Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency.

AIM: We report on seizures, paroxysmal events, and electroencephalogram (EEG) findings in four female infants with pyridoxine-dependent epilepsy (PDE) and in one female with pyridoxine phosphate oxidase deficiency (PNPO). METHOD: Videos and EEGs were analysed and compared with videos of seizures and paroxysmal events archived from 140 neonates. PDE and PNPO were proven by complete control of seizures once pyridoxine or pyridoxal 5'-phosphate was administered and by recurrence when withdrawn. Mutations in the antiquitin gene were found in three patients and in the PNPO gene in one child. RESULTS: Seizures began within 48 hours after birth in four newborns and at age 3 weeks in one. Frequent multifocal and generalized myoclonic jerks, often intermixed with tonic symptoms, abnormal eye movement, grimacing, or irritability, were observed in all infants with PDE and PNPO, but rarely in the other archived videos of neonates. EEGs were inconstant and frequently no discernable ictal changes were recorded during the seizures and the paroxysmal events. In addition, interictal EEGs were inconclusive, with normal and abnormal recordings. In older children tonic-clonic seizures, abnormal behaviour, inconsolable crying, frightened facial expression, sleep disturbance, loss of consciousness, paraesthesia, or intermittent visual symptoms were described during controlled and uncontrolled withdrawal or insufficient dosage. INTERPRETATION: PDE or PNPO should be considered in infants with prolonged episodes of mixed multifocal myoclonic tonic symptoms, notably when associated with grimacing and abnormal eye movements.

Cerebral sinus venous thrombosis in Swiss children.

UNLABELLED: AIMo describe the characteristics of paediatric cerebral sinus venous thrombosis (CSVT) in Switzerland. METHOD: data on clinical features, neuroimaging, risk factors, and treatment were collected for all children in Switzerland younger than 16 years of age who had CSVT between January 2000 and December 2008. A follow-up examination and a cognitive assessment were performed (mean follow-up period 26mo). Differences between neonates and children (patients older than 28d) were assessed and predictors of outcome were determined. RESULTS: twenty-one neonates (14 males, seven females; mean age 9d, SD 8d) and 44 children (30 males, 14 females; mean age 8y 7mo, SD 4y 5mo) were reported. The incidence of paediatric CSVT in Switzerland was 0.558 per 100000 per year. In neonates, the deep venous system was more often involved and parenchymal injuries were more common. The strongest predictor of poor outcome was neonatal age (odds ratio 17.8, 95% confidence interval 0.847-372.353). Most children showed global cognitive abilities within the normal range, but impairments in single cognitive subdomains were frequent. INTERPRETATION: paediatric CSVT is rare. Its outcome is poor in neonates. Most children have good neurological outcomes, but some patients have individual neuropsychological impairments.

Neuroimaging in childhood arterial ischaemic stroke: evaluation of imaging modalities and aetiologies.

AIM: The aim of this study was to describe neuroimaging patterns associated with arterial ischaemic stroke (AIS) in childhood and to differentiate them according to stroke aetiology. METHOD: Clinical and neuroimaging (acute and follow-up) findings were analysed prospectively in 79 children (48 males, 31 females) aged 2 months to 15 years 8 months (median 5 y 3 mo) at the time of stroke by the Swiss Neuropaediatric Stroke Registry from 2000 to 2006. RESULTS: Stroke was confirmed in the acute period in 36 out of 41 children who underwent computed tomography, in 53 of 57 who underwent T2-weighted magnetic resonance imaging (MRI) and in all 48 children who underwent diffusion-weighted MRI. AIS occurred in the anterior cerebral artery (ACA) in 63 participants and in all cases was associated with lesions of the middle cerebral artery (MCA). The lesion was cortical-subcortical in 30 out of 63 children, cortical in 25 out of 63, and subcortical in 8 of 63 children. Among participants with AIS in the posterior circulation territory, the stroke was cortical-subcortical in 8 out of 16, cortical in 5 of 16, and thalamic in 3 out of 16 children. INTERPRETATION: AIS mainly involves the anterior circulation territory, with both the ACA and the MCA being affected. The classification of Ganesan is an appropriate population-based classification for our Swiss cohort, but the neuroimaging pattern alone is insufficient to determine the aetiology of stroke in a paediatric population. The results show a poor correlation between lesion pattern and aetiology.

Incidence and outcomes of symptomatic neonatal arterial ischemic stroke.

BACKGROUND AND OBJECTIVES: Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. METHODS: This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. RESULTS: One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11-17) per 100,000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. CONCLUSIONS: NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.

Factors affecting cognitive outcome in early pediatric stroke.

OBJECTIVE: We examined cognitive performance in children after stroke to study the influence of age at stroke, seizures, lesion characteristics, neurologic impairment (NI), and functional outcome on cognitive outcome. METHODS: This was a prospectively designed study conducted in 99 children who sustained an arterial ischemic stroke (AIS) between the age of 1 month and 16 years. All children underwent cognitive and neurologic follow-up examination sessions 2 years after the insult. Cognitive development was assessed with age-appropriate instruments. RESULTS: Although mean cognitive performance was in the lower normative range, we found poorer results in subtests measuring visuoconstructive skills, short-term memory, and processing speed. Risk factors for negative cognitive outcome were young age at stroke, seizures, combined lesion location (cortical and subcortical), as well as marked NI. CONCLUSIONS: We recommend that all children with a history of AIS undergo regularly scheduled neuropsychological assessment to ensure implementation of appropriate interventions and environmental adjustments as early as possible.