Shinpei Abe

Lissencephaly with marked ventricular dilation, agenesis of corpus callosum, and cerebellar hypoplasia caused by TUBA1A mutation

We described the clinical course and pathological findings in a child with TUBA1A mutation. MRI revealed marked ventricular dilation with thin cortex, poorly differentiated basal ganglia, agenesis of corpus callosum, cerebellar hypoplasia with preserved vermis at 2 months of age. No gain of developmental milestones was observed until she died with respiratory failure at 23 months of age. A de novo missense mutation of c.1096G>A (G366R) was identified in TUBA1A gene. Pathological findings included a lack in lamination in the cerebral cortex, absent corpus callosum without Probst bundle, blurred demarcation among the striatum, internal capsule and globus pallidus in association with irregular running of myelinated fibers, cerebellar hypoplasia with irregular undulation in the dentate nucleus and inferior olivary nucleus, absent olfactory bulbs and tracts, and pyramidal tract hypoplasia. These findings are consistent with previous reports and will be a clue to diagnosis of TUBA1A mutation.

PRRT2 mutation in Japanese children with benign infantile epilepsy

Mutations in PRRT2 genes have been identified as a major cause of benign infantile epilepsy and/or paroxysmal kinesigenic dyskinesia. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We explored PRRT2 mutations in Japanese children who had had unprovoked infantile seizures or convulsion with mild gastroenteritis. The probands included 16 children with benign infantile epilepsy, 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. Statistical analyses were performed to identify differences in probands with benign infantile epilepsy according to the presence or absence of PRRT2 mutation. Among a total of 24 probands, PRRT2 mutations was identified only in 6 probands with benign infantile epilepsy. A common insertion mutation, c.649_650insC, was found in 5 families and a novel missense mutation, c.981C>G (I327M), in one. The family history of paroxysmal kinesigenic dyskinesia was more common in probands with PRRT2 mutations than in those without mutations. Our study revealed that PRRT2 mutations are common in Japanese patients with benign infantile epilepsy, especially in patients with a family history of paroxysmal kinesigenic dyskinesia.

Depressive tendency in children with growth hormone deficiency

Aim:  This study assessed changes in depressive tendency of children with growth hormone deficiency.

De novo microdeletion of 5q14.3 excluding MEF2C in a patient with infantile spasms, microcephaly, and agenesis of the corpus callosum.

The 5q14.3 microdeletion syndrome has recently been recognized as a clinical entity manifesting as severe intellectual disability, epilepsy, and brain malformations. Analysis of the shortest region of overlap among patients with this syndrome and subsequent identification of nucleotide alterations in the coding region of myocyte enhancer factor 2C gene (MEF2C) have suggested MEF2C as the gene responsible for the 5q14.3 microdeletion syndrome. We identified a de novo 3.4‐Mb deletion of 5q14.3 in a patient with infantile spasms, microcephaly, and brain malformation. The deleted region in the present patient was positional toward the centromere, and MEF2C was not included in the deleted region. However the neurological and dysmorphic features of the present patient resembled those of patients with the 5q14.3 microdeletion syndrome. We consider that a positional effect is the likely explanation for this evidence. To study the precise mechanism of this positional effect, further information is required on patients showing atypical deletions neighboring MEF2C.

Early infantile manifestations of incontinentia pigmenti mimicking acute encephalopathy

OBJECTIVE We retrospectively reviewed six patients with incontinentia pigmenti (IP) who had encephalopathic manifestations during early infancy. METHODS We enrolled six patients who met the following criteria from the mailing list of the Annual Zao Conference: (1) diagnosis of IP; (2) encephalopathic manifestations with reduced consciousness and clusters of seizures by 6 months of age; and (3) no evidence of central nervous system infection or metabolic derangement. RESULTS The onset of the encephalopathic events was within the first 2 months of life in all but one patient. All had clusters of focal clonic seizures. The duration of seizures was typically 5 min. The seizures ceased within 5 days in all patients. Various degrees of reduced consciousness were observed in association with the frequent seizures. Diffusion-weighted imaging during the acute phase showed reduced water diffusion in the subcortical white matter, corpus callosum, basal ganglia, thalami, and internal capsule in two patients. Scattered subcortical white matter lesions were observed on fluid-attenuated inversion-recovery images in two patients. CONCLUSIONS The encephalopathic manifestations in patients with incontinentia pigmenti were characterized by seizure clusters and reduced consciousness, albeit of relatively short duration. Magnetic resonance imaging abnormalities were predominant in the subcortical areas in most patients.

Refractory neonatal epilepsy with a de novo duplication of chromosome 2q24.2q24.3

There are only two reports on epileptic patients associated with microduplication of 2q. We found a de novo duplication of chromosome 2q24.2q24.3 in another infant with neonatal epilepsy. The patient had refractory focal seizures since the third day of life. Her seizures were refractory against phenobarbital and levetiracetam, but were controlled by valproate. Array comparative genomic hybridization revealed a 5.3‐Mb duplication of 2q24.2q24.3, where at least 22 genes including a cluster of voltage‐gated sodium channel genes (SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A) and one noncoding RNA are located.

Amplitude-integrated electroencephalography in patients with acute encephalopathy with refractory, repetitive partial seizures

We report amplitude-integrated EEG findings in two children with acute encephalopathy with refractory, repetitive partial seizures. Both patients had a febrile illness one week before the onset of seizure. They had reduction of consciousness and repetitive seizures refractory to first-line antiepileptic drugs. Seizure frequency rapidly increased and evolved into status epilepticus. Continuous seizure monitoring with amplitude-integrated EEG revealed frequent subclinical seizures which were missed by direct observation. In addition, the site of origin of seizures was multifocal, and seizure foci shifted from one hemisphere to the other. Their seizures were controlled after an administration of high-dose phenobarbital. Continuous seizure monitoring with amplitude-integrated EEG will contribute to correct estimation of seizure burden and efficacy of antiepileptic drugs in children with acute encephalopathy with refractory, repetitive partial seizures.

3p Interstitial Deletion Including PRICKLE2 in Identical Twins With Autistic Features

BACKGROUND Microdeletion and microduplication syndromes without characteristic dysmorphic features are difficult to diagnose without chromosomal microarrays. PATIENTS We describe the clinical course and genetic findings of monozygotic twins with intellectual disabilities and autistic features associated with mild facial dysmorphism and microdeletion of chromosome 3p14. RESULTS The postnatal course of the second twin was complicated by intestinal malrotation, whereas that of the first twin was unremarkable. Both twins had several mild dysmorphic features including upswept frontal hair, low-set posterior rotated ears, arched down-slanting eyebrows, prominent forehead, epicanthic folds, micrognathia, hypertelorism, broad nasal bridge, short philtrum, and camptodactyly of the bilateral fifth fingers. They had autistic features such as poor eye contact and no social smile, stereotyped behaviors, and preference for solitary play. Array comparative genomic hybridization analysis revealed de novo 6.88-Mb deletions of 3p14 (chr3: 60,472,496-67,385,119) involving 17 genes in both twins. The deleted region contained 17 genes, five of which are known or presumed to be related to central nervous system disorders: FEZF2, SYNPR, ATXN7, PRICKLE2, and MAGI1. CONCLUSIONS We consider that PRICKLE2 is the most likely causative gene for the autistic features exhibited by these individuals.

Transiently reduced water diffusion in the corpus callosum in infants with benign partial epilepsy in infancy

Neuroimaging findings are usually normal in children with benign partial epilepsy in infancy. However, we found a transient reduction of water diffusion in the corpus callosum in two patients with probable benign partial epilepsy in infancy. The patients were admitted to our hospital because of seizure clusters. No delay in the developmental milestones was seen, and no neurological abnormalities were observed during the interictal period. Interictal electroencephalography was normal in both infants. However, the diffusion-weighted images showed abnormal high intensities in both the genu and splenium in one patient and in the splenium only in the other. No diffusion abnormalities were observed in follow-up magnetic resonance imaging. The clustered seizures may be related to the transient callosal lesions seen in our patients.

Single Nucleotide Variations in CLCN6 Identified in Patients with Benign Partial Epilepsies in Infancy and/or Febrile Seizures

Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6). A cohort study of 48 BPEI patients without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6. Chloride channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6. Although we could not detect significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants that may underlie the genetic susceptibility to convulsive disorders.