Masakazu Mimaki

Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay

De novo GNAO1 variants have been found in four patients including three patients with Ohtahara syndrome and one patient with childhood epilepsy. In addition, two patients showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes. Here we report an additional four patients with de novo missense GNAO1 variants, one of which was identical to that of the previously reported. All the three novel variants were predicted to impair Gαo function by structural evaluation. Two patients showed early-onset epileptic encephalopathy, presenting with migrating or multifocal partial seizures in their clinical course, but the remaining two patients showed no or a few seizures. All the four patients showed severe intellectual disability, motor developmental delay, and involuntary movements. Progressive cerebral atrophy and thin corpus callosum were common features in brain images. Our study demonstrated that GNAO1 variants can cause involuntary movements and severe developmental delay with/without seizures, including various types of early-onset epileptic encephalopathy.

Hepatoblastoma in a patient with sotos syndrome.

We report a case of hepatoblastoma that developed in a child with Sotos syndrome, an overgrowth syndrome with an increased risk of neoplasms. Genome-wide analysis of copy number alterations showed a gain of chromosome 2, uniparental disomy of 18q, and microdeletion of 5q35.

Holoprosencephaly with cerebellar vermis hypoplasia in 13q deletion syndrome: Critical region for cerebellar dysgenesis within 13q32.2q34

We describe two unrelated patients with terminal deletions in the long arm of chromosome 13 showing brain malformation consisting of holoprosencephaly and cerebellar vermis hypoplasia. Array comparative genomic hybridization analysis revealed a pure terminal deletion of 13q31.3q34 in one patient and a mosaic ring chromosome with 13q32.2q34 deletion in the other. Mutations in ZIC2, located within region 13q32, cause holoprosencephaly, whereas the 13q32.2q32.3 region is associated with cerebellar vermis hypoplasia (Dandy-Walker syndrome). The rare concurrence of these major brain malformations in our patients provides further evidence that 13q32.2q32.3 deletion, harboring ZIC2 and ZIC5, leads to cerebellar dysgenesis.

Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway

Background:  Germline mutations in several members of RAS/RAF/MEK/ERK pathway cause clinically similar genetic disorders, including Noonan syndrome (NS), Costello syndrome (CS) and cardio‐facio‐cutaneous syndrome (CFC). Each of these syndromes has a wide spectrum of molecular etiology. The aim of the present study was to conduct a comprehensive genetic analysis of RAS/RAF/MEK/ERK pathway in these syndromes.

Interstitial deletion of 13q14.13-q32.3 presenting with Arima syndrome and bilateral retinoblastoma

A patient with a large deletion of the distal part of the long arm of chromosome 13 showed severe psychomotor retardation, a characteristic face, nystagmus, retinopathy, cystic kidney disease, and brain malformation with molar tooth sign and cerebellar vermis hypoplasia, a phenotype typical of Arima syndrome. This patient also had bilateral retinoblastoma. Fluorescent in situ hybridization and single-nucleotide-polymorphism genotyping microarray demonstrated an interstitial deletion of 54 Mbp, ranging from 13q14.13 to 13q32.3 and involving the RB1 gene. This patient is the first case of Arima syndrome, or a Joubert syndrome-related disorder, that showed linkage to chromosome 13q.

Cortical gray matter lesions in acute encephalopathy with febrile convulsive status epilepticus

In acute encephalopathy with febrile convulsive status epilepticus (AEFCSE), subcortical white matter lesions on diffusion-weighted images are sometimes encountered on magnetic resonance imaging (MRI), such as in acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). We report here a severe case of AEFCSE following respiratory syncytial virus infection, with emphasis on the cranial MRI findings. MRI in this patient showed widespread T2-hyperintensity along the cerebral cortical gray matter from day 3 to day 22. Lesions with reduced diffusion were noted on day 3 in the deep zone of gray matter of the left occipito-temporo-parietal cortex, but on day 7 they shifted to the subcortical white matter of both the cerebral hemispheres. These MRI findings provide radiologic evidence for damage to the cortical gray matter in AEFCSE. The serial change of diffusion-weighted images suggests that the cortical gray matter may be injured prior to the involvement of the subcortical white matter.

Two patients with 19p13.2 deletion (Malan syndrome) involving NFIX and CACNA1A with overgrowth, developmental delay, and epilepsy

Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto and Division of Medial Genetics, Kanagawa Children’s Medical Center, Kanagawa, Japan Correspondence to Kenji Kurosawa, MD, PhD, Division of Medical Genetics, Kanagawa Children’s Medical Center, 2-138-4 Mutsukawa, Minami-ku, Yokohama 232-8555, Japan Tel: + 81 45 711 2351; fax: + 81 45 742 7821; e-mail: kkurosawa@kcmc.jp

Partial monosomy of 10p and duplication of another chromosome in two patients

Partial monosomy of 10p is a rare chromosomal abnormality. Common features are hypoparathyroidism, deafness, renal anomalies, distinctive facies, and mental retardation, with phenotypic variability. We report two patients with chromosomal abnormalities identified on single‐nucleotide polymorphism (SNP) array analysis. Although patient 1 had common features of monosomy10p, G‐banding indicated a normal karyotype. SNP array and fluorescence in situ hybridization (FISH), however, indicated unbalanced translocation of a 10p terminal deletion of 11.7 Mb and a 15q terminal duplication of 8.2 Mb. In patient 2, SNP array and FISH indicated a 10p terminal deletion of 12.6 Mb and a 7q terminal duplication of 1.9 Mb. This is the first case report of monosomy 10p combined with trisomy 15q (patient 1). Because the clinical heterogeneity of the 10p deletion syndrome would be affected by duplication of another chromosome, we emphasize that SNP/microarray analysis is necessary to confirm genotype–phenotype correlation.

Brain edema with clasmatodendrosis complicating ataxia telangiectasia

Ataxia-telangiectasia is a chronic progressive disorder affecting the nervous and immune systems, caused by a genetic defect in the ATM protein. Clasmatodendrosis, a distinct form of astroglial death, has rarely been reported in ataxia-telangiectasia. Neuropathology of our patient disclosed diffuse edema of the cerebral and cerebellar white matter with prominent clasmatodendrosis, implicating ATM in the regulation of astroglial cell death.