Tony McShane

Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis

In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.

Childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study

BACKGROUND Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. METHODS Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture-recapture analysis was used to estimate completeness of ascertainment. FINDINGS We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100 000 per year (95% CI 1·30-1·96). Capture-recapture analysis suggested that case ascertainment was 89% (95% CI 77-97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100 000 per year, 95% CI 2·36-6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100 000 per year [95% CI 1·18-2·12] for boys and 1·61 per 100 000 per year [1·18-2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11-3·85; p=0·017) and black (2·28, 1·00-4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. INTERPRETATION Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. FUNDING The Stroke Association, UK.

Diagnostic delays in paediatric stroke

Background Stroke is a major cause of mortality in children. Conditions that mimic stroke also cause severe morbidity and require prompt diagnosis and treatment. We have investigated the time to diagnosis in a cohort of children with stroke. Methods A population-based cohort of children with stroke was prospectively identified in the south of England. Case notes, electronic hospital admission databases and radiology records were reviewed. Timing of symptom onset, presentation to hospital, first neuroimaging, first diagnostic neuroimaging and presenting clinical features were recorded. Results Ninety-six children with an arterial ischaemic stroke (AIS) and 43 with a haemorrhagic stroke (HS) were identified. The median time from symptom onset to diagnostic neuroimaging was 24.3 h in AIS and 2.9 h in HS. The initial imaging modality was CT in 68% of cases of AIS. CT was diagnostic of AIS in 66% of cases. MRI was diagnostic in 100%. If initial neuroimaging was non-diagnostic in AIS, then median time to diagnosis was 44 h. CT was diagnostic in 95% of HS cases. Presentation outside normal working hours resulted in delayed neuroimaging in AIS (13 vs 3 h, p=0.032). Diffuse neurological signs or a Glasgow Coma Scale <9 resulted in more expeditious neuroimaging in both HS and AIS. Conclusions The diagnosis of AIS in children is delayed at every stage of the pathway but most profoundly when the first neuroimaging is CT scanning, which is non-diagnostic. MRI should be the initial imaging modality of choice in any suspected case of childhood AIS.

Early use of high‐dose riboflavin in a case of Brown–Vialetto–Van Laere syndrome

Brown–Vialetto–Van Laere syndrome (BVVLS) is a genetic condition caused by a mutation in the C20orf54 gene, which also codes for an intestinal riboflavin transporter. We report the case of a female who presented at 22 months with acute‐onset stridor and generalized muscle weakness, in whom a genetic diagnosis of BVVLS was made, and whose symptoms improved on therapy with high‐dose riboflavin. She had previously been developing normally and was able to walk at 11 months, then developed progressive muscle weakness at 22 months, and within 2 weeks was unable to sit without support. She also demonstrated stridor and paradoxical breathing indicating diaphragmatic weakness, and required continuous non‐invasive ventilation (NIV) through a tracheostomy. After treatment with riboflavin she was able to walk unaided, and her Gross Motor Functional Classification level improved from level IV to level I, having fully regained the motor function she showed before symptom onset. There were no longer signs of diaphragmatic paralysis while on NIV, and she was able to tolerate 10‐minute periods off NIV before paradoxical breathing again became apparent. We therefore recommend that in all cases suspected to be in the BVVLS or Fazio–Londe spectrum, early treatment with high‐dose riboflavin must be considered.

Outcome and recurrence one year after paediatric arterial ischaemic stroke in a population-based cohort

Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population‐based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population‐based cohort.

Milder phenotypes of glucose transporter type 1 deficiency syndrome

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile‐onset epilepsy and severe developmental delay. Non‐classical phenotypes with movement disorders and early‐onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose<2.2mmol/l) in the presence of normoglycaemia with a CSF/blood glucose ratio of less than 0.4. GLUT1DS is due to a mutation in the solute carrier family 2, member 1 gene (SLC2A1). We present five individuals (four males, one female), all of whom had a mild phenotype, highlighting the importance of considering this diagnosis in unexplained neurological disorders associated with mild learning difficulties, subtle motor delay, early‐onset absence epilepsy, fluctuating gait disorders, and/or dystonia. The mean age at diagnosis was 8 years 8 months. This paper also shows phenotypical parallels between GLUT1DS and paroxysmal exertion‐induced dyskinesia.

GNAO1 encephalopathy Broadening the phenotype and evaluating treatment and outcome

Objective: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. Methods: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. Results: Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. Conclusions: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

Isolated paediatric neurosarcoidosis presenting as epilepsia partialis continua: A case report and review of literature

Isolated paediatric neurosarcoidosis (IPN) is exceptionally rare and only seven cases have been reported so far in the literature. We report the clinical and radiological profile of a 7 year-old boy with epilepsia partialis continua (EPC) who was initially thought to have Acute Disseminated Encephalomyelitis (ADEM), but was subsequently found to have isolated neurosarcoidosis. Additionally, we performed a literature search on Medline and Embase and secondary sources of data such as reference list of articles reviewed. Whilst cranial neuropathy is the commonest presenting feature in adults with neurosarcoidosis, paediatric patients are more likely to present with seizures. Diagnosis presents a clinical challenge as a result of its protean manifestations. Due to its rarity, there remains a lack of evidence base to inform the best choice of treatment for these children. Our patient was successfully treated with a combination of various immunomodulants.

Factors associated with serious skin reactions in children aged 12 years and under taking lamotrigine

aged 12 years and under taking lamotrigine’ The incidence of serious skin reactions, irrespective of cause, in children aged ≤ 12 years taking lamotrigine has been reported as being between 1 in 300 and 1 in 1001. We reviewed all such cases identified from clinical add-on trials. Several factors associated with the skin reactions were identified; the importance of each has yet to be determined. However, avoiding some of these factors might increase the safety of prescribing lamotrigine in children. Ten children with serious skin reactions were identified from 967 children, aged ≤ 12 years, who were documented in clinical add-on trials. We were fortunate in being given full access, by the pharmaceutical company, to the limited data provided by clinicians participating in these international trials. However, we had no control over the quality of the data collected and in many cases further detail, such as an opinion from a dermatologist examining the child, would have been helpful. Serious skin reaction was defined as a rash leading to hospitalization and any case identified by the reporting clinician as possible Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Of the 10 children identified, nine were admitted to hospital. Five were diagnosed with possible Stevens–Johnson syndrome but none was reported as having been confirmed by a dermatologist. One of these five children was not admitted to hospital. No cases of TEN were identified. There was one fatality which was attributed to an identified viral infection and not to lamotrigine. In all 10 children, we identified one or more associated factors which may have contributed to the skin reactions, such as higher initial dose or more rapid dose escalation than currently recommended by manufacturers (eight children), viral infection (two children), and use of antibiotics known to cause skin reactions (four children). The symptoms may have been less severe if lamotrigine had been discontinued at the first sign of hypersensitivity or rash (three children). Eight of the 10 children who had serious skin reactions were taking sodium valproate as co-medication, suggesting that this is a significant risk factor. Sodium valproate prolongs the half-life of lamotrigine, raising the plasma level for a given dose. The available data suggest that the risk of skin reactions, including those described as serious, may be significantly reduced by using a sufficiently slow escalation of the lamotrigine dose. We strongly advise that the starting doses and escalation rates should be no higher than those recommended by the manufacturer, particularly when lamotrigine is used in combination with sodium valproate (Tables I and II)2. Any patient who develops a skin rash in the early weeks of treatment should be evaluated promptly and lamotrigine should be stopped immediately unless the reaction is clearly not related to the

Paediatric video-telemetry safety survey

Synchronous video and EEG recording is carried out when there is a desire to correlate the clinical behaviour of a child with their EEG activity;1 this is known as video-telemetry (VT). After a death during paediatric VT in 2010, the British Paediatric Epilepsy Group (BPEG), a subgroup of the British Paediatric Neurology Association (BPNA) surveyed members about their current practice for VT monitoring. A Medline search revealed few previous publications on this topic.1,–,3 Following a preliminary paper survey, we used the online system ‘Survey Monkey’4 to ask all BPNA BPEG members to complete a simple questionnaire. Nine of 16 units replied, giving a response rate of 56%. The indications described for VT were