Leucine-485 deletion variant of BRAF may exhibit the severe end of the clinical spectrum of CFC syndrome.

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.

A case of new PCDH12 gene variants presented as dyskinetic cerebral palsy with epilepsy.

Here we report a Japanese patient with new compound heterozygous truncating variants in the PCDH12 gene. As compared to the previously reported families who had congenital microcephaly, intrauterine growth retardation, intracranial calcification, and neonatal seizure associated with dysplasia of the midbrain-hypothalamus-optic tract, the present patient showed no midbrain-hypothalamus dysplasia or congenital/postnatal microcephaly, but dyskinetic cerebral palsy and severe intellectual disability as well as multifocal epilepsy. To understand phenotypic spectrum associated with PCDH12 variants, more reports are needed.

Efficacy of vigabatrin therapy for tuberous sclerosis with infantile spasms.

Objective: To evaluate the effects and tolerability of vigabatrin (VGB) in children with tuberous sclerosis (TS) with infantile spasms or tonic seizures. Methods: We examined the impact of VGB on a series of 17 children with TS visiting Tohoku University Hospital in Japan during April 2010 and May 2015. To minimize potential adverse effects, VGB was given to the patients for limited 6 months with titration from 30 mg/kg/day as an initial dose. Results: Main seizure types were classified into spasms (n=10) or tonic seizures (n=7). Seizure reduction was positively associated with seizure type of infantile spasms, lower maximum dosage, younger age on VGB administration, and earlier VGB treatment after the diagnosis. Seizure type of infantile spasm was an independent favorable predictor and also associated with long-term seizure reduction. Major adverse events included psychiatric symptoms (n=7) and electroretinogram (ERG) abnormalities (n=2). All symptoms were recovered by reducing the dosage of VGB. Conclusion: VGB is effective and well tolerated as first-line treatment for TS children with infantile spasms. Our "low dosage and limited period" protocol is efficient for improving seizure control as well as minimizing the potential risks of VGB.

Recurrent acute necrotizing encephalopathy in a boy with RANBP2 mutation and thermolabile CPT2 variant: The first case of ANE1 in Japan.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a severe encephalopathy associated with acute viral infection. While most ANE cases are sporadic, pathogenic variants in the gene RAN binding protein 2 (RANBP2) have been identified as a major cause of familial or recurrent ANE (ANE1). Although sporadic ANE predominantly affects Asian children, ANE1 is very rare in east Asia. CASE REPORT: A 1-year-7-month-old boy, born to unrelated Japanese parents, presented with a seizure and impaired consciousness after 3 days of fever. Brain magnetic resonance imaging (MRI) showed a characteristic involvement of the bilateral thalami, external capsules, insular cortices, and brainstem, suggesting ANE. He received intravenous steroids. Two months later, he had another episode of acute encephalopathy during respiratory syncytial virus infection, from which he recovered relatively well. The recurrent encephalopathic episodes and the characteristic MRI suggested ANE1. Genetic analyses revealed two variants: a rare heterozygous missense variant of RANBP2 [c.1754C>T; p.Thr585Met], and a thermolabile polymorphism in carnitine palmitoyltransferase 2 (CPT2) [c. 1055T>G; p.Phe352Cys]. CONCLUSION: This is the first case of recurrent ANE with an RANBP2 mutation in Japan. The patient also harbored a CPT2 polymorphism that is linked to acute encephalopathy in Japanese patients. Thus, he had a genetic background with two susceptibility variants for acute encephalopathy, RANBP2 (frequent in the Caucasians), and CPT2 (frequent in the Japanese). Further studies are needed to fully discover the genetic predisposition to familial or recurrent ANE in the Asian population.

Familial hemiplegic migraine with a PRRT2 mutation: Phenotypic variations and carbamazepine efficacy.

OBJECTIVE: To understand the clinical characteristics of familial hemiplegic migraine (FHM) caused by a PRRT2 mutation and to examine the efficacy of preventive treatment. METHODS: Using the literature, we investigated clinical details of FHM in 3 generations of patients with a PRRT2 mutation and compared them with those in 17 patients with the same mutation from 6 families. RESULTS: In most of the affected patients, the onset was observed during the teen years. Complicated phenotypes tended to be shared in each family, and five patients showed spontaneous remission. With regard to treatment, low-dose carbamazepine (CBZ) was effective in three patients. CONCLUSION: Considering the clinical features, we suggest that low-dose CBZ is efficacious for FHM treatment in patients with a PRRT2 mutation. The treatment duration should be carefully considered because some patients show spontaneous remission. More accumulated data from familial cases might help elucidate PRRT2 function and establish standard treatment for FHM.

A severe female case of arthrogryposis multiplex congenita with brain atrophy, spastic quadriplegia and intellectual disability caused by ZC4H2 mutation.

Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous multiple congenital contractures appearing at birth. Mutations in X-linked zinc-finger gene ZC4H2 were recently identified in some families and individuals with variable forms of AMC associated with dysmorphic signs, intellectual disability and spastic paresis. We present a non-consanguineous Japanese female presenting AMC with severe intellectual disability and spastic quadriplegia who also had progressive brain atrophy. Microarray-based comparative genomic hybridization identified 395 kb microdeletions at Xq11.2 which only included ZC4H2 gene. Previous reports showed that affected females have lesser symptoms and slight abnormality on brain MRI compared to male due to X-inactivation. Our case, however, showed severe manifestation than as ever reported as well as progressive diffuse brain atrophy, which implicated contribution of other genetic or environmental factors or extremely skewed X inactivation.

Intra-individual cognitive imbalance in ASD between perceptual reasoning and ambiguity-solving related to tool use: Comparison among children exhibiting ASD, AD/HD, and typical development.

OBJECTIVE: Several studies have suggested that objective deficits in the processing of abstract information in conjunction with an enhanced ability to process concrete information is a definitive characteristic of autism spectrum disorder (ASD). However, this cognitive imbalance is not necessarily clear in high-functioning autistic individuals who do not display absolute differences relative to typically developing (TD) populations. Thus, the purpose of this study was to identify this cognitive tendency in high-functioning autistic individuals using intra-individual cognitive comparisons. METHODS: The reaction times (RTs) of TD children, children with ASD, and children with attention deficit hyperactivity disorder (AD/HD) (n=17 in each group, mean age=11.9years, age range=9.8-15.8years) were compared using the Which/How-to-Apply Tools (W/HAT) test, which consists of tasks requiring the adaptive use of novel tools and familiar tools in atypical and typical situations. Differences in RTs between the atypical and typical trials ([A-T]) were used to assess intra-individual cognitive imbalances. RESULTS: As predicted, the [A-T] scores of the ASD group were significantly higher than those of the TD group even though the RTs in the atypical and typical trials did not differ. Additionally, the [A-T] values were significantly higher in the ASD group than in the AD/HD group, which indicates that the cognitive imbalance was specific to ASD individuals. No significant interaction was detected between the trial and subject group. CONCLUSIONS: The findings of this study demonstrate that a cognitive imbalance in ASD individuals may enhance the current understanding of the pathophysiology of this disorder, which is found in a range of individuals, including those with obvious cortical dysfunction to those with only intra-individual imbalances.

Genomic analysis identifies masqueraders of full-term cerebral palsy.

OBJECTIVE: Cerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full-term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders. METHODS: A total of 107 patients-all full-term births-without specific findings on brain MRI were identified among 897 patients diagnosed with cerebral palsy who were followed at our center. DNA samples were available for 17 of the 107 cases for trio whole-exome sequencing and array comparative genomic hybridization. We prioritized variants in genes known to be relevant in neurodevelopmental diseases and evaluated their pathogenicity according to the American College of Medical Genetics guidelines. RESULTS: Pathogenic/likely pathogenic candidate variants were identified in 9 of 17 cases (52.9%) within eight genes: CTNNB1,CYP2U1,SPAST,GNAO1,CACNA1A,AMPD2,STXBP1, and SCN2A. Five identified variants had previously been reported. No pathogenic copy number variations were identified. The AMPD2 missense variant and the splice-site variants in CTNNB1 and AMPD2 were validated by in vitro functional experiments. INTERPRETATION: The high rate of detecting causative genetic variants (52.9%) suggests that patients diagnosed with cerebral palsy in full-term births without specific MRI findings may include genetic diseases masquerading as cerebral palsy.

A patient with Muenke syndrome manifesting migrating neonatal seizures.

We report a patient with Muenke syndrome who had repetitive apneic spell followed by focal status epilepticus in the early infancy. Ictal EEG showed focal spikes bursts originated from the left hemisphere and sifted to the right hemisphere, during which he had migrating tonic seizures from right side of the body to the left side of the body. Brain MRI showed abnormal development of bilateral hippocampus, which was characterized as abnormal folding of hippocampal gyri. However, the long-term seizure prognosis was favorable. Results from this and previous studies failed to support the notion that FGFR3 (P250) mutation results in epileptic encephalopathy.

A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.

We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16 years old. She presented dysmorphic facial features, growth retardation and severe psychomotor retardation associated with 3p deletion syndrome. We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located. Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma. She showed no other tumors associated VHL disease till 24 years old. This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease. Repeat imaging studies were recommended for the patients with 3p deletion syndrome.