Kiyokuni Miura

Epilepsy in Angelman syndrome associated with chromosome 15q deletion

Summary: We report eight sporadic cases of typical Angelman syndrome (AS) associated with chromosome 15q12 deletion. Age at first visit was 3–35 months (average 18 months), and follow‐up period was 4‐20 years (average 14.1 years). The characteristic features of epilepsy in AS are (a) seizure onset in early childhood (8 of 8); (b) evolution of seizure type with age (8 of 8); (c) EEG abnormality changes from high‐voltage slow bursts (HVS) in infancy to diffuse spike and waves in middle childhood (4 of 5); (d) atypical absence seizures (8 of 8), often occurring as atypical absence status (4 of 8); and (e) diminution of seizure discharges and clinical seizures after puberty (7 of 7). We believe that AS may frequently exist in the intractable epilepsies of childhood with severe mental retardation. We stress the importance of AS as one of the main etiologic background diseases of the intractable epilepsies with infantile onset such as West syndrome, Lennox‐Gastaut syndrome, and others.

Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22–q24.1

Hirschsprung disease (HSCR), a clinically complex syndrome often associated with a combination of mental retardation, microcephaly, and characteristic facial features, is genetically heterogeneous.1–10 Recently, mutations in ZFHX1B , which encodes Smad-interacting protein 1 (SIP1), were identified by our group11 and Cacheux et al 12 in patients with t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively. These patients had clinical profiles consistent with a dominant form of the disease (Mowat-Wilson syndrome: MIM 235730).9,13 These and subsequent articles have demonstrated a link between patients with nonsense and frameshift mutations of the gene and the presence in these patients of the following clinical findings: profound mental retardation, delayed motor development, and specific facial features, including hypertelorism, a broad nasal bridge, strabismus, a pointed chin, prognathism, a nose with a prominent columella, and posteriorly rotated ears. Often associated with these features were microcephaly, epilepsy, congenital heart disease, HSCR, and midline defects such as agenesis or hypoplasia of the corpus callosum and hypospadias.13–19 This variety of clinical features is observed not only in patients with nonsense and frameshift mutations but also in patients harbouring deletions involving ZFHX1B at 2q22,9,11,15,20 including a previously reported isolated case.6 Thus, ZFHX1B clearly plays a critical role in the manifestation of clinical features of Mowat-Wilson syndrome. However, several points remain to be elucidated: (1) How broad are the clinical features in patients with ZFHX1B mutations and deletions? (2) What are the underlying molecular mechanisms by which the deletion of ZFHX1B at 2q22 affects the clinical phenotype? (3) What kind of clinical features might appear if the deletions were extended to include 2q23–q24.1? To address these questions, we have characterized the clinical features and underlying molecular basis of 27 cases with mutations or deletions in ZFHX1B , including 12 previously reported cases comprising …

A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations

BackgroundSLC19A3 (solute carrier family 19, member 3) is a thiamin transporter with 12 transmembrane domains. Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes, biotin-responsive basal ganglia disease and Wernickes-like encephalopathy. Biotin and/or thiamin are effective therapies for both diseases.MethodsWe conducted on the detailed clinical, brain MRI and molecular genetic analysis of four Japanese patients in a Japanese pedigree who presented with epileptic spasms in early infancy, severe psychomotor retardation, and characteristic brain MRI findings of progressive brain atrophy and bilateral thalami and basal ganglia lesions.ResultsGenome-wide linkage analysis revealed a disease locus at chromosome 2q35-37, which enabled identification of the causative mutation in the gene SLC19A3. A pathogenic homozygous mutation (c.958G > C, [p.E320Q]) in SLC19A3 was identified in all four patients and their parents were heterozygous for the mutation. Administration of a high dose of biotin for one year improved neither the neurological symptoms nor the brain MRI findings in one patient.ConclusionOur cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments.

Magnetic resonance imaging and positron emission tomography of band heterotopia

A case of band heterotopia was reported with findings of positron emission tomography (PET). The patient was an 8-year-old girl who had mild mental retardation and intractable partial epilepsy. Her MRI showed another diffuse layer of gray matter underlying the normal-looking cortex and separated from it by an apparently normal layer of white matter. PET scan with [18F]fluorodeoxyglucose revealed that band heterotopia had the same degree of glucose metabolism as that of the overlying cortex.

Epilepsy in Peroxisomal Diseases

Summary: Purpose: To clarify the electroclinical manifestation of epileptic seizures and the evolution of epilepsy in patients with peroxisomal diseases.

Moyamoya disease presenting with chorea

Three children with moyamoya disease are reported whose initial and predominant manifestations were choreic movements. Two of the patients presented with unsteady gait and the other with clumsiness. Choreic movements were recurrent and were often triggered by excitement, emotional tension, or crying. They occurred unilaterally or bilaterally and often alternated between the right and left. Moyamoya disease must be considered in the differential diagnosis of acquired chorea in children.

The Spectrum of ZEB2 Mutations Causing the Mowat-Wilson Syndrome in Japanese Populations

Mowat–Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E‐box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild‐type ZEB2. There was no obvious genotype–phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3′‐end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.

Epilepsies of neonatal onset: seizure type and evolution

Most neonatal seizures are occasional seizures and not true epilepsy. This study investigates seizure types of true neonatal epilepsies and their evolution with development. Seventy‐five children with epilepsies of onset within 1 month of life, who were examined between 1970 and 1995, and whose seizure types could be confirmed with ictal EEG recordings, were studied. The patients were followed up for a minimum of 3 years and the evolution of epileptic syndromes was investigated. Sixty‐three (84%) of 75 patients had partial seizures, while nine had generalized seizures, and only three had both generalized and partial seizures. Twenty‐three of 24 neonates with benign familial or non‐familial neonatal convulsions presented with partial seizures; these syndromes should not necessarily be categorized into generalized epilepsy as they are in the present International Classification. Age‐dependent changes were a common feature of symptomatic neonatal epilepsies. Eighteen (41%) of 44 patients with symptomatic epilepsies of neonatal onset developed West syndrome in infancy. Fifteen (83%) of these 18 patients presented with symptomatic localization‐related epilepsy in the neonatal period. In seven of these 15 patients, West syndrome was followed by localization‐related epilepsy. Symptomatic localization‐related epilepsy with transient West syndrome in infancy is another type of age‐dependent epileptic syndrome.

Frameshift mutations of the ARX gene in familial Ohtahara syndrome

Purpose:  Ohtahara syndrome is one of the most severe and earliest forms of epilepsy and is frequently associated with brain malformations, such as hemimegalencephaly. Recently, longer expansion of the first polyalanine tract of ARX was found to be causative for Ohtahara syndrome without brain malformation, whereas premature termination mutations of ARX were found to cause severe brain malformations, such as lissencephaly or hydranencephaly. Both are designated as ARX‐related interneuronopathies.

Evolutional Changes and Outcome of West Syndrome: Correlation with Magnetic Resonance Imaging Findings

Summary: The prognosis and evolutional changes of 77 patients with West syndrome (WS) were studied after patients were classified into four groups on the basis of their magnetic resonance imaging (MRI) findings: anomaly, perinatal injury, normal, and the other groups. The average age at onset of spasms was earliest in the patients with anomalies and latest in patients with normal MRI findings. Patients with normal MRI findings had the shortest duration of spasms, and patients with anomalies had the longest duration of spasms. Antecedent seizures were observed in 6 patients (3 patients with anomalies, 1 patient with normal MRI findings, and 2 patients with other abnormalities). Thirty‐five patients had subsequent seizures. Patients with anomalies often had partial seizures and patients with perinatal injuries often had generalized seizures. Seizures were infrequent in patients with normal MRI findings. Developmental outcome was best in the patients with normal MRI findings and worst in patients with perinatal injuries. Various types of epileptic syndromes occurred subsequent to WS in patients with anomalies, although nonspecific symptomatic generalized epilepsy was common in patients with perinatal injuries. These results suggest that seizure prognosis, evolutional changes in seizures, and developmental outcome are different among the types of brain lesions.