Neurodevelopmental Outcomes of High-Risk Preterm Infants: A Prospective Study in Japan.

OBJECTIVES: To determine the neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs, birth weight <1,500 g) after 9 years of follow-up. METHODS: This study prospectively recruited 224 VLBWIs born from 2003 to 2009 in Kyushu University Hospital, Japan. Comorbidities of neurocognitive impairment, epilepsy, and autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) were assessed at age 3, 6, and 9 years. RESULTS: Neurodevelopmental profiles were obtained from 185 (83%), 150 (67%), and 119 (53%) participants at age 3, 6, and 9 years, respectively. At age 9 years, 25 (21%) VLBWIs showed intelligence quotient (IQ) <70, 11 (9%) developed epilepsy, and 14 (12%) had a diagnosis of ASD/ADHD. The prevalence of epilepsy was higher in children with an IQ <70 at age 9 years than in those with an IQ ≥70 (44% vs 0%). In contrast, ASD/ADHD appeared at similar frequencies in children with an IQ <70 (16%) and ≥70 (11%). Perinatal complications and severe brain lesions on MRI were considered common perinatal risks for developmental delay and epilepsy but not for ASD/ADHD. Male sex was identified as a unique risk factor for ASD/ADHD. CONCLUSION: These data suggest that VLBWIs showed a higher prevalence of developmental delay, epilepsy, and ASD/ADHD at age 9 years than the general population. Distinct mechanisms might be involved in the pathogenic process of ASD/ADHD from those of developmental delay and epilepsy.

Age-related morphological differences in the spike-and-wave complexes of absence epilepsy.

OBJECTIVE: Absence epilepsy shows age-related clinical features, as is observed in childhood and juvenile absence epilepsy. Electroencephalogram (EEG) is characterized by bursts of 3 Hz spike-and-wave complex (SWC). We noticed a morphological variation of the slow-wave component of SWCs between patients. This study investigated whether the waveform of SWC might be associated with the child's age of this epilepsy. METHODS: Digitally-recorded EEGs under medication-free conditions were collected from 25 children who received the diagnosis of childhood or juvenile absence epilepsy. The morphology of slow wave in SWC in the frontal midline region was quantitatively compared between younger and older children using a cluster-based permutation test. RESULTS: At <7 years of age (2.9-6.5 years of age, n = 6), the electrical potential of the descending slope in the slow wave was positively correlated with age whereas this correlation was not observed in patients of ≥7 years of age (7.1-12.9 years, n = 19). A cluster-based permutation test confirmed the results-among the entire slow wave period (0-285 msec), the period of the descending slope (195-260 msec) showed significantly lower potential in patients of <7 years of age in comparison to patients of ≥7 years of age (sum of t-values: 46.57, p-value: 0.011). CONCLUSIONS: The current study demonstrated an age-dependent morphological difference in the slow-wave components of SWCs in EEGs of patients with pediatric absence epilepsy. This finding may provide a clue to understanding the age-related clinical manifestations of this epilepsy.

Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan.

Importance: The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined. Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD. Objective: To assess the role of droplet or contact transmission in the etiopathogenesis of KD. Design, Setting, and Participants: This multicenter, longitudinal, cross-sectional study was conducted from 2015 to 2020 at Fukuoka Children's Hospital and 5 adjacent general hospitals. The number of admissions for KD and infectious diseases were analyzed. Participants were pediatric patients admitted to the participating hospitals for KD or infectious diseases. Exposures: Quarantine and isolation owing to the COVID-19 state of emergency. Main Outcomes and Measures: The primary end points were the ratios of patients with KD to patients with respiratory tract or gastrointestinal infections admitted from April to May in 2015 to 2019 and 2020. A Poisson regression model was used to analyze them. Results: The study participants included 1649 patients with KD (median [interquartile range] age, 25 [13-43] months; 901 boys [54.6%]) and 15 586 patients with infectious disease (data on age and sex were not available for these patients). The number of admissions for KD showed no significant change between April and May in 2015 to 2019 vs the same months in 2020 (mean [SD], 24.8 [5.6] vs 18.0 [4.0] admissions per month; 27.4% decrease; adjusted incidence rate ratio [aIRR], 0.73; 95% CI, 0.48-1.10; P = .12). However, the number of admissions for droplet-transmitted or contact-transmitted respiratory tract infections (mean [SD], 157.6 [14.4] vs 39.0 [15.0] admissions per month; 75.3% decrease; aIRR, 0.25; 95% CI, 0.17-0.35; P < .001) and gastrointestinal infections (mean [SD], 43.8 [12.9] vs 6.0 [2.0] admissions per month; 86.3% decrease; aIRR, 0.14; 95% CI, 0.04-0.43; P < .001) showed significant decreases between April and May in 2015 to 2019 vs the same months in 2020 (total, 12 254 infections). Thus, the ratio of KD to droplet- or contact-transmitted respiratory tract and gastrointestinal infections incidence in April and May 2020 was significantly increased (ratio, 0.40 vs 0.12; χ21 = 22.76; P < .001). Conclusions and Relevance: In this study, the significantly increased incidence of KD compared with respiratory tract and gastrointestinal infections during the COVID-19 state of emergency suggests that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne infections in most cases.

GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons.

Developmental and epileptic encephalopathy (DEE) represents a group of neurodevelopmental disorders characterized by infantile-onset intractable seizures and unfavorable prognosis of psychomotor development. To date, hundreds of genes have been linked to the onset of DEE. GNAO1 is a DEE-associated gene encoding the alpha-O1 subunit of guanine nucleotide-binding protein (GαO ). Despite the increasing number of reported children with GNAO1 encephalopathy, the molecular mechanisms underlying their neurodevelopmental phenotypes remain elusive. We herein present that co-immunoprecipitation and mass spectrometry analyses identified another DEE-associated protein, SPTAN1, as an interacting partner of GαO . Silencing of endogenous Gnao1 attenuated the neurite outgrowth and calcium-dependent signaling. Inactivation of GNAO1 in human-induced pluripotent stem cells gave rise to anomalous brain organoids that only weakly expressed SPTAN1 and Ankyrin-G. Furthermore, GNAO1-deficient organoids failed to conduct synchronized firing to adjacent neurons. These data indicate that GαO and other DEE-associated proteins organize the cytoskeletal remodeling and functional polarity of neurons in the developing brain.

De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature.

BACKGROUND: The collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations. CASE REPORT: We report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge. RESULTS: Targeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy. CONCLUSIONS: This case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age.

Decision-making dilemmas of paediatricians: a qualitative study in Japan.

OBJECTIVE: To delineate the critical decision-making processes that paediatricians apply when treating children with life-threatening conditions and the psychosocial experience of paediatricians involved in such care. DESIGN: We conducted semistructured, individual face-to-face interviews for each participant from 2014 to 2015. The content of each interview was subjected to a comprehensive qualitative analysis. The categories of dilemma were extracted from a second-round content analysis. PARTICIPANTS: Participants were board-certified paediatricians with sufficient experience in making decisions in relation to children with severe illnesses or disabilities. We repeated purposive sampling and analyses until we reached saturation of the category data. RESULTS: We performed interviews with 15 paediatricians. They each reported both unique and overlapping categories of dilemmas that they encountered when making critical decisions. The dilemmas included five types of causal elements: (1) paediatricians' convictions; (2) the quest for the best interests of patients; (3) the quest for medically appropriate plans; (4) confronting parents and families and (5) socioenvironmental issues. Dilemmas occurred and developed as conflicting interactions among these five elements. We further categorised these five elements into three principal domains: the decision-maker (decider); consensus making among families, colleagues and society (process) and the consequential output of the decision (consequence). CONCLUSIONS: This is the first qualitative study to demonstrate the framework of paediatricians' decision-making processes and the complex structures of dilemmas they face. Our data indicate the necessity of establishing and implementing an effective support system for paediatricians, such as structured professional education and arguments for creating social consensus that assist them to reach the best plan for the management of severely ill children.

An acute encephalopathy with reduced diffusion in BRAF-associated cardio-facio-cutaneous syndrome.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder characterized by cardiovascular anomalies, dysmorphic faces, ectodermal abnormalities and developmental delays. Mutations in BRAF and other RAS-MAPK pathway-associated genes are commonly identified in patients with CFCS. While this molecular pathway is known to be associated with neuro-inflammatory conditions, only one case with CFCS has been reported thus far to develop acute encephalopathy in childhood. CASE REPORT: A 3-year-old boy with dysmorphic features and mild psychomotor delay developed acute encephalopathy. After a 45-min long, generalized seizure, the magnetic resonance imaging revealed that the restricted diffusion signals spread to the bilateral subcortical white matters on day 1 of illness. Despite the 14 days of intensive care, the acute symptoms of encephalopathy left him intractable epilepsy and severe neurocognitive impairments. The whole-exome sequencing analysis identified a de novo heterozygous mutation of BRAF (NM_004333:p.Thr241Met) in this case. CONCLUSION: The present case suggests that the hyperactive condition of ERK signals might augment the development of acute encephalopathy and post-encephalopathic epilepsy in childhood.

Early Intervention With Adrenocorticotropin for Acute Encephalopathy-Associated Epileptic Spasms: Report of Two Cases.

PURPOSE: Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) is a leading cause of childhood-onset encephalopathy in Japan. Children with AESD frequently develop intractable epilepsy, whereas their treatment options remain to be determined. METHOD: We present 2 unrelated girls, who developed AESD at 25 months (case 1) and 12 months of age (case 2). Both cases underwent intensive cares from the first day of illness, whereas severe neurological impairments were left on discharge. They showed repeated signs of epileptic spasms at 2 months (case 1) and 8 months (case 2) after the onset of AESD. Video-monitoring electroencephalograms (EEG) detected the recurrent attacks accompanying slow-wave bursts and transient suppressions of the precedent epileptiform discharges, as typically observed in epileptic spasms. RESULTS: Intramuscular injection of adrenocorticotropic hormone (ACTH, 0.0125 mg/kg/d) was introduced within 1 month from the onset of epileptic spasms and continued for 2 weeks. The ACTH treatment disrupted the paroxysmal activity in EEG, and it has relieved these patients from epileptic seizures for more than 1 year. CONCLUSION: This report illustrates the potential efficacy of ACTH for a group of children with epileptic spasms after AESD.

Vascular pathomechanism in acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood-onset encephalopathy, but the precise pathophysiology remains unclear. We encountered a child with Moyamoya syndrome and AESD. He exhibited left-predominant stenosis of the middle cerebral artery (MCA), and later developed broad lesions in the left hemisphere, raising the possibility that insufficient blood supply relates to formation of the lesions. To test the hypothesis, we investigated the relationship between MCA volume and lesion extent in seven AESD children without preexisting diseases. The MCA volume and lesion extent were quantified with time of flight images for construction of magnetic resonance angiography and apparent diffusion coefficient maps, respectively. Lateralization indices ([right - left]/[right + left]) of the MCA volume and lesion extent were calculated. We found that the lateralization indices were negatively correlated (r = -0.786, p = .036), that is, when the MCA volume was smaller in one side than the other side, the lesions were likely to develop more extensively in the ipsilateral side than the contralateral side. This indicates the association of insufficient blood supply with the lesions. The present study provides the first observation to suggest the involvement of vascular mechanism in AESD and has potential implications for novel therapeutic approach.

A rightward saccade to an unexpected stimulus as a marker for lateralised visuospatial attention.

The human brain is lateralised to the right for visuospatial attention, particularly when reorienting attention to unexpected stimuli. However, the developmental characteristics of lateralisation remain unclear. To address this question, we devised a saccade task applicable for both adults and children. To assess the utility of this system, we investigated the correlation between line bisection test performance and the saccade task for 54 healthy adult volunteers. Participants followed a visual target that jumped 10 times, alternating between two fixed positions across the midline with a constant pace. In both the rightward and leftward directions, saccadic reaction time (RT) to the target jump decreased and reached a plateau from the first to the tenth jumps. Furthermore, we obtained the time required for reorienting in the contralateral hemisphere using the corrected value of the first RT. We found that longer corrected RTs in the rightward saccade were associated with greater deviation to the left in the line bisection task. This correlation was not observed for leftward saccades. Thus, corrected RTs in rightward saccades reflected the strength of individual hemispheric lateralisation. In conclusion, the rightward saccade task provides a suitable marker for lateralised visuospatial attention, and for investigating the development of lateralisation.

Predictive indicators for the development of epilepsy after acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a newly defined clinicoradiologic syndrome characterized by biphasic seizures and altered consciousness followed by restricted diffusion in the white matter on magnetic resonance imaging in acute phase. Intractable epilepsy commonly occurs as the late complication. This study aimed to search predisposing factors to the development of epilepsy after AESD. Consecutively treated 22 patients with AESD in our institution from 2006 to 2016 were grouped into those with post-encephalopathic epilepsy (PEE, n = 10) or without PEE (n = 12). There was no difference between two groups in age at the onset of AESD, duration of the initial seizures, or the follow-up periods after discharge. PEE group patients more frequently showed coma or involuntary movements during the course of AESD than non-PEE group patients (36% vs. 8%, p = 0.008). The quantitative analysis of apparent diffusion coefficient (ADC) map revealed that PEE group showed broader areas with reduced diffusion in the posterior lobes at the onsets of AESD than non-PEE group (0.113 vs. 0.013, p = 0.035). On the other hand, the atrophy on day 30-ADC map did not correlate with the development or control of epilepsy. These results suggest that the clinical severity and ADC profiles in acute phase, rather than the brain atrophy in convalescent phase, may predict the development of post-AESD epilepsy.

Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2.

Advance in the exome-wide sequencing analysis contributes to identifying hundreds of genes that are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders. On the basis of massive sequencing data, functional interactions among different genes are suggested to explain the common molecular pathway underlying the pathogenic process of these disorders. However, the relevance of such interactions with the phenotypic severity or variety in an affected individual remains elusive. In this report, we present a 45-year-old woman with neurofibromatosis type 1 (NF1), infantile-onset epileptic encephalopathy, and severe developmental delay. Whole-exome sequencing identified de novo pathogenic mutations in NF1 and the Schaaf-Yang syndrome-associated gene, MAGEL2. Literature-curated interaction data predicted that NF1 and MAGEL2 proteins were closely connected in this network via their common interacting proteins. Direct conversion of fibroblasts into neurons in vitro showed that neuronal cells from 9 patients with NF1 expressed significantly lower levels of MAGEL2 (54%, p = 0.0047) than those from healthy individuals. These data provide the first evidence that pathogenic mutations of NF1 deregulate the expression of other neurodevelopmental disease-associated genes. De novo mutations in multiple genes may lead to severe developmental phenotypes through their cumulative effects or synergistic interactions.

A male case with CDKL5-associated encephalopathy manifesting transient methylmalonic acidemia.

Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive. We herein report a 16-year-old boy, who suffered from intractable seizures 20 days after birth. Serial electroencephalograms detected recurrent focal epileptiform discharges from age 4 months, which evolved to hypsarrhythmia later in infancy. Mass-spectrometric analyses revealed increase in urinary excretion of methylmalonic acid without perturbed concentrations of propionic acid, homocystein and methionine. Whole-exome sequencing identified a de novo, truncating mutation in CDKL5 (NM_003159.2:c.419dupA, p.Asn140Lysfs*8). Targeted sequencing excluded concomitant mutations in methylmalonic academia-associated genes. No methylmalonic acidemia has been reported in children with CDKL5 disorder. Extensive analyses on organic acid metabolism for males with CDKL5 mutations will gain more insight into their biochemical profiles in infancy.

Sustained endocrine profiles of a girl with WAGR syndrome.

BACKGROUND: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined. CASE PRESENTATION: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions. CONCLUSIONS: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.

A childhood-onset intestinal toxemia botulism during chemotherapy for relapsed acute leukemia.

BACKGROUND: Botulism is a potentially fatal infection characterized by progressive muscle weakness, bulbar paralysis, constipation and other autonomic dysfunctions. A recent report suggested that cancer chemotherapy might increase the risk for the intestinal toxemia botulism in both adults and children. CASE PRESENTATION: We report a 5-year-old boy, who developed general muscle weakness, constipation, ptosis and mydriasis during the third induction therapy for relapsed acute myeloid leukemia. He had recent histories of multiple antibiotic therapy for bacteremia and intake of well water at home. Repeated bacterial cultures identified Clostridium botulinum producing botulinum neurotoxin A. Botulinum toxin A was isolated from his stools at 17, 21, and 23 days after the onset. Symptoms were self-limiting, and were fully recovered without anti-botulinum toxin globulin therapy. CONCLUSION: This is the second report of a pediatric case with cancer chemotherapy-associated intestinal toxemia botulism. Our case provides further evidence that the immunocompromised status due to anti-cancer treatments increases the risk for the development of botulism at all ages in childhood.

High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats.

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14-15-day-old male rats were divided into four groups: high-dose HMGB1 (100 µg), moderate-dose (10 µg), low-dose (1 µg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10-11-day-old rats were divided into four groups: pHS + HMGB1 (10 µg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.

Transient dysautonomia in an acute phase of encephalopathy with biphasic seizures and late reduced diffusion.

Paroxysmal sympathetic hyperactivity (PSH) is a dysautonomic condition that is associated with various types of acquired brain injuries. Traumatic brain lesions have been documented as the leading cause of PSH. However, detailed clinical features of pediatric PSH caused by intrinsic brain lesions remain to be elusive. We present a 3-year-old boy, who had been diagnosed as having cerebral palsy, developmental delay and epilepsy after perinatal hypoxia-induced brain injury. He developed status epilepticus with fever on the third day of respiratory infection. Whereas the seizure was terminated by systemic infusion of midazolam, consciousness remained disturbed for the next 48h. Serial magnetic resonance imaging studies revealed that acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) evolved on 3days after the seizure. Therapeutic hypothermia was immediately introduced, however, the brain lesion extended to the whole subcortical white matters on day 8. The intermittent bilateral dilation of pupils with increased blood pressure and tachycardia were observed until day 12. Real-time monitoring of electroencephalograms ruled out the recurrent attacks of seizures. The abnormal signs of autonomic nervous system gradually ceased and never relapsed after recovery from the hypothermia. PSH or a transient condition of dysautonomia may emerge and persist during the acute phase of AESD.

Involuntary movements and coma as the prognostic marker for acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) occurs in children associated with infection. It is characterized by a prolonged febrile seizure in the first phase, and a cluster of seizures, deterioration of consciousness and the white matter lesions with reduced diffusion in the second phase. The patients often have severe neurological sequelae, but the prognostic indicators remain unknown. The present study aimed to clarify the characteristics of AESD patients who subsequently exhibited severe neurological sequelae. We retrospectively analyzed the clinical and laboratory findings along with the brain imaging in patients who had severe (n=8) and non-severe neurodevelopmental outcomes (n=12). Severe group more frequently showed coma (p=0.014) or involuntary movements including dystonia and oral dyskinesia (p=0.018) before the second phase than non-severe group. Severe group exhibited higher levels of serum alanine aminotransferase than non-severe group (p=0.001). Quantitatively assessed MRI in the second phase revealed that severe group had more extensive lesions than non-severe group, in the anterior (p=0.015) and posterior parts (p=0.011) of the cerebrum and basal ganglia (p=0.020). Early appearing involuntary movements or coma might account for the extension of acute brain lesions and the poor neurological outcomes in AESD patients.

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis.

BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder that manifests recurrent attacks of hemiplegia, oculogyric, and choreoathetotic involuntary movements. De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes. It remains to be determined whether or not a rare mutation in ATP1A3 may cause atypical phenotypes. CASE PRESENTATION: A 7-year-old boy presented with recurrent symptoms of generalized paralysis since 1 year and 5 months of age. Hypotonia, dystonia, and choreoathetosis persisted with exacerbation under febrile conditions, but no cerebellar ataxia had ever evolved in 6 years. Whole-exome sequencing (WES) was performed to determine his genetic background, and mutations were validated by the Sanger method. Crude protein extracts were prepared from the cultured cells, and expression of the wild-type or mutant ATP1A3 proteins were analyzed by Western blotting. WES identified a de novo pathogenic mutation in ATP1A3 (c.2266C > T:p.R756C) for this patient. A literature overview of two reported cases with p.R756C and p.R756H mutations showed both overlapping and distinct phenotypes when compared with those of the present case. The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins. CONCLUSIONS: This study confirmed that p.R756C mutation of ATP1A3 cause atypical forms of AHC-associated disorders. The wide spectra of neurological phenotypes in AHC are linked to as-yet-unknown deficits in the functions of mutant ATP1A3.