Kyoko Hirasawa

STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome—Result of Japanese cohort study

We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox‐Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct‐sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause.

CDKL5 alterations lead to early epileptic encephalopathy in both genders

Purpose:  Genetic mutations of the cyclin‐dependent kinase‐like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe‐to‐profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders.

Magnetic resonance imaging and clinical findings examined in adulthood-studies on three adults with Rett syndrome

PURPOSE To clarify magnetic resonance imaging (MRI) findings in three adult patients with Rett syndrome who had been diagnosed with mental retardation and autism. METHOD Clinical and MRI findings in three adult cases with Rett syndrome were studied. Ages (in years) in three adult cases with Rett Syndrome were 46 in Case 1, 35 in Case 2 and 20 in Case 3. They were able to walk and their convulsions were well controlled. RESULTS MRI findings in all patients showed mild cerebral atrophy, especially in the frontal and temporal lobes and two of the cases also had mild cerebellar atrophy. One case also showed a narrowing of the brainstem and thinning of the corpus callosum. CONCLUSIONS These results indicate that abnormalities in MRI imaging, in cases where there is narrowing of the brainstem and thinning of the corpus callosum, may be due to congenital hypoplasia. It was also seen that cerebellar atrophy became more distinct in older cases.

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.

Clinical manifestations of Xq28 functional disomy involving MECP2 in one female and two male patients

Subtelomeric imbalances are a frequent cause of cytogenetic abnormalities in patients with unexplained intellectual disability. Functional disomy of Xq28 involving the methyl‐CpG‐binding protein 2 gene (MECP2) has been observed mostly in subtelomeric duplications. We identified three patients with functional disomy of Xq28. A female patient showed an unbalanced translocation between 12q24.33 and Xq28. Two male patients showed an unbalanced translocation between Xq27.1‐ Yq11.22 and a recombinant X‐chromosome containing duplicated material from Xq27.1 on Xp telomere, respectively. All three patients exhibited severe developmental delay, hypotonia, seizures, and distinctive facial features, including flat nasal bridge and hypertelorism. Additionally, brain magnetic resonance imaging (MRI) showed characteristic findings in each patient, including frontal dominant brain atrophy and hypoplasia of the corpus callosum, which are common findings in patients with functional disomies of Xq28 and interstitial duplications of Xq28, including MECP2. Brain MRI revealed a cystic lesion in the periventricular white matter in a patient, similar to our previous experience in patients with MECP2 duplication syndrome. Thus, white matter abnormalities may frequently be seen in cases of patients with additional MECP2 copies.

Novel compound heterozygous EPG5 mutations consisted with a missense mutation and a microduplication in the exon 1 region identified in a Japanese patient with Vici syndrome

Vici syndrome is a rare, autosomal recessive, multisystem disorder, characterized by agenesis of the corpus callosum, cataracts, psychomotor delay, cardiomyopathy, hypopigmentation, and recurrent infections. Mutations in the ectopic P‐granules autophagy protein 5 homolog gene (EPG5), which encodes a key autophagy regulator, are responsible for this syndrome. A 3‐year‐old Japanese girl manifesting similar symptoms to those found in patients with Vici syndrome showed intractable diarrhea, rather than immunodeficiency. Whole exome sequencing identified only a heterozygous variant in EPG5, NM_020964.2(EPG5):c.3389A > C (p.His1130Pro), which was inherited from her mother. Sequencing analyses of the EPG5 messenger RNA showed only an altered nucleotide “C” at position, c.3389, indicating decreased expression of the wild‐type allele. Microarray‐based comparative genomic hybridization revealed a de novo microduplication in the exon 1 region. Large exon deletions and duplications of EPG5 have never been reported so far. This was considered the cause of the decreased expression of the wild‐type allele. In conclusion, we successfully identified novel compound heterozygous mutations in EPG5 in a patient who was clinically considered to have Vici syndrome.

Effect of sitting position on respiratory status in preterm infants

Abstract Objective: To evaluate whether using a sitting-type car safety seats for preterm infants is advisable. Patients and methods: A total of 65 preterm infants underwent polysomnography in the supine and sitting positions. The infants with <95% of SpO2 were assigned to the desaturation (DS) group. Their backgrounds, breathing patterns, and breathing types were analyzed. Results: Of the 65 cases, 18 were assigned to the DS group. No significant differences were observed between the DS and non-DS groups in their background characteristics. Of the 18 DS cases, 15 were included in the non-obstructive group (8, periodic breathing; 6, tachypnea; 1, irregular breathing). Conclusions: Immaturity of the respiratory center and decompensation for the respiratory changes caused by the sitting position were suspected to cause DS in infants. Sitting-type car safety seats should be used with caution for preterm infants, and all preterm infants need to be screened by polysomnographic examination in the sitting position.

An autopsy case of cerebral hemiatrophy with tuberculous meningitis sequelae

mg/day (27.6 mg/kg/day) and the serum level, 2 h after the morning dose, was 10.0 pg/dl. Other laboratory findings included: serum total cholesterol, 246 mg/dl (normal range for infants, 45-182); triglyceride, 180 mg/dl (32-99); LDL, 806 mg/dl (165-465 for adults); total ketone bodies, 1917 pmol/l; 3-OHBA, 1551/2 pmol/l; ketone body ratio, 4.23; T3, 106 ng/dl (lOO-260): T4,6.2 pg/dl(7-15); and TSH, 4.0 pU/ml (0.2-4.0 in adults). Ketonuria was not remarkable. No clinical manifestation commonly associated with ketonuria, such as anorexia, vomiting or lassitude, was present. There were slight increases in GOT and GPT and the ketonemia returned to the normal range with the tapering of CBZ. Discussion: The epileptogenic focus in this case lies in the left fronto-temporal area. CBZ did not work at all even at a high dosage, the seizures being aggravated conversely. A few recent papers reported the effect of CBZ on the serum cholesterol level. The degrees of increase in serum cholesterol and lipids in our case were very great. It is clear that hyperlipidemia and ketosis of great degree were repeatedly observed at the time of the administration of a high dose of CBZ, and gradually decreased and eventually normalized along with the tapering of CBZ.