Tomohiro Kumada

Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study

Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme‐replacement and substrate‐reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD.

Multi-institutional study on the correlation between chromosomal abnormalities and epilepsy

While there is an abundance of literature describing the association of chromosome aberrations with epilepsy, only a few refer to the detailed features of epilepsy. It is important to investigate the associations between specific chromosome abnormalities and features of epilepsy to identify genes involved in epilepsy and treat them more effectively. We investigated the correlation between specific chromosome aberrations and epilepsy by sending questionnaires to the members of Kyoto Multi-institutional Study Group of Pediatric Neurology. Seventy-six patients were collected from 10 institutions. Chromosome abnormalities included: Down syndrome (n = 19); Angelman syndrome (n = 8); Prader-Willi syndrome (n = 4); 4p- syndrome (n = 3); 1q- syndrome (n = 2); 5p- syndrome (n = 2); Miller-Dieker syndrome (n = 2); 18q- syndrome; (n = 2); Klinefelter syndrome; (n = 2); and 32 other individual chromosomal aberrations. Overall, the severity of mental retardation correlated with the severity of epilepsy. We could abstract characteristic features of epilepsy in some syndromes. In Angelman and Prader-Willi syndromes, febrile seizures occurred frequently, the onset of epilepsy was in early childhood and seizure phenotype was multiple. Paroxysmal discharge of the occipital region and diffuse high voltage slow wave on electroencephalography were characteristic in Angelman syndrome. In Down syndrome, West syndrome and focal epilepsy were common and the prognosis of epilepsy in West syndrome with Down syndrome was good. In 4p- syndrome, febrile seizures were often seen, and unilateral or generalized clonic or tonic-clonic status epilepticus were characteristic. For the other chromosomal aberrations investigated here, the patient numbers were too small to abstract common features of epilepsy.

Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality

Borealin/DasraB is a member of the chromosomal passenger protein complex (CPC) required for proper segregation of chromosomes during mitosis. In Drosophila melanogaster, inactivation of Borealin/DasraB results in polyploidy, delayed mitosis and abnormal tissue development, indicating its critical role for cell proliferation. However, the in vivo role of mammalian Borealin/DasraB remains unclear. Here, we analyzed the expression of Borealin/DasraB and found that borealin is widely expressed in embryonic tissues and later restricted to adult tissues which relies on rapid cell proliferation. To determine the role of borealin during mouse development, we generated borealin-null mice through targeted disruption. While heterozygous mice developed normally, disruption of both borealin alleles resulted in early embryonic lethality by 5.5 dpc (days postcoitus) due to mitotic defects and apoptosis in blastocyst cells that showed microtubule disorganization and no CPC enrichment. At 5.5 dpc, borealin-null embryos exhibited excessive apoptosis and elevated expression of p53. However, loss of p53 did not abrogate or delay embryonic lethality, revealing that Borealin/DasraB inactivation triggered impaired mitosis and apoptosis though p53-independent mechanisms. Our data show that Borealin/DasraB is essential for cell proliferation during early embryonic development, and its early embryonic lethality cannot be rescued by the loss of p53.

Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications

OBJECTIVE Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. METHOD In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. RESULTS We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. CONCLUSION The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.

Efficacy of pyruvate therapy in patients with mitochondrial disease: a semi-quantitative clinical evaluation study.

BACKGROUND Disorders of oxidative phosphorylation (OXPHOS) cause an increase in the NADH/NAD(+) ratio, which impairs the glycolysis pathway. Treatment with pyruvate is expected to decrease the ratio and thereby restore glycolysis. There are some case reports on the efficacy of pyruvate treatment for mitochondrial diseases. However, few of these reports assessed their results using a standardized scale. METHODS We monitored 4 bedridden patients with OXPHOS disorders who continued therapies of 0.5-1.0 g/kg/day of sodium pyruvate for more than 12 months. The efficacies of these treatments were evaluated with the Newcastle Pediatric Mitochondrial Disease Scale and the Gross Motor Function Measure with 88 items. RESULTS The ages of the patients at the treatment initiation ranged from 8-100 months. Of the 4 patients, 3 exhibited improvements within 1-3 months from the initiation of treatment. Among these 3 patients, one maintained the improvement for over 2 years. The remaining 2 regressed 3-6 months after the initiation of treatment. The blood lactate/pyruvate ratios did not correlate with the efficacy of treatment. CONCLUSION Pyruvate was effective even in bedridden patients with OXPHOS disorders, at least in the short term. Clinical trials with more patients and less severe disabilities are necessary to evaluate the long-term efficacy of this treatment. Biomarkers other than lactate and pyruvate need to be identified to biochemically monitor the efficacy of this treatment.

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.

Ttyh1, a Ca2+-binding protein localized to the endoplasmic reticulum, is required for early embryonic development

Using comprehensive genetic studies on neuronal stem/progenitors cells through genome‐wide screening with oligonucleotide arrays, we identified an endoplasmic reticulum (ER) ‐resident protein, Tweety homologue 1 (ttyh1). Ttyh1 encodes a glycosylated protein composed of five predicted transmembrane segments and a C‐terminus that is enriched in negatively charged residues capable of Ca2+ binding. Ttyh1‐containing membranes changed to segmented tubuloreticular structures during mitosis, suggesting that the ER‐containing Ttyh1 could be responsible for Ca2+ sequestration and Ca2+ concentration regulation during mitosis. Ttyh1 inactivation in mice resulted in early embryonic lethality before organization of the nervous system, revealing that ttyh1 is essential in murine embryonic development. Our findings indicate that Ttyh1 plays an indispensable role during mitosis in early embryogenesis, possibly by maintaining Ca2+ homeostasis in the ER. Developmental Dynamics 239:2233–2245, 2010.

Epileptic Apnea in a Trisomy 18 Infant

Trisomy 18 is frequently associated with neurologic abnormalities, including hypotonia in infancy, mental retardation, central apnea, and epilepsy. Although central apnea and epilepsy are common complications in children with trisomy 18, epileptic apnea in these children was not previously reported. We describe an infant with trisomy 18 who developed epileptic apnea. Her apneic episodes began at age 10 months, occurring in clusters over several days each month. According to ictal electroencephalogram, interictal [(11)C] flumazenil-positron emission tomography, and [(18)F] fluorodeoxyglucose-positron emission tomography, the apneic episodes represented complex partial seizures (autonomic seizures), probably originating in the left frontotemporal area, probably related to cortical microdysgenesis. The condition was successfully treated with zonisamide. In infants with trisomy 18, differentiation of epileptic apnea from central apnea is crucial, because medications used to treat central apnea, including caffeine and theophylline, can be harmful to children with epileptic apnea.

Grisel syndrome as a complication of Kawasaki disease: a case report and review of the literature

Grisel syndrome is a non-traumatic atlantoaxial subluxation and a rare complication of any inflammatory condition of the upper neck and otolaryngological procedures. Delayed diagnosis causes neurological impairment, ranging from radiculopathy to paralysis and death. Kawasaki disease is a very frequent and important acute febrile vasculitis of childhood that is seen worldwide, and upper neck involvement (cervical lymphadenopathy) is one of the common symptoms of Kawasaki disease. A case of Grisel syndrome that occurred as a complication of Kawasaki disease is reported. This is the first case report, in English, of Grisel syndrome as a complication of Kawasaki disease. Conclusion: Pediatricians should be aware of Grisel syndrome as a possible complication of Kawasaki disease.