Takehiko Inui

Brain magnetic resonance imaging and motor and intellectual functioning in 86 patients born at term with spastic diplegia.

Aim  To investigate the association between magnetic resonance imaging (MRI) patterns and motor function, epileptic episodes, and IQ or developmental quotient in patients born at term with spastic diplegia.

Evolution of hemiplegic attacks and epileptic seizures in alternating hemiplegia of childhood

To delineate the evolution of non-epileptic and epileptic paroxysmal events in alternating hemiplegia of childhood (AHC), we reviewed clinical information of nine patients (4-40 years) with AHC. Paroxysmal abnormal ocular movements, head turning, and tonic, clonic, or myoclonic limb movements were the initial symptoms (birth-8m) in each patient. Ictal electroencephalography (EEG) of these episodes, as well as hemiplegic periods that accompanied these symptoms later in infancy showed unremarkable findings or generalized slow background activity. Presumptive epileptic seizures appeared at 2-16y in seven patients: generalized tonic, clonic, myoclonic, tonic-clonic, or complex partial seizures often accompanied by cyanosis or prolonged respiratory arrest. Ictal EEGs recorded in four patients revealed focal slow or fast activities during facial or limb twitching, and widespread sharp waves or polyspike-wave activities during clonic/myoclonic seizures. Four patients with neonatal disease onset showed lower psychomotor developmental achievements compared with other patients, and experienced repeated status epilepticus followed by progressive deterioration. Cerebellar atrophy and hippocampal high signal changes on magnetic resonance imaging were common to this group with severe phenotypes. Apart from the paroxysmal motor symptoms accompanying the hemiplegic episodes, many AHC patients suffer from true epilepsies during childhood. Status epilepticus in AHC is linked to severe outcome with psychomotor deterioration. The variations in clinical phenotypes may imply multiple causative genes for AHC. This variation should be considered while managing patients with this disorder.

Two cases of early-onset myoclonic seizures with continuous parietal delta activity caused by EEF1A2 mutations.

BACKGROUND Mutations in the elongation factor 1 alpha 2 (EEF1A2) gene have recently been shown to cause severe intellectual disability with early-onset epilepsy. The specific manifestations of mutations in this gene remain unknown. CASE REPORT We report two cases of severe intellectual disability accompanied by early-onset epilepsy with continuous delta activity evident on electroencephalography. Both cases presented with developmental delay and repetitive myoclonic seizures in early infancy. Both cases showed continuous high-voltage delta activity over both parietal areas when awake, as revealed by interictal electroencephalograms. After the emergence of continuous delta activity, development stagnated. One case showed some development after relief of the seizures and epileptic activity, but drug resistant seizures recurred, and the development again became stagnant. In both cases, a de novo recurrent heterozygous mutation in EEF1A2 [c.364G>A (p.E122K)] was identified by whole-exome sequencing. CONCLUSION This report provides clinical data on epileptic encephalopathy in patients with EEF1A2 mutation. Continuous high-voltage delta activity seen over both parietal areas may be a unique manifestation of EEF1A2 mutation. Epileptic activity may aggravate the effect of the mutation on brain development.

FDG-PET study of patients with Leigh syndrome

We conducted a [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) study in five patients (median age 11 (range 4-13) years) with Leigh syndrome to evaluate its usefulness for understanding the functional brain dysfunction in this disease and in future drug trials. Four patients were found to have reported mitochondrial DNA gene mutations. The brain T2-weighted magnetic resonance imaging (MRI) showed high-intensity areas in the putamen bilaterally in five patients, caudate bilaterally in four, thalamus bilaterally in two, and brainstem in one. Cerebellar atrophy was observed in older two patients. For disease control, seven age-matched epilepsy patients who had normal MRI and FDG-PET studies were selected. For semiquantitative analysis of the lesions with decreased (18)F-FDG uptake, the mean standard uptake value (SUV) was calculated in regions of interest (ROIs) placed in each brain structure. We compared the SUV of nine segments (the frontal, temporal, parietal, and occipital lobes, thalami, basal ganglia, mid-brain, pons, and cerebellum) between patients with Leigh syndrome and controls. The glucose uptake was decreased significantly in the cerebellum and basal ganglia, which could explain the ataxia and dystonia in patients with Leigh syndrome. Although this study had some limitations, FDG-PET might be useful for evaluating the brain dysfunction and treatment efficacy of new drugs in patients with Leigh syndrome. Further study with more patients using advanced methods to quantify glucose uptake is needed before drawing a conclusion.

The first report of Japanese patients with asparagine synthetase deficiency

BACKGROUND Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder of non-essential amino acids, and presents as severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures. METHODS Two Japanese children with progressive microcephaly born to unrelated patients were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions. RESULTS We describe the first known Japanese patients with ASNS deficiency. Their clinical manifestations were very similar to reported cases of ASNS deficiency. Progressive microcephaly was noted during the prenatal period in patient 1 but only after birth in patient 2. Both patients had novel ASNS mutations: patient 1 had p.L145S transmitted from his mother and p.L247W which was absent from his mother, while patient 2 carried p.V489D and p.W541Cfs*5, which were transmitted from his mother and father, respectively. Three of the four mutations were predicted to affect protein folding, and in silico analyses suggested that they would be pathogenic. CONCLUSION We report the first two Japanese patients with ASNS deficiency. Disease severity appears to vary among patients, as is the case for other non-essential amino acid metabolic disorders.

Outcome of hemiplegic cerebral palsy born at term depends on its etiology

OBJECTIVES To elucidate the etiology and its relationship to the outcomes of hemiplegic cerebral palsy (HCP). PARTICIPANTS AND METHODS MR images and outcomes of 156 children with HCP born at term and older than three years were investigated in two major centers for cerebral palsy in Japan. Etiologies were classified into perinatal ischemic stroke (PIS), cerebral dysgenesis (CD), and others. PIS was divided into periventricular venous infarction (PVI) and two types of arterial infarction; middle cerebral artery infarction (MCAI) and deep gray matter infarction (DGMI). Initial signs and the time of presentation were investigated among the three types of PIS. As functional outcomes, laterality of paresis, age at initial walk, affected hands function, intellectual development, and occurrence of epilepsy were compared among all the four types. RESULTS ETIOLOGY PIS was found in 106 children (68%), while CD accounted for 28 (18%). Among PIS, venous infarction was more common than arterial infarction (62:44). OUTCOMES PVI revealed later presentation of motor asymmetry and more involvement of lower extremity as the initial sign among PIS groups. Only MCAI showed right-side predominance in laterality of paresis. DGMI related to better intellectual development and PVI showed lower occurrence of epilepsy, while there was no significant difference in affected hands function among the four groups. PIS groups showed significantly earlier attainment of independent walk, better intellectual development, and lower occurrence of epilepsy than CD. CONCLUSIONS PVI was the most common cause of HCP born at term, and the etiology closely related to the initial signs of hemiplegia and overall outcomes.

Clinical Course and Images of Four Familial Cases of Allan-Herndon-Dudley Syndrome With a Novel Monocarboxylate Transporter 8 Gene Mutation

BACKGROUND Allan-Herndon-Dudley syndrome, an X-linked condition characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia, is associated with defects in the monocarboxylate transporter 8 gene (MCT8). The long-term prognosis of Allan-Herndon-Dudley syndrome remains uncertain. PATIENTS We describe the clinical features and course of four adults in a family with Allan-Herndon-Dudley syndrome with athetoid type cerebral palsy. RESULTS We identified an MCT8 gene mutation in this family. Two of the four affected family members died at 32 and 24 years of age. CONCLUSIONS Individuals with Allan-Herndon-Dudley syndrome are at increased risk for recurrent infection, such as aspiration pneumonia. These individuals require careful management with consideration for this increased risk of recurrent infection.

Neuroepidemiology of Porencephaly, Schizencephaly, and Hydranencephaly in Miyagi Prefecture, Japan

BACKGROUND No population-based surveys of porencephaly, schizencephaly, and hydranencephaly have been conducted in Japan or other Asian countries. We performed a neuroepidemiologic analysis to elucidate the incidence of porencephaly, schizencephaly, and hydranencephaly in Miyagi prefecture, Japan, during 2007-2011. METHODS We sent inquiry forms in February 2012 to three neonatal intensive care units, 25 divisions of orthopedic surgery in municipal hospitals, 33 divisions of pediatrics including one university hospital, municipal hospitals, pediatric practitioners, and institutions for physically handicapped children located in Miyagi prefecture. These covered all clinics related to pediatric neurology and orthopedic surgery in Miyagi prefecture. In the inquiry, diagnostic criteria for porencephaly, schizencephaly, and hydranencephaly were described and representative images of magnetic resonance imaging were shown. We obtained an 82% (27 of 33) response rate from the divisions of pediatrics, a 100% (3 of 3) response rate from the neonatal intensive care units, and a 68% (17 of 25) response rate from orthopedic surgery clinics. The magnetic resonance imaging scans of each patient were retrieved and inspected. RESULTS Five, one, and two individuals developed porencephaly, schizencephaly, and hydranencephaly, respectively. The estimated incidence rates of porencephaly, schizencephaly, and hydranencephaly were 5.2 (95% confidence interval [CI], 0.6-9.8), 1.0 (95% CI, 0.0-3.1), and 2.1 (95% CI, 0.0-5.0) per 100,000 live births, respectively. CONCLUSIONS The prevalence rates of porencephaly, schizencephaly, and hydranencephaly at birth reported herein are compatible with results reported previously in the United States and European countries. The overall prevalence rate of these three diseases was 8.3 (95% CI, 2.6-14.1) per 100,000 live births.

Xq26.1-26.2 gain identified on array comparative genomic hybridization in bilateral periventricular nodular heterotopia with overlying polymicrogyria

Periventricular nodular heterotopia (PNH) with overlying polymicrogyria (PMG) is a recently described, developmental brain malformation; however, the causative genes of this malformation have not yet been identified. We report on a 5‐year‐old Japanese male with bilateral PNH with overlying PMG. He had mild intellectual disability, distinctive facial features, short stature, and microcephaly, with cardiac disorders. No mutation was identified in Sanger sequences for FLNA and ARFGEF2; however, array comparative genomic hybridization revealed an approximately 0.8Mb gain at Xq26.1‐26.2, which included three genes: IGSF1, OR13H1, and FIRRE. We identified the same 3‐copy gain in his mother; despite identifying the same abnormality in the mother, it must still be considered as a possible cause for the abnormalities, as X‐inactivation in the mother could have led to her not expressing the same phenotype. This case may provide important clues for identifying the genes responsible and help in the understanding of the pathogenesis of this disorder.

Absence of small-vessel abnormalities in alternating hemiplegia of childhood

OBJECTIVE To investigate whether Japanese patients with alternating hemiplegia of childhood (AHC) have the similar small-vessel abnormalities in skin reported in European patients with AHC. METHODS Electron microscopic observation of biopsied skin specimens were carried out in six Japanese patients with AHC. All patients (aged 5-17, all boys) had been diagnosed with AHC through their typical clinical courses and symptoms. RESULTS No abnormal findings in both endothelial cells and smooth muscle cells in skin small-vessels were obtained in the present study, either in the five flunarizine responders or in the one non-responder. CONCLUSIONS From our observations, we hypothesized that there may be some subtypes of AHC. The diverse clinical courses in patients with AHC and the differing efficacy of flunarizine treatment could be explained because of the heterogeneity of AHC subtypes.