Tateo Sugimoto

Effect of l-carnitine treatment for valproate-induced hepatotoxicity

The authors analyzed the association of l-carnitine treatment with hepatic survival in 92 patients with severe, symptomatic, valproate-induced hepatotoxicity. Forty-eight percent of the 42 patients treated with l-carnitine survived, but only 10% of the 50 patients treated solely with aggressive supportive care survived (p < 0.001). Early intervention with IV rather than enteral l-carnitine was associated with the greatest hepatic survival. Specifically, all 10 patients who were diagnosed in <5 days and treated with IV l-carnitine survived. Most patients had features of chronic illness and most children appeared to be malnourished.

Epilepsy with Continuous Spike‐Waves During Slow Sleep and Its Treatment

SUMMARY: Five children with epilepsy with “continuous spike‐waves during slow sleep” (CSWS) are reported. The main clinical features of CSWS include (a) onset between 5 and 7 years of age, (b) the occurrence of several types of seizure (i.e., partial motor, generalized motor, and atypical absence), and (c) the presence of language disturbances and abnormal behavior based on emotional impairment. The EEG findings were characterized by sleep tracings showing almost continuous (>95%), diffuse slow spike and wave activity. After treatment with valproate (VPA) (or ethosuximide, ESM) and clonazepam (CZP), the spike and wave complex status disappeared. Symptoms and signs of the CSWS also decreased. We suggest that combined treatment is an appropriate treatment for CSWS.

Sotos syndrome and haploinsufficiency of NSD1: clinical features of intragenic mutations and submicroscopic deletions

Sotos syndrome (MIM 117550) is a congenital developmental disorder characterised by overgrowth and advanced bone age in infancy to early childhood, mental retardation, and various minor anomalies such as macrocephaly, prominent forehead, hypertelorism, downward slanting palpebral fissures, large ears, high and narrow palate, and large hands and feet.1,2 It is also frequently associated with brain, cardiovascular, and urinary anomalies3–6 and is occasionally accompanied by malignant lesions such as Wilms tumour and hepatocarcinoma.7,8 This condition has been classified as an autosomal dominant disorder, because several familial cases consistent with dominant inheritance have been described previously.9 Thus, sporadic cases accounting for most of the Sotos syndrome patients are assumed to be the result of de novo dominant mutations. We have recently shown that Sotos syndrome is caused by haploinsufficiency of the gene for NSD1 (nuclear receptor binding Su-var, enhancer of zeste, and trithorax domain protein 1).10 NSD1 consists of 23 exons and encodes at least six functional domains possibly related to chromatin regulations (SET, PWWP-I, PWWP-II, PHD-I, PHD-II, and PHD-III), in addition to 10 putative nuclear localisation signals.11 It is expressed in several tissues including fetal/adult brain, kidney, skeletal muscle, spleen, and thymus11 and is likely to interact with nuclear receptors as a bifunctional transcriptional cofactor.12 In this paper, we report on clinical findings in Japanese patients with proven point mutations in NSD1 and those with submicroscopic deletions involving the entire NSD1 gene and discuss genotype-phenotype correlation. This study consisted of five patients with heterozygous NSD1 point mutations and 21 patients with heterozygous submicroscopic deletions involving the entire NSD1 gene. The mutations were identified by direct sequencing of exons 2–23 and their flanking introns covering the whole coding region of NSD1 ,11 using genomic DNA extracted from peripheral leucocytes or …

Angelman Syndrome in Three Siblings: Characteristic Epileptic Seizures and EEG Abnormalities

Summary: Neurologic findings in 3 siblings with Angelman syndrome (AS) with apparently normal karyotype but DNA deletion of 15q11‐q12 deriving from their mother are described. Increased auditory brainstem response (ABR) thresholds were noted in all 3. Interictal EEG findings included periodic 2‐ to 3‐Hz high‐voltage slow wave bursts bioccipitally and sporadic slow spike wave complexes mainly bifrontally. EEG findings suggestive of minor epileptic status were apparent in the elder brother and may be a characteristic feature in young AS patients. Seizures suggestive of generalized epilepsy have been reported in 90% of AS patients. AS is considered a good model of symptomatic generalized epilepsy associated with chromosomal DNA deletion of the (GABA), receptor β3‐subunit gene.

Effect of L-carnitine supplementation on acute valproate intoxication.

Summary: We analyzed urinary valproate (VPA) metabolites and carnitine concentrations in a child who accidentally ingested 400 mg/kg VPA. The concentration of 4‐en VPA, the presumed major factor in VPA‐induced hepato‐toxicity, was markedly increased, without liver dysfunction or hyperammonemia. The other major abnormality was decreased β‐oxidation and markedly increased ω‐oxidation. After L‐carnitine supplementation, VPA metabolism returned to normal. The level of valproylcarnitine was not increased and therefore was not affected by L‐carnitine. L‐Carnitine may be useful in treating patients with coma after VPA overdose.

When do brain abnormalities in cerebral palsy occur? An MRI study

The authors used MRI to analyse retrospectively the brain images of patients with cerebral palsy (CP) to evaluate its the role in the assessment of brain abnormalities and injury, and the relationship of pre‐, peri‐ and postnatal events to CP. 70 patients with CP aged two to 16 years who underwent MRI were divided into four groups: group 1 (26 patients) comprised subjects whose CP was considered to have been caused by neuronal migration disorders in the embryonal stage; group 2 (30 patients) contained subjects whose cause was vascular disorders; in group 3 patients (five) the cause was intra‐uterine infection; and CP clearly attributable to birth asphyxia (group 4) was noted in only nine patients. The results indicate that CP of term infants is often the result of prenatal factors, and their MRI findings indicated migration and cerebral infarction. Brain MRI is an essential examination in identifying the factors causing brain damage in CP.

Reye-like syndrome associated with valproic acid

A case of a Reye-like syndrome during the course of treatment with VPA was reported. Hyperammonemia and severe liver damage as well as diffuse small droplets in the liver biopsy material were demonstrated. On analysis by gas chromatography/mass spectrometry of the urine immediately after the onset, the metabolites of VPA were detected together with lactate and other substances, and electron microscopic observation of liver biopsy material revealed deformation of mitochondria, disappearance of cristae and electron dense deposits in the matrix.

Hepatotoxicity in Rat Following Administration of Valproic Acid: Effect of L-Carnitine Supplementation

Summary: The effect of prolonged administration (7 days) of valproate (VPA, 500 mg/kg/day), or VPA (500 mglkglday) with L‐carnitine (200 mg/kg/day) on blood carnitine levels and the appearance of liver mitochondria were assessed in the rat. VPA‐treated rats showed hypo‐ carnitinemia and enlarged mitochondria when compared with saline‐injected control rats. In rats treated with bothVPA and L‐carnitine, serum and liver carnitine levels were increased by the L‐carnitine supplement and the liver mitochondria were not enlarged. L‐Carnitine supplement in VPA‐medicated patients seems to prevent hepatotoxicity, especially mitochondrial dysfunction.

Hepatotoxicity in Rat Following Administration of Valproic Acid

Summary: Chronic injections of valproic acid (VPA), VPA with phenobarbital (PB), and PB were studied for their effects on liver mitochondrial morphology and carnitine metabolism in rats. Mitochondrial enlargement was induced by the administration of VPA (500 mg/kg/day) for a period of 7 consecutive days. The administration of VPA (500 mg/kg/day)‐plus‐PB (20 mg/kg/day) for 7 days, however, did not induce megamitochondrial formation, but in these livers an unusual increase was observed in the number of liver mitochondria, microvesicular steatoses, and myeloid bodies. VPA‐treated rats had significantly lower levels of serum‐free and total carnitine and higher levels of acylcarnitine and acyl to free ratio than those of the controls. The free carnitine concentrations in serum and liver of the rats treated with VPA‐plus‐PB were much lower as compared with those treated with either VPA or PB. These morphological and biochemical results, especially of carnitine metabolism, suggest that inhibition of 0‐oxidation in liver mitochondria occurred in rats treated with VPA and PB and that, in particular, polytherapy with VPA‐plus‐PB could be clinically hazardous in causing hepatic injury.

Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy

We analyzed the urinary metabolic profiles of valproate (VPA) and carnitine metabolism in an epileptic patient who died of acute encephalopathy during VPA therapy. On admission, the serum free carnitine level was greatly decreased and gas chromatographic mass spectrometric analysis of organic acids in urine showed a complete lack of beta-oxidation metabolites of VPA, while omega-oxidation was markedly increased. After administration of L-carnitine, the levels of acylcarnitine in both serum and urine, and of serum free carnitine increased, and the metabolites of beta-oxidation appeared in urine, while there was no improvement in the liver and renal functions. This is not a typical case of VPA-induced hepatotoxicity and the main cause of the disease is not clear. But the results show that the mitochondrial beta-oxidation of VPA was greatly disturbed in this patient, which may be related to the carnitine deficiency induced by the chronic VPA-therapy.