrome. GENERAL SIGNIFICANCE Sodium pyruvate may be effective for ameliorating the clinical manifestations of mitochondrial diseases. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.

Efficacy and tolerability of modified Atkins diet in Japanese children with medication-resistant epilepsy

Ten Japanese patients aged 1.5-17years with medication-resistant epilepsy were placed on the modified Atkins diet (MAD) for 3weeks during admission to our hospital. Dietary carbohydrate was restricted to 10g per day. We studied the efficacy of the diet regarding the seizure frequency and tolerability of the diet at the end of the 3weeks on the diet. Those who decided to continue the MAD at the time of discharge were followed up in the out-patient clinic to observe the effect of the diet on the seizure frequency. Three of the 10 patients could not continue the diet during the 3-week admission; one had rotavirus enterocolitis and the other 2 disliked the diet. Among the remaining 7 patients who could continue the diet for 3weeks, 3 achieved the seizure reduction; 2 became seizure-free and 1 showed about 75% reduction in the seizure frequency within 10days on the diet. All of these 3 patients continued the diet after the 3-week admission. The other 4 patients did not show a reduction of the seizure frequency by the end of the 3weeks on the diet. Two of them discontinued the diet on discharge. The remaining 2 still continued the diet at home and one became seizure-free 3months after the start of the diet. In total, 4 of 10 patients achieved>75% reduction in the seizure frequency, although relapse occurred in 2 of the patients, at 5months and 2years after seizure reduction, respectively. The MAD was effective and well-tolerated in children with medication-resistant epilepsy in Japan.

Glycine plays a crucial role as a co-agonist of NMDA receptors in the neuronal circuit generating body movements in rat fetuses

Neuronal circuits generating fetal movements in mammals are localized in the brainstem and the spinal cord. It has been shown that glycine plays an important role through the strychnine-sensitive glycine receptors in these circuits. However, the role of glycine as the NMDA receptor co-agonist in fetal period is not fully understood. In this study, we examined the contribution of glycine to the perinatal rat spinal circuit generating forelimb movements utilizing isolated brainstem-cervical-spinal-cord preparations. In late embryonic-days-preparations, spontaneous motor bursts related to forelimb movements (forelimb-movement-related bursts; FMRBs) and respiration-related activity were observed. In neonatal preparations, spontaneous FMRBs were not observed but periodic motor bursts resembling the FMRBs could be induced after bath application of strychnine (strychnine-induced motor bursts; SIMBs). Both FMRBs and SIMBs were blocked by either the NMDA receptor antagonist APV or the antagonists of the glycine binding site of NMDA receptors [5,7-dichlorokynurenic acid (DCKA) or L-689560]. Furthermore, these motor bursts were facilitated by the glycine uptake blocker sarcosine. This effect of sarcosine was blocked by DCKA. The findings indicate that glycine plays a crucial role as a NMDA receptor co-agonist in generating spontaneous fetal motor activity before functioning as a classical inhibitory neurotransmitter in suppressing the fetal neuronal circuits.

Epilepsy in pervasive developmental disorder without brain MRI abnormalities

BACKGROUND Epilepsy has been reported in patients with pervasive developmental disorder (PDD), with an incidence ranging from 5% to 40%; however most of the studies included patients with brain magnetic resonance imaging (MRI) abnormalities (e.g., tuberous sclerosis) and patients with epilepsy whose seizure onset was in the first year of life. METHODS We retrospectively examined 67 patients (45 males, 22 females) with PDD and epilepsy, who did not have brain MRI abnormalities. Patients who had seizures in the first year of life were excluded. We divided the patients into two groups: group A included 34 patients with an IQ<50, and group B included 33 patients with an IQ≥50. RESULTS The median age of epilepsy onset was higher in group A than group B (8.8 vs. 5.2 years, P<0.01). Only one patient (3%) in group A and nine patients (27%) in group B were classified with generalized epilepsy (P<0.05). At the last observation, 16 patients (47%) in group A and 25 patients (76%) in group B were seizure-free for ≥1year (not statistically significant). CONCLUSION The relationship between PDD and epilepsy may be different between patients with lower (group A) and higher (group B) IQs in patients who do not have brain MRI abnormalities.

Late-onset ornithine transcarbamylase deficiency caused by a somatic mosaic mutation

An 18-month-old boy was diagnosed with late-onset ornithine transcarbamylase deficiency. Genetic analysis revealed a mosaic frameshift mutation (p.Q279fs) in the OTC gene. Despite the presence of a null mutation, he exhibited a milder phenotype, suggesting that the wild-type allele could rescue the function of OTC. The presence of mosaicism has great effects on the clinical phenotype and recurrence-risk assessment, which should be taken into consideration for genetic counseling.