De novo PHACTR1 mutations in West syndrome and their pathophysiological effects.

Trio-based whole exome sequencing identified two de novo heterozygous missense mutations [c.1449T > C/p.(Leu500Pro) and c.1436A > T/p.(Asn479Ile)] in PHACTR1, encoding a molecule critical for the regulation of protein phosphatase 1 (PP1) and the actin cytoskeleton, in unrelated Japanese individuals with West syndrome (infantile spasms with intellectual disability). We then examined the role of Phactr1 in the development of mouse cerebral cortex and the pathophysiological significance of these two mutations and others [c.1561C > T/p.(Arg521Cys) and c.1553T > A/p.(Ile518Asn)], which had been reported in undiagnosed patients with intellectual disability. Immunoprecipitation analyses revealed that actin-binding activity of PHACTR1 was impaired by the p.Leu500Pro, p.Asn479Ile and p.Ile518Asn mutations while the p.Arg521Cys mutation exhibited impaired binding to PP1. Acute knockdown of mouse Phactr1 using in utero electroporation caused defects in cortical neuron migration during corticogenesis, which were rescued by an RNAi-resistant PHACTR1 but not by the four mutants. Experiments using knockdown combined with expression mutants, aimed to mimic the effects of the heterozygous mutations under conditions of haploinsufficiency, suggested a dominant negative effect of the mutant allele. As for dendritic development in vivo, only the p.Arg521Cys mutant was determined to have dominant negative effects, because the three other mutants appeared to be degraded with these experimental conditions. Electrophysiological analyses revealed abnormal synaptic properties in Phactr1-deficient excitatory cortical neurons. Our data show that the PHACTR1 mutations may cause morphological and functional defects in cortical neurons during brain development, which is likely to be related to the pathophysiology of West syndrome and other neurodevelopmental disorders.

Reading impairment after neonatal hypoglycemia with parieto-temporo-occipital injury without cortical blindness: A case report.

BACKGROUND: Perinatal brain injury may lead to later neurodevelopmental disorders, whose outcomes may vary due to neuroplasticity in young children. Recent neuroimaging studies have shown that the left parietotemporal area (which includes the left inferior parietal lobe) is associated with phonological awareness and decoding skills, which are essential skills for reading acquisition in children. However, the literature on the effect of perinatal cerebral injury on the development of phonological awareness or decoding ability in childhood is limited. CASE SUMMARY: We report the case of an 8-year-old boy who presented with reading difficulty following a perinatal injury in the parieto-temporal-occipital lobes. The patient was born at term and was treated for hypoglycemia and seizures during the neonatal period. Diffusion-weighted brain magnetic resonance imaging on postnatal day 4 revealed cortical and subcortical hyperintensities in the parieto-temporo-occipital lobe. At the age of 8 years, physical examination was unremarkable, aside from mild clumsiness. Despite occipital lobe injury, the patient had adequate visual acuity, normal eye movement, and no visual field defects. Full-scale intelligence quotient and verbal comprehension index on Wechsler Intelligence Scale for Children-Fourth Edition were 75 and 90, respectively. Further assessment revealed adequate recognition of Japanese Hiragana letters. However, he had significantly slower reading speed in the Hiragana reading test than control children. The phonological awareness test revealed significant errors (standard deviation +2.7) in the mora reversal task. CONCLUSION: Patients with perinatal brain injuries in the parietotemporal area require attention and may benefit from additional reading instructions.

Splenial Lesions in Benign Convulsions With Gastroenteritis Associated With Rotavirus Infection.

OBJECTIVE: To investigate clinical risk factors for acute magnetic resonance imaging (MRI) abnormalities in patients with benign convulsions with mild gastroenteritis or benign infantile epilepsy. STUDY DESIGN: We investigated clinical and diffusion-weighted imaging findings in 32 patients with benign convulsions with mild gastroenteritis and 22 patients with benign infantile epilepsy who underwent MRI within seven days of seizure onset between 2010 and 2015. RESULTS: Diffusion-weighted imaging showed signal hyperintensity in the splenium of the corpus callosum in seven patients with benign convulsions with mild gastroenteritis, but no abnormalities in patients with benign infantile epilepsy. Patients with benign convulsions with mild gastroenteritis with splenial lesions showed a higher rate of rotavirus detection from feces (P = 0.006), higher serum level of C-reactive protein (P = 0.04), and shorter interval between seizure onset and MRI (P = 0.002) than patients with benign convulsions with mild gastroenteritis without splenial lesions. Multivariate analysis revealed rotavirus infection as a significant risk factor for splenial lesions on diffusion-weighted imaging in patients with benign convulsions with mild gastroenteritis (P = 0.02). CONCLUSIONS: Splenial lesions are often seen during acute period in patients with benign convulsions with mild gastroenteritis. Rotavirus infection is a risk factor for splenial lesions in patients with benign convulsions with mild gastroenteritis, suggesting the role of rotavirus to cause edema in the corpus callosum. From our observations, benign convulsions with mild gastroenteritis with a splenial lesion on diffusion-weighted imaging suggests good outcomes, and extensive evaluation of these patients may be unnecessary.

Is hiragana decoding impaired in children with periventricular leukomalacia?

BACKGROUND: There are few studies on hiragana reading skill and phonological awareness in Japanese schoolchildren with periventricular leukomalacia (PVL). METHODS: Three seven-year-old children with PVL who had no intellectual disabilities or dysarthria were recruited. Their perinatal information, brain magnetic resonance image (MRI) at term equivalent age, accompanying neurodevelopmental disorders, ophthalmologic features, Kaufman Assessment Battery for Children (K-ABC), a hiragana reading test (four tasks), and a phonological awareness task (mora reversal tasks) were analyzed. RESULTS: Patient (Pt) 1 and pt2 were male. Pt2 and pt3 were siblings of triplets. Their gestational age was 28 or 32 weeks, and their birth weights were 1196, 1554, and 1848 g, respectively. Their brain MRI revealed cystic or non-cystic periventricular white matter injury involving the deep white matter at the trigone of both lateral ventricles. Pt1 had attention-deficit/hyperactivity disorder and pt3 had pervasive developmental disorder not otherwise specified. All patients had strabismus with spared best-corrected visual acuity. Scores of Reading/Decoding in K-ABC ranged from 89 to 99. As for the single mora reading task or the non-word reading task in the kana reading test, Z scores of their reading time ranged from 2.3 to 5.9 compared to control children. Pt1 and pt3 made significant errors in the mora reversal task of three-mora words, whereas all patients could answer all words correctly in the mora reversal task of two-mora words. CONCLUSION: All children showed significantly prolonged reading time despite their adequate letter recognition. Two patients showed delayed phonological awareness. It was suggested that hiragana decoding impairment due to subcortical and/or cortical injury related to PVL affected their reading ability.

Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report.

Arts syndrome is characterized by early-onset hypotonia, ataxia, intellectual disability, sensorineural hearing impairment, progressive optic atrophy, and a tendency to develop infections. Arts syndrome is an X-linked disorder caused by a loss-of-function mutation in the PRPS1 gene, which encodes phosphoribosylpyrophosphate synthetase 1. Only three families have been reported. Here, we report another family with Arts syndrome. The initial symptoms of the 1-year-old proband were hypotonia and ataxia, worsening recurrent infection-triggered muscle weakness, motor and intellectual developmental delay, and hearing loss. Both central nervous system involvement and peripheral neuropathy were demonstrated. His three maternal uncles had died before the age of 3years. A genetic analysis of PRPS1 revealed a novel missense mutation, c.367C>G (p.His123Asp). PRPS enzymatic activity was markedly reduced in the patient. His mother was supposed to be an asymptomatic carrier. Arts syndrome should be included in the differential diagnosis of infantile hypotonia and weakness aggravated by recurrent infection with a family history of X-linked inheritance.

Thalamic lesions in acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: We aimed to assess the characteristics of thalamic lesions in children with acute encephalopathy with biphasic seizures and late reduced diffusion. METHODS: Using the Tokai Pediatric Neurology Society database, we identified and enrolled 18 children with acute encephalopathy with biphasic seizures and late reduced diffusion from 2008 to 2010. Using diffusion-weighted images, we identified patients with thalamic lesions and compared their clinical factors with those of patients without thalamic lesions. We analyzed the time sequence of thalamic, sucortical, and cortical lesions. To study the topography of thalamic lesions, we divided the thalamus into five sections: anterior, medial, anterolateral, posterolateral, and posterior. Subsequently, we analyzed the relationship between the topography of thalamic lesions and the presence of central-sparing. RESULTS: Seven children presented with symmetrical thalamic lesions associated with bilateral subcortical or cortical lesions. No statistical difference in the clinical features was observed between individuals with and without thalamic lesions. These lesions were observed only when subcortical or cortical lesions were present. In 5 children, thalamic lesions were present in bilateral anterior or anterolateral sections and were associated with subcortical or cortical lesions in bilateral frontal lobes with central-sparing. In the other two children, thalamic lesions were extensive and accompanied by diffuse subcortical and cortical lesions without central-sparing. CONCLUSION: Thalamic lesions in patients with acute encephalopathy with biphasic seizures and late reduced diffusion involve the anterior sections. The thalamocortical network may play a role in development of thalamic lesions in patients with acute encephalopathy with biphasic seizures and late reduced diffusion.