Jao-Shwann Liang

STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome—Result of Japanese cohort study

We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox‐Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct‐sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause.

CDKL5 alterations lead to early epileptic encephalopathy in both genders

Purpose:  Genetic mutations of the cyclin‐dependent kinase‐like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe‐to‐profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders.

A functional analysis of GABARAP on 17p13.1 by knockdown zebrafish

Array-based comparative genomic hybridization identified a 2.3-Mb microdeletion of 17p13.2p13.1 in a boy presenting with moderate mental retardation, intractable epilepsy and dysmorphic features. This deletion region was overlapped with the previously proposed shortest region overlapped for microdeletion of 17p13.1 in patients with mental retardation, microcephaly, microretrognathia and abnormal magnetic resonance imaging (MRI) findings of cerebral white matter, in which at least 17 known genes are included. Among them, DLG4/PSD95, GPS2, GABARAP and KCTD11 have a function in neuronal development. Because of the functional importance, we paid attention to DLG4/PSD95 and GABARAP, and analyzed zebrafish in which the zebrafish homolog of human DLG4/PSD95 and GABARAP was knocked down and found that gabarap knockdown resulted in small head and hypoplastic mandible. This finding would be similar to the common findings of the patients with 17p13.1 deletions. Although there were no pathogenic mutations in DLG4/PSD95 or GABARAP in a cohort study with 142 patients with idiopathic developmental delay with/without epilepsy, further studies would be required for genes included in this region.

Hyperactivity and Impulsivity in Children with Untreated Allergic Rhinitis: Corroborated by Rating Scale and Continuous Performance Test

BACKGROUND Allergic rhinitis (AR) is the most common chronic allergic disease in school-age children. An increased prevalence of attention deficit hyperactivity disorder (ADHD) in AR patients has been reported; however, inattention and hyperactivity in AR children have not been investigated using objective and scientific measurements. METHODS We used AR symptom score, ADHD symptom scale, and computerized continuous performance test (CPT) to study the attention and impulsivity in AR children, age-matched controls, and ADHD children (aged 6-15 years). Univariate and multivariate linear regression analyses were applied to identify risk factors for impulsivity and inattention in AR children. RESULTS Twenty-nine controls, 10 ADHD, and 105 AR children were enrolled. There were no differences in age and sex among the three groups. The scores of Hyperactivity/Impulsivity subscales of ADHD symptoms from both parents and teachers were significantly higher in the AR children. The CPT in AR children revealed higher commission errors, shorter reaction times, and more perseveration. Risk factors for inattention and impulsivity in AR children included younger age, male sex, higher AR symptom scores, persistent AR, moderate/severe AR, multiple atopic diseases, family history of atopy, and possible comorbidity with ADHD. CONCLUSION Care for AR children should not only involve treating their allergy, but also monitoring the possible comorbidities of impulsivity and inattention. In children with impulsivity, AR should be considered in addition to ADHD.

Application of Array-based Comparative Genome Hybridization in Children with Developmental Delay or Mental Retardation

Children with developmental delay or mental retardation (DD/MR) are commonly encountered in child neurology clinics, and establishing an etiologic diagnosis is a challenge for child neurologists. Among the etiologies, chromosomal imbalance is one of the most important causes. However, many of these chromosomal imbalances are submicroscopic and cannot be detected by conventional cytogenetic methods. Microarray-based comparative genomic hybridization (array CGH) is considered to be superior in the investigation of chromosomal deletions or duplications in children with DD/MR, and has been demonstrated to improve the diagnostic detection rate for these small chromosomal abnormalities. Here, we review the recent studies of array CGH in the evaluation of patients with idiopathic DD/MR.

Schizencephaly: Correlation between Clinical and Neuroimaging Features

Schizencephaly is an uncommon congenital brain malformation. We report our experience of 13 patients with schizencephaly and evaluate the clinical, neuroradiologic, electroencephalographic (EEG), and nosological features. Of these 13 patients, 8 were unilateral forms, 5 were bilateral forrms and 11 were open-lip type schizencephaly. One patient was proven to have cytomegalovirus (CMV) infection. The clinicalfeatures and neurodevelopmental outcomes are variable. Although seizure developed in 9 patients (5 patients from unilateral and 4 from bilateral forms), the severity of epilepsy was not totally related to the degree of malformations. The neurodevelopmental outcome depended on the extent of schizencephaly as well as the seizure control. Those with bilateral forms and intractable seizures had the worst outcome. Other central nervous system (CNS) anomalies were observed in 11 patients. Six out of 11 patients had focal cortical dysplasia. We conclude that children with schizencephaly usually have variable neurological impairment. Earlier diagnosis of schizencephaly and related CNS malformation with neuroimaging is helpful in predicting the neurodevelopmental outcomes in these patients.

Attention deficits revealed by passive auditory change detection for pure tones and lexical tones in ADHD children

Inattention (IA) has been a major problem in children with attention deficit/hyperactivity disorder (ADHD), accounting for their behavioral and cognitive dysfunctions. However, there are at least three processing steps underlying attentional control for auditory change detection, namely pre-attentive change detection, involuntary attention orienting, and attention reorienting for further evaluation. This study aimed to examine whether children with ADHD would show deficits in any of these subcomponents by using mismatch negativity (MMN), P3a, and late discriminative negativity (LDN) as event-related potential (ERP) markers, under the passive auditory oddball paradigm. Two types of stimuli—pure tones and Mandarin lexical tones—were used to examine if the deficits were general across linguistic and non-linguistic domains. Participants included 15 native Mandarin-speaking children with ADHD and 16 age-matched controls (across groups, age ranged between 6 and 15 years). Two passive auditory oddball paradigms (lexical tones and pure tones) were applied. The pure tone oddball paradigm included a standard stimulus (1000 Hz, 80%) and two deviant stimuli (1015 and 1090 Hz, 10% each). The Mandarin lexical tone oddball paradigm’s standard stimulus was /yi3/ (80%) and two deviant stimuli were /yi1/ and /yi2/ (10% each). The results showed no MMN difference, but did show attenuated P3a and enhanced LDN to the large deviants for both pure and lexical tone changes in the ADHD group. Correlation analysis showed that children with higher ADHD tendency, as indexed by parents’ and teachers’ ratings on ADHD symptoms, showed less positive P3a amplitudes when responding to large lexical tone deviants. Thus, children with ADHD showed impaired auditory change detection for both pure tones and lexical tones in both involuntary attention switching, and attention reorienting for further evaluation. These ERP markers may therefore be used for the evaluation of anti-ADHD drugs that aim to alleviate these dysfunctions.

Attention-deficit/hyperactivity disorder-related symptoms improved with allergic rhinitis treatment in children.

Background Increased prevalence of attention-deficit/hyperactivity disorder (ADHD) in children with allergic rhinitis (AR) has been reported. Our previous study showed that children with untreated AR had higher ADHD scores than did the controls. Objective This prospective follow-up study aimed to investigate whether elevated ADHD scores in children with AR could be decreased by AR treatment. Methods Sixty-eight children with AR (age range, 6-14 years) and who were drug naive were enrolled and evaluated by AR symptom score, ADHD symptom scores, and computerized continuous performance test, before and after AR therapy, which included nonpharmacologic intervention, oral antihistamines, and topical steroids. Thirty-one age-matched controls and 13 children with pure ADHD were also enrolled for comparison. The relationship between the AR and ADHD score change was analyzed by a partial correlation test, and univariate and multivariate linear regression models were applied to investigate possible predictors for the improvement of ADHD scores by AR treatment. Results AR symptom scores in children with AR decreased significantly after treatment (p < 0.001), and their ADHD scores also decreased significantly (p < 0.001). An improved AR symptom score was positively correlated with improved detectability (rp = 0.617, p = 0.001) and commission error (rp = 0.511, p = 0.011). Significant predictors for the improvement of ADHD scores included age, AR drugs, AR subtypes, and multiple atopic diseases (ps < 0.05). Conclusion Higher ADHD scores in children with AR compared with healthy controls decreased significantly with AR treatment. For children with AR and borderline ADHD symptoms, who do not meet full ADHD diagnostic criteria, we recommend initially treating their AR and monitoring improvement of ADHD symptoms.

Schizencephaly in LEOPARD Syndrome

We report on a 2-year-old boy with facial dysmorphism, multiple lentigines, and hypertrophic cardiomyopathy. Mutation analyses of the patient and his mother revealed a Y279G mutation in exon 7 of the PTPN11 gene. The presence of LEOPARD syndrome was confirmed by a genetic study and clinical phenotypes. Since age 18 months, the patient had manifested frequent seizures that were poorly controlled by multiple anticonvulsants. Neurologic examinations indicated severe developmental delay and sensorineural deafness. Brain imaging demonstrated open-lip schizencephaly in the right frontoparietal area. Central nervous system anomalies are rarely reported in this disease. To the best of our knowledge, this is the first report of LEOPARD syndrome with associated schizencephaly. Psychomotor retardation is not uncommon in LEOPARD syndrome. We advocate brain-imaging studies of patients with LEOPARD syndrome and neurologic abnormalities such as developmental delay or epilepsy.

Agyria-pachygyria: clinical, neuroimaging, and neurophysiologic correlations

Agyria-pachygyria complex is a disorder of neuronal migration and organization. Patients suffer either motor or intellectual retardation. We report our experiences of 10 patients with agyria-pachygyria complex and evaluate their clinical features, electroencephalography, and evoked potentials. Of nine electroencephalography examinations, five patients demonstrated characteristically high-amplitude fast activity. One of nine patients had an abnormal brainstem auditory-evoked potential. Three of seven patients had abnormal goggled visual-evoked potential. Six patients received somatosensory-evoked potential examinations, and five of these were abnormal, including four with prolonged central conduction times. Of the 10 patients, eight survived with variable intellectual and motor retardation; two died of sepsis. Patients with grades 1-4 agyria-pachygyria had high incidences of somatosensory-evoked potential abnormalities and also suffered worse neurologic outcomes. Normal brainstem auditory-evoked potential but abnormal cortical somatosensory-evoked potential components and prolonged central conduction time in these patients indicate that agyria-pachygyria is a supratentorial disease. We conclude that somatosensory-evoked potential examination is supplemental to neuroimaging in predicting the neurologic prognosis of patients with agyria-pachygyria.