An Open-Label Administration of Bioavailable-Form Curcumin in Patients With Pelizaeus-Merzbacher Disease.

BACKGROUND: Two preclinical studies using mouse models of Pelizeaus-Merzbacher disease (PMD) have revealed the potential therapeutic effects of curcumin. In this study, we examined the effects of curcumin in patients with PMD. METHODS: We conducted a study administering an open-label oral bioavailable form of curcumin in nine patients genetically confirmed to have PMD (five to 20 years; mean 11 years) for 12 months (low doses for two months followed by high doses for 10 months). We evaluated changes in clinical symptoms as the primary end point using two scales, Gross Motor Function Measure (GMFM) and the PMD Functional Disability Score (PMD-FDS). The level of myelination by brain magnetic resonance imaging (MRI) and the electrophysiological state by auditory brainstem response (ABR) were evaluated as secondary end points. The safety and tolerability of oral curcumin were also examined. RESULTS: Increase in GMFM and PMD-FDS were noted in five and three patients, respectively, but overall, no statistically significant improvement was demonstrated. We found no clear improvement in their brain MRI or ABR. No adverse events associated with oral administration of curcumin were observed. CONCLUSIONS: Although we failed to demonstrate any significant therapeutic effects of curcumin after 12 months, its tolerability and safety were confirmed. This study does not exclude the possibility of therapeutic effects of curcumin, and a trial of longer duration should be considered to compare the natural history of the disease with the effects of curcumin.

An integrated genetic analysis of epileptogenic brain malformed lesions.

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay.

BACKGROUND: Heterozygous variants in TMEM63A have been recently identified as the cause of infantile-onset transient hypomyelination. To date, four TMEM63A variants have been reported in five patients. These patients exhibited favorable clinical course, developmental progress, and completion of myelination. CASE REPORT: The patient was a 5-year-old girl with severe global developmental delay, absent speech, no turning over, no gazing, hypotonia, and daily episodes of autonomic seizures. Brain MRI showed hypomyelination of deep and subcortical white matter that appeared hyperintense in T2-weighted imaging from 2 months of age and that showed no change at 4 years of age. Exome sequencing of the patient and her parents revealed a novel de novo missense variant, NM_014698.3:c.1658G>T, p.(Gly553Val), in the TMEM63A gene, which was confirmed by Sanger sequencing. The variant has not been registered in public databases, and it substitutes a highly conserved glycine residue located in a pore-lining transmembrane helix. No other candidate variants were identified. CONCLUSIONS: Although TMEM63A variants are generally thought to cause transient hypomyelination with favorable developmental progress, identification of a de novo TMEM63A variant in our patient suggests that the TMEM63A-related clinical spectrum is broad and includes severe developmental delay with seizures.

Novel HSD17B4 Variants Cause Progressive Leukodystrophy in Childhood: Case Report and Literature Review.

D-bifunctional protein (DBP) deficiency is a peroxisomal disorder with a high degree of phenotypic heterogeneity. Some patients with DBP deficiency develop progressive leukodystrophy in childhood. We report a 6-year-old boy with moderate hearing loss who presented with developmental regression. Brain magnetic resonance imaging demonstrated progressive leukodystrophy. However, very long chain fatty acids (VLCFAs) in the plasma were at normal levels. Whole-exome sequencing revealed compound heterozygous variants in HSD17B4 (NM_000414.3:c.[350A > T];[394C > T], p.[[Asp117Val]];[[Arg132Trp]]). The c.394C > T variant has been identified in patients with DBP deficiency and is classified as likely pathogenic, while the c.350A > T variant was novel and classified as uncertain significance. Although one of the two variants was classified as uncertain significance, an accumulation of phytanic and pristanic acids was identified in the patient, confirming type III DBP deficiency. DBP deficiency should be considered as a diagnosis in children with progressive leukodystrophy and hearing loss even if VLCFAs are within normal levels.

Familial periodic paralysis associated with a rare KCNJ5 variant that supposed to have incomplete penetrance.

BACKGROUND: The periodic paralyses are a group of skeletal muscle channelopathies caused by variants in several ion channel genes. Potassium Inwardly Rectifying Channel Subfamily J Member 5 (KCNJ5) encodes the G-protein-activated inwardly rectifying potassium channel 4 (Kir3.4) and the heterozygous KCNJ5 variants cause familial hyperaldosteronism and long QT syndrome (LQTS). Recent studies suggested that variants in KCNJ5 are also causative for Andersen-Tawil syndrome, which showed periodic paralysis and characteristic electrocardiogram features. CLINICAL REPORT: We found a heterozygous KCNJ5 variant c.1159G > C, p.(Gly387Arg) in an individual with familial periodic paralysis using exome sequencing. Sanger sequencing revealed that this variant was inherited from his affected mother. The same variant had been previously found in two cases of familial LQTS or Andersen-Tawil syndrome, and functional analysis suggested that this variant might have loss of function effect on channel activity. However, the allele frequency of c.1159G > C variant in an East Asian population of public databases ranged from 0.21% to 0.25%, indicating possible incomplete penetrance. CONCLUSIONS: Our two patients expand the phenotypic spectrum associated with the c.1159G > C KCNJ5 variant, though the variant has very low penetrance.

Functional analysis of a double-point mutation in the KCNJ2 gene identified in a family with Andersen-Tawil syndrome.

Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy with autosomal dominant inheritance resulting in periodic paralysis, arrhythmia characterized by QT prolongation, and dysmorphic features. The KCNJ2 gene has been identified as the causative gene of ATS. Herein, we reported 2 cases of a 21-year-old man and his mother, with episodic paralytic attacks and/or arrhythmia, which are characteristic of ATS. Both G144A, a reported ATS mutation, and V296F, a novel mutation, were identified in the KCNJ2 gene on the same allele from the proband and his mother, but not from his father. In the present study, we investigated the functional effect of these variants on the potassium channel Kir2.1 and the significance of the double mutation. G144A, V296F, and G144A-V296F mutant channels expressed in cultured cells revealed a loss-of-function effect of these mutations on Kir2.1. The K+ currents of G144A and G144A-V296F channels were more suppressed than that of V296F channel alone, whereas was no difference between G144A and G144A-V296F. To our knowledge, a double mutation in the KCNJ2 gene has not been reported previously. While either of 2 mutations potentially causes ATS, the G144A mutation might cause the dominant effect on the patients' clinical presentation.

Rapidly progressive fatal idiopathic hypertrophic pachymeningitis with brainstem involvement in a child.

BACKGROUND: Hypertrophic pachymeningitis (HP) is a rare disorder characterized by diffuse thickening of the dura mater with resultant neurologic deficits. HP develops secondary to various conditions or idiopathically usually in adults but rarely in children. CASE REPORT: We describe a 3-year-old female child with idiopathic HP. Her HP involved the entire central nervous system with progression into the brainstem. The lesion responded poorly to pulsed steroids or any immunosuppressants. The brainstem lesion grew rapidly and formed various nodules that ultimately resulted in brain death. This is the first fatal case of HP in a child.

Germ-line mutation of KCNQ2, p.R213W, in a Japanese family with benign familial neonatal convulsion.

BACKGROUND: Benign familial neonatal convulsion (BFNC) is an autosomal-dominantly inherited epilepsy of neonates. The KCNQ2 and KCNQ3 genes have been cloned as the responsible genes for BFNC. Detection of mutations in these genes is helpful for confirmation of BFNC or differential diagnosis of convulsive disorders in the neonatal period. METHODS: A Japanese family with BFNC was investigated. Two siblings were clinically diagnosed as having BFNC. KCNQ2 and KCNQ3 were screened for mutations using a combination of polymerase chain reaction and denaturing high-performance liquid chromatography. Nucleotide substitutions were confirmed by direct sequencing. RESULTS: In the affected siblings a C-to-T heterozygous substitution was detected at nucleotide 683 (c.683C>T) in KCNQ2, leading to substitution of arginine with tryptophan at amino acid position 213 (p.R213W) in the S4 voltage-sensing domain of the KCNQ2 protein. The detected mutation may disrupt this highly conserved region among potassium channel proteins. The c.683C>T substitution in KCNQ2 was not present in the parents. KCNQ3 was also analyzed and a single nucleotide polymorphism, c.1241A>G (National Center for Biotechnology Information (NCBI), SNP ID: rs2303995), was detected in the index family. CONCLUSIONS: Two siblings with BFNC had a novel heterozygous missense mutation, p.R213W, in KCNQ2. This mutation may affect potassium gating, leading to neuronal excitability or convulsions in the patients. Furthermore, neither of the parents had the p.R213W mutation, indicating that it was a germ-line mutation. The possibility of recurrence of such a germ-line mutation in the next siblings should be explained during genetic counseling.

Isolation of sphingoid bases of sea cucumber cerebrosides and their cytotoxicity against human colon cancer cells.

Sea cucumber is a health-beneficial food, and contains a variety of physiologically active substances including glycosphingolipids. We show here the sphingoid base composition of cerebrosides prepared from sea cucumber and the cytotoxicity against human colon cancer cell lines. The composition of sphingoid bases prepared from sea cucumber was different from that of mammals, and the major constituents estimated from mass spectra had a branched C17-19 alkyl chain with 1-3 double bonds. The viability of DLD-1, WiDr and Caco-2 cells treated with sea cucumber sphingoid bases was reduced in a dose-dependent manner and was similar to that of cells treated with sphingosine. The sphingoid bases induced such a morphological change as condensed chromatin fragments and increased the caspase-3 activity, indicating that the sphingoid bases reduced the cell viability by causing apoptosis in these cells. Sphingolipids of sea cucumber might therefore serve as bioactive dietary components to suppress colon cancer.

Evaluation of change of cerebral circulation by SpO2 in preterm infants with apneic episodes using near infrared spectroscopy.

BACKGROUND: In the neonatal intensive care unit (NICU), hemodynamics in very low-birthweight infants are generally examined for oxygen saturation (SpO2), heart rate, respiration rate, and blood pressure. The present study examined how changes in cerebral circulation in preterm infants can be evaluated by the SpO2 monitoring method with near infrared spectroscopy (NIRS) to detect the cerebral circulation. METHODS: The study was conducted in 11 low-birthweight neonates with a mean weight of 1252 g (940-1948 g), mean post-conceptional age of 28.9 weeks (28-31 weeks) and in whom a total of 145 apneic episodes were examined. Changes in cerebral circulation at the apneic attack were evaluated by two parameters of Delta HbD ( micro mol/L) for reduction in cerebral oxygenation and Delta cHb (mL/100 g brain) for variation in cerebral blood volume using the near infrared spectroscopy (NIRS). RESULTS: There was a tendency for a reduction in cerebral oxygenation and a change in cerebral blood volume as SpO2 was reduced. In the event of apneic attacks where SpO2 was reduced to <85%, cerebral oxygen saturation was extensively reduced. In addition, cerebral blood volume was also greatly changed when the SpO2 was reduced to <85%, and changed further still when SpO2 was reduced again to < or =75%. CONCLUSION: Reduction in SpO2 (<85%) was suggested to be an effective indication to changes in cerebral circulation. In the case of apneic attacks where SpO2 was < or =85%, the cerebral circulation in preterm low-birthweight neonates was extensively changed and, therefore, attention should be paid to changes in the concentration of SpO2 when managing apnea of prematurity in NICU.

Gly71Arg mutation of the bilirubin UDP-glucuronosyltransferase 1A1 gene is associated with neonatal hyperbilirubinemia in the Japanese population.

The serum bilirubin level of Japanese newborn infants in their first few days is significantly higher than that in Caucasian newborn infants, suggesting that there might be genetic risk factors for the development of neonatal hyperbilirubinemia in the Japanese population. Recently, it has been reported that a variant TATA box in the promoter region of the bilirubin UDP-glucuronosyltransferase 1 (UGT1A1) gene is associated with the development of neonatal hyperbilirubinemia. This finding led us to the idea that a mutation, glycine to arginine at codon 71 (G71R), in the coding region of the UGT1A1 gene can cause neonatal hyperbilirubinemia. In this study, we determined the genotypic distribution of the G71R mutation in 72 Japanese newborn infants: 23 infants with hyperbilirubinemia and 49 infants without hyperbilirubinemia. In the hyperbilirubinemia group, 15 of 23 newborn infants had the G71R mutation (3 homozygotes and 12 heterozygotes), whereas in the non-hyperbilirubinemia group 16 of 49 newborn infants had the G71R mutation (1 homozygote and 15 heterozygotes). Therefore, the G71R mutation was present significantly more frequently in the hyperbilirubinemia group than in the non-hyperbilirubinemia group. This finding strongly suggests that the presence of the G71R mutation contributes to the development of neonatal hyperbilirubinemia in the Japanese population.