Gait characteristics of children with Williams syndrome with impaired visuospatial recognition: a three-dimensional gait analysis study.

Williams syndrome (WS) is a genetically based neurodevelopmental disorder characterized by intellectual disability and impaired visuospatial recognition. The aim of this study was to analyze the gait characteristics of WS children with impaired visuospatial recognition using a three-dimensional gait analysis (3DGA) to clarify the gait adaptation needed to compensate for it. 3DGA was performed in 8 WS children with impaired visuospatial recognition (mean age, 11.8 years) and 9 age-, sex-, height-, and weight-matched controls. Clinical data, fundamental motor tests, and gait variables while walking on a flat surface and walking up a mat were compared between the two groups, and the correlations between variables were analyzed in the WS children. WS children showed impairment of balance function without muscle weakness. In walking on a flat surface, the WS group showed reduced walking speed, short step length, increased variability of step length, increased knee flexion throughout the stance phase, increased horizontal pelvic range of motion (ROM), and a low Gait Deviation Index and a high Gait Profile Score, which are indices of gait quality. In walking up a mat, the WS group showed further reduced walking speed and decreased sagittal hip flexion and ankle dorsiflexion ROM in the swing phase. Impaired balance function was significantly correlated with increased variability of step length and decreased sagittal ankle dorsiflexion ROM in the swing phase. The detailed gait pattern of WS children with impaired visuospatial recognition was presented. These findings show that impaired visuospatial recognition and balance function contribute to gait adaptation.

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.

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.

Distinctive facies, macrocephaly, and developmental delay are signs of a PTEN mutation in childhood.

BACKGROUND: Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated. METHODS: PTEN mutations were investigated by multiplex targeted sequencing of genomic DNA from 33 children with increased head circumference (>+2 SD) and developmental delay. The clinical features of all the patients with a PTEN mutation were abstracted by dysmorphologists. RESULTS: We have identified six children with a PTEN mutation. Clinical dissection of these six patients, in addition to patient reports in the literature, revealed distinctive facial features that included frontal bossing, dolichocephaly, horizontal eyebrows, and a depressed nasal bridge. Macrocephaly (+3.2 to +6.0 SD) was noticeable compared to their height (-0.8 to +2.1 SD), and the difference in the SD value of head circumference and height was more than 3 SD in all patients. CONCLUSION: The presence of distinctive facies, extreme macrocephaly with normal to mildly high stature, and developmental delay may be useful for identifying patients with a PTEN mutation in childhood. Early identification of patients with a PTEN mutation would help uncover the natural course of tumor development in this group of individuals who have a possible predisposition to cancer, and be important for the development of an optimal surveillance strategy.

Preserved search asymmetry in the detection of fearful faces among neutral faces in individuals with Williams syndrome revealed by measurement of both manual responses and eye tracking.

BACKGROUND: Individuals with Williams syndrome (WS) exhibit an atypical social phenotype termed hypersociability. One theory accounting for hypersociability presumes an atypical function of the amygdala, which processes fear-related information. However, evidence is lacking regarding the detection mechanisms of fearful faces for individuals with WS. Here, we introduce a visual search paradigm to elucidate the mechanisms for detecting fearful faces by evaluating the search asymmetry; the reaction time when both the target and distractors were swapped was asymmetrical. METHODS: Eye movements reflect subtle atypical attentional properties, whereas, manual responses are unable to capture atypical attentional profiles toward faces in individuals with WS. Therefore, we measured both eye movements and manual responses of individuals with WS and typically developed children and adults in visual searching for a fearful face among neutral faces or a neutral face among fearful faces. Two task measures, namely reaction time and performance accuracy, were analyzed for each stimulus as well as gaze behavior and the initial fixation onset latency. RESULTS: Overall, reaction times in the WS group and the mentally age-matched control group were significantly longer than those in the chronologically age-matched group. We observed a search asymmetry effect in all groups: when a neutral target facial expression was presented among fearful faces, the reaction times were significantly prolonged in comparison with when a fearful target facial expression was displayed among neutral distractor faces. Furthermore, the first fixation onset latency of eye movement toward a target facial expression showed a similar tendency for manual responses. CONCLUSIONS: Although overall responses in detecting fearful faces for individuals with WS are slower than those for control groups, search asymmetry was observed. Therefore, cognitive mechanisms underlying the detection of fearful faces seem to be typical in individuals with WS. This finding is discussed with reference to the amygdala account explaining hypersociability in individuals with WS.

Characteristics of epilepsy in patients with Kabuki syndrome with KMT2D mutations.

BACKGROUND: The characteristics of epilepsy in patients with Kabuki syndrome with KMT2D mutations (KABUK1) have not yet been well documented. This is the first review to explore this. MATERIALS & METHODS: We enrolled 14 patients with KABUK1, whose median age was 13.6years (range=4.1-21.3years). Their medical records from October 1981 to May 2016 were retrospectively analyzed. RESULTS: Epilepsy was present in 5 (36%) patients. Four of these patients presented with nonsense mutations and one with missense mutations. None presented with brain abnormalities. Four patients presented with annual or monthly focal seizures, of which three evolved to bilateral convulsive seizures. Median onset age of focal epilepsy was 11.8years (range=9.5-12.8years). One presented with monthly myoclonic seizures from age 11.2, whose mother with no other KABUK1 features, had focal epilepsy. The cumulative incidence of epilepsy related to KABUK1 up until age 13 was 45%. Interictal electroencephalogram revealed focal paroxysmal epileptiform discharges (in frontal, central, and parietal regions) in three patients, diffuse high-voltage spike-and-waves in one patient, and normal sleep record in one patient. Myoclonic seizures were rapidly controlled by levetiracetam. In contrast, focal seizures were not controlled in the early period of antiepileptic therapy. CONCLUSION: This long-term follow-up of patients with KABUK1 revealed a higher prevalence of epilepsy than previously reported. The age of epilepsy onset and rate of focal seizures evolving to bilateral convulsive seizures in KABUK1 were also higher than previously reported in patients with clinically diagnosed Kabuki syndrome. Although seizure outcome is reported to be favorable in Kabuki syndrome, focal seizures in patients with KABUK1 were not immediately responsive to medication.

Typical visual search performance and atypical gaze behaviors in response to faces in Williams syndrome.

BACKGROUND: Evidence indicates that individuals with Williams syndrome (WS) exhibit atypical attentional characteristics when viewing faces. However, the dynamics of visual attention captured by faces remain unclear, especially when explicit attentional forces are present. To clarify this, we introduced a visual search paradigm and assessed how the relative strength of visual attention captured by a face and explicit attentional control changes as search progresses. METHODS: Participants (WS and controls) searched for a target (butterfly) within an array of distractors, which sometimes contained an upright face. We analyzed reaction time and location of the first fixation-which reflect the attentional profile at the initial stage-and fixation durations. These features represent aspects of attention at later stages of visual search. The strength of visual attention captured by faces and explicit attentional control (toward the butterfly) was characterized by the frequency of first fixations on a face or butterfly and on the duration of face or butterfly fixations. RESULTS: Although reaction time was longer in all groups when faces were present, and visual attention was not dominated by faces in any group during the initial stages of the search, when faces were present, attention to faces dominated in the WS group during the later search stages. Furthermore, for the WS group, reaction time correlated with eye-movement measures at different stages of searching such that longer reaction times were associated with longer face-fixations, specifically at the initial stage of searching. Moreover, longer reaction times were associated with longer face-fixations at the later stages of searching, while shorter reaction times were associated with longer butterfly fixations. CONCLUSIONS: The relative strength of attention captured by faces in people with WS is not observed at the initial stage of searching but becomes dominant as the search progresses. Furthermore, although behavioral responses are associated with some aspects of eye movements, they are not as sensitive as eye-movement measurements themselves at detecting atypical attentional characteristics in people with WS.

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.

The effects of co-medications on lamotrigine clearance in Japanese children with epilepsy.

PURPOSE: Although it has been reported that some antiepileptic drugs have inducing or inhibiting effects on lamotrigine (LTG) clearance, whether they have the same effects in Asian epilepsy patients as in those in other countries has not been clarified, especially in children. The aim of this study was to determine the effects of co-medications on LTG clearance in Japanese children with epilepsy. METHODS: A total of 342 routine serum concentration measurements of LTG in 102 Japanese epilepsy patients under 20years of age were reviewed. The dose-corrected concentration (DCC) of LTG was calculated as [concentration]/[dose/(body weight)], and the DCC of LTG was compared by co-medication. The difference in the DCC of LTG was compared between patients with and without valproic acid (VPA) and between those with and without drugs inducing glucuronic acid conjugation (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB)). RESULTS: The DCC of LTG was significantly higher in patients on VPA and significantly lower in patients on drugs inducing glucuronic acid conjugation than in patients on LTG monotherapy. The DCC of LTG was significantly higher in patients on CBZ than in patients on PHT or PB. There was no correlation between the DCC of LTG and the concentration of VPA or metabolic inducers within the therapeutic range. Other antiepileptic drugs including clobazam, clonazepam, zonisamide, and levetiracetam had little effect on LTG concentration. CONCLUSION: LTG concentration changes dramatically with concomitant antiepileptic drugs in Japanese children, as previously reported from other countries, and special attention is required. Although the dose of LTG should be adjusted when starting or discontinuing VPA or metabolic inducers, no adjustment is needed when changing the dose of VPA or metabolic inducers in the therapeutic range.

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.

Developmental changes in mental rotation ability and visual perspective-taking in children and adults with Williams syndrome.

Williams syndrome (WS) is a genetic disorder caused by the partial deletion of chromosome 7. Individuals with WS have atypical cognitive abilities, such as hypersociability and compromised visuospatial cognition, although the mechanisms underlying these deficits, as well as the relationship between them, remain unclear. Here, we assessed performance in mental rotation (MR) and level 2 visual perspective taking (VPT2) tasks in individuals with and without WS. Individuals with WS obtained lower scores in the VPT2 task than in the MR task. These individuals also performed poorly on both the MR and VPT2 tasks compared with members of a control group. For the individuals in the control group, performance scores improved during development for both tasks, while the scores of those in the WS group improved only in the MR task, and not the VPT2 task. Therefore, we conducted a second experiment to explore the specific cognitive challenges faced by people with WS in the VPT2 task. In addition to asking participants to change their physical location (self-motion), we also asked them to adopt a third-person perspective by imagining that they had moved to a specified location (self-motion imagery). This enabled us to assess their ability to simulate the movement of their own bodies. The performance in the control group improved in both the self-motion and self-motion imagery tasks and both performances were correlated with verbal mental age. However, we did not find any developmental changes in performance for either task in the WS group. Performance scores for the self-motion imagery task in the WS group were low, similar to the scores observed for the VPT2 in this population. These results suggest that MR and VPT2 tasks involve different processes, and that these processes develop differently in people with WS. Moreover, difficulty completing VPT2 tasks may be partly because of an inability of people with WS to accurately simulate mental body motion.

EEG for predicting early neurodevelopment in preterm infants: an observational cohort study.

OBJECTIVE: To clarify the prognostic value of conventional EEG for the identification of preterm infants at risk for subsequent adverse neurodevelopment in the current perinatal care and medicine setting. METHODS: We studied 780 EEG records of 333 preterm infants born <34 weeks' gestation between 2002 and 2008. Serial EEG recordings were conducted during 3 time periods; at least once each within days 6 (first period), during days 7 to 19 (second period), and days 20 to 36 (third period). The presence and the grade of EEG background abnormalities were assessed according to an established classification system. Neurodevelopmental outcomes were assessed at a corrected age of 12 to 18 months. RESULTS: Of the 333 infants, 33 (10%) had developmental delay and 34 (10%) had cerebral palsy. The presence of EEG abnormalities was significantly predictive of developmental delay and cerebral palsy at all 3 time periods: the first period (n = 265; odds ratio [OR], 4.5; 95% confidence interval [CI], 2.2-9.4), the second period (n = 278; OR, 7.6; 95% CI, 3.6-16), and the third period (n = 237; OR, 5.9; 95% CI, 2.8-13). The grade of EEG abnormalities correlated with the incidence of developmental delay or cerebral palsy in all periods (P < .001). After controlling for other clinical variables, including severe brain injury, EEG abnormality in the second period was an independent predictor of developmental delay (OR, 3.2; 95% CI, 1.1-9.7) and cerebral palsy (OR, 6.8; 95% CI 2.0-23). CONCLUSIONS: EEG abnormalities within the first month of life significantly predict adverse neurodevelopment at a corrected age of 12 to 18 months in the current preterm survivor.