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Adenylosuccinase deficiency is a rare inborn error of metabolism. We present a newborn who died at 52 days of age with clinical features suggestive of severe epileptic encephalopathy and leukodystrophy of unknown cause. Post-mortem examination showed an unusual vacuolar appearance of the brain. A molecular autopsy performed via singleton clinical exome analysis revealed a known pathogenic and a variant of uncertain significance in ADSL that encodes adenylosuccinase. Tests on previously stored plasma samples showed elevated succinyladenosine and succinylaminoimidazole carboxamide riboside levels. Adenylosuccinase activity in stored fibroblasts was only similar to 5% of control confirming the diagnosis of adenylosuccinase deficiency in the child. The parents opted for a chorionic villus biopsy in a subsequent pregnancy and had a child unaffected by adenylosuccinase deficiency. This report adds vacuolating leukodystrophy as a novel feature of adenylosuccinase deficiency and shows the power of biochemical investigations directed by genomic studies to achieve accurate diagnosis. Importantly, this case demonstrates the importance of anticipatory banking of biological samples for reverse biochemical phenotyping in individuals with undiagnosed disorders who may not survive.

Acute Encephalopathy with Reduced Subcortical Diffusion or AED is a unique subtype of acute paediatric encephalopathy which presents with altered mental status, prolonged seizures and developing characteristic radiological signal changes within the subcortical white matter. Reports of such cases have mainly been from Japan (Takanashi, 2009) and this radiological finding has been recognised as a novel feature of AED. We present three paediatric cases from a tertiary paediatric neurosciences centre in Manchester (Royal Manchester Children's hospital) with characteristic subcortical signal change, and furthermore, follow up imaging which in all 3 patients demonstrated a varying degree of cerebral atrophy. We recommend that children presenting with prolonged seizures should be considered for MR imaging ideally after 48hours if clinically stable, and early MR imaging follow-up (at 2-3 months) be performed routinely in patients with AED to assess for presence and degree of parenchymal volume loss for prognostication and to start neuroprotective therapy.

Neurofibromatosis type 1 (NF1) manifests itself in many ways in the spine. This study aims to report the types of spinal lesions, clinical and demographic data in a large cohort from a complex NF1 centre. The characteristics of those with spinal neurofibromatosis, where neurofibromas are present on every spinal nerve root, were sought for comparison with the wider group of NF1 patients. This is a retrospective review of MDT minutes of 303 patients from a UK NF1 centre and the largest reported series of NF1 patients based on radiological data. Prevalence of each symptom and lesion was calculated and statistically significant associations were established. The most reported findings were cutaneous lesions (44.9%) and neurological deficit (27.4%). 28.4% had dural ectasia, 52.5% had some form of spinal deformity. 57.8% had spinal nerve root tumours, the most common of which were at C2. The most progressive lesions were spinal nerve root tumours (29.1%). The only statistically significant association found was between dural ectasia and spinal deformity (P 0.003), where dural ectasia is associated with a 32.6% increase in spinal deformity incidence. This is the largest descriptive study of spinal lesions in NF1. Spinal tumours and spinal deformity are prevalent in NF1. The predilection of spinal tumours for flexible spinal regions suggests that repetitive movement might be an important factor in pathogenesis. Physicians and patients should be alert to the observation that although many spinal neurofibromatosis patients display no neurological deficit, they often have significant lesions which require monitoring and sometimes surgery.

Neurofibromatosis 1 (NF1) is a single gene disorder associated with working Memory (WM) impairments. The aim of this study was to investigate P300 event-related potential (ERP) associated with WM in NF1. Sixteen adolescents with NF1 were compared with controls on measures of WM and EEG was recorded during a WM nback task. The NF1 group showed poorer performance on measures of WM as compared to the control group. No group differences were observed in P300 amplitude at Pz, but P300 latency was shorter in the NF1 group. Topographic analyses of P300 amplitude showed group differences indicating neural processing differences in the NF1 group relative to controls, which possibly contribute to the cognitive deficits seen in this population.

Introduction Neurofibromatosis 1 (NF1) is a single-gene disorder associated with cognitive impairments, particularly with deficits in working memory. Prior research indicates that brain structure is affected in NF1, but it is unclear how these changes relate to aspects of cognition. Methods 29 adolescents aged 11-17 years were compared to age and sex-matched controls. NF1 subjects were assessed using detailed multimodal measurements of working memory at baseline followed by a 3T MR scan. A voxel-based morphometry approach was used to estimate the total and regional gray matter(GM) volumetric differences between the NF1 and control groups. The working memory metrics were subjected to a principal component analysis (PCA) approach. Results The NF1 groups showed increased gray matter volumes in the thalamus, corpus striatum, dorsal midbrain and cerebellum bilaterally in the NF1 group as compared to controls. Principal component analysis on the working memory metrics in the NF1 group yielded three independent factors reflecting high memory load, low memory load and auditory working memory. Correlation analyses revealed that increased volume of posterior cingulate cortex, a key component of the default mode network (DMN) was significantly associated with poorer performance on low working memory load tasks. Conclusion These results are consistent with prior work showing larger subcortical brain volumes in the NF1 cohort. The strong association between posterior cingulate cortex volume and performance on low memory load conditions supports hypotheses of deficient DMN structural development, which in turn may contribute to the cognitive impairments in NF1.

We report on the location, symptoms, and management of plexiform neurofibroma (PN) in children with Neurofibromatosis Type 1 (NF1) attending the 2 National Complex Neurofibromatosis 1 Services at Guy's and St. Thomas' NHS Foundation Trust, London and St Mary's Hospital, Manchester. Retrospective data collection was performed from patient chart reviews from April 2018 to April 2019. There were 127 NF1 patients with PN, age range 0.8-17.0, mean age was 9.9 years (SD ± 4.2 years). The main location of the PN was craniofacial in 35%, and limb in 19%. Disfigurement was present in 57%, pain in 28%, impairment of function in 23%, and threat to function in 9% of children. Fifty-four percent of patients were managed conservatively, 28% surgically, and 19% are either taking or due to start a mitogen-activated protein kinase kinase (MEK) inhibitor (selumetinib or trametinib), either through a clinical trial or compassionate usage scheme. This national study provides a comprehensive overview of the management of children with PN in an era where new therapies (MEK inhibitors) are becoming more widely available. We anticipate that there will be a shift to more patients receiving MEK inhibitor therapy and combination therapy (surgery and MEK inhibitor) in the future.

BackgroundNeurofibromatosis 1 (NF1) is a single-gene neurodevelopmental disorder associated with cognitive and behavioural impairments, particularly with deficits in working memory. This study investigates the cerebral volumetric differences in adolescents with NF1 as compared to typically developing controls and how working memory task performance is associated with these differences.Methods31 adolescents aged 11-17 years were compared to age and sex-matched controls. NF1 subjects were assessed using detailed measurement of working memory at baseline followed by a 3T MR scan. A voxel-based morphometry approach was used to estimate the total and regional gray matter volumetric differences between the NF1 and control groups. The working memory metrics were subjected to a principal component analysis (PCA) approach. Finally, we examined how the components derived from PCA correlated with the changes in gray matter volume in the NF1 group, after adjusting for age, sex and total intracranial volume.ResultsThe NF1 cohort showed increased gray matter volumes in the thalamus, globus pallidus, caudate, putamen, dorsal midbrain and cerebellum bilaterally as compared to controls. The PCA yielded three independent behavioural components reflecting high memory load, low memory load and auditory working memory. Correlation analyses revealed that increased volume of the inferior lateral parietal cortex was associated with poorer performance on the high working memory load tasks. Increased volume of posterior cingulate cortex, a key component of the default mode network (DMN) was significantly associated with poorer performance on low working memory load tasks.DiscussionThis is the first study to examine the neuroanatomical correlates of working memory in NF1 adolescents. Consistent with prior literature we show larger subcortical brain volumes in in the NF1 cohort. The strong association between posterior cingulate cortex volume and performance on low memory load conditions supports previously suggested hypotheses of deficient DMN structural development, which in turn may contribute to the cognitive impairments in NF1.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

International audience; The impact of the Neurofibromatosis type 1 (NF1) on cognition have been subject to much clinical investigation, but environmental modifiers of disease expression have not yet been systematically investigated. The aim of this paper is to determine the role of demographic and environmental factors such as age, sex, socioeconomic status, parental NF1 status and neurological complications on the cognitive, behavioural and academic outcomes in NF1. Participants included 206 children aged 4-18 years seen within the Manchester clinical research NF1 service. Multiple linear regression models were used to study the effect of the hypothesized predictor variables on cognitive, behavioural and academic outcomes. Relative to population norms, 80% of the NF1 sample demonstrated significantly lower scores in at least one cognitive, behavioural or academic domains. Family history of NF1 and lower SES were independently associated with poorer cognitive, behavioural and academic outcomes. Neurological problems such as epilepsy and hydrocephalus were associated with lower IQ and academic skills. Cognitive and behavioural phenotypes emerge commonly via a complex interplay between genes and environmental factors, and this is true also of a monogenic condition such as NF1. Early interventions and remedial education may be targeted to risk groups such those with familial NF1, families with lower SES and those with associated neurological comorbidities.

Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi-quantitative flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-QTOF/MS) N-glycan assay, we report subtle abnormalities in N-glycans that normally account for

Background Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design. Methods A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death. Results Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting 40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004). Conclusion Understanding disease course improves prognostication, allowing for better-informed decisions about care.

ObjectiveTo describe characteristics and course of a large UK cohort of children with moyamoya from multiple centers and examine prognostic predictors.MethodsRetrospective review of case notes/radiology, with use of logistic regression to explore predictors of outcome.ResultsEighty-eight children (median presentation age 5.1 years) were included. Thirty-six presented with arterial ischemic stroke (AIS) and 29 with TIA. Eighty had bilateral and 8 unilateral carotid circulation disease; 29 patients had posterior circulation involvement. Acute infarction was present in 36/176 hemispheres and chronic infarction in 86/176 hemispheres at the index presentation. Sixty-two of 82 with symptomatic presentation had at least one clinical recurrence. Fifty-five patients were treated surgically, with 37 experiencing fewer recurrences after surgery. Outcome was categorized as good using the Recovery and Recurrence Questionnaire in 39/85 patients. On multivariable analysis, presentation with TIA (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.02–0.35), headache (OR 0.10, 95% CI 0.02–0.58), or no symptoms (OR 0.08, 95% CI 0.01–0.68) was less likely to predict poor outcome than AIS presentation. Posterior circulation involvement predicted poor outcome (OR 4.22, 95% CI 1.23–15.53). Surgical revascularization was not a significant predictor of outcome.ConclusionsMoyamoya is associated with multiple recurrences, progressive arteriopathy, and poor outcome in half of patients, especially with AIS presentation and posterior circulation involvement. Recurrent AIS is rare after surgery. Surgery was not a determinant of overall outcome, likely reflecting surgical case selection and presentation clinical status.

Linear scleroderma is a characteristic form of scleroderma that typically affects children. Ocular manifestations may be present, especially when the frontoparietal area of the head is affected. We present the case of a 5-year-old boy with craniofacial linear scleroderma ("en coup de sabre") who developed exudative retinal detachment. Angiographic and neuroimaging findings are presented, and the importance of regular fundus examination is highlighted.

Background A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered. Objective To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families. Methods Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts. Results Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls. Conclusion Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.

Objectives Aqueduct stenosis (AS) and fourth ventricle outflow obstruction are rare associations of neurofibromatosis type 1 (NF1), resulting in ventriculomegaly and hydrocephalus requiring surgical treatment. This study aims to identify the prevalence of AS and its patterns of clinical presentation, aetiology and treatment in the paediatric complex NF1 population. Patients and methods Patients with NF-1 aged 0-18 years were recruited from the Regional Genetic Family Register, following institutional review board approval. Magnetic resonance imaging data and clinical documents were reviewed with respect to clinical presentation, degree of ventriculomegaly, aetiological factors and management of AS and fourth ventricle outflow obstruction. Results 24 of the 233 paediatric patients seen within the NHS highly specialised service for complex NF1 were found to have AS or and fourth ventricle outflow obstruction. This included 13 males and 11 females with a mean age of 9 years 5 months (range 8 months - 17 years). The majority of patients with AS or fourth ventricle outflow obstruction presented with symptoms of raised intracranial pressure associated with ventriculomegaly and/or hydrocephalus (n = 18). However, in 25 % of patients, AS was an incidental finding on MRI and was observed both in the presence (n = 2) and absence (n = 4) of ventriculomegaly. In the majority of cases a single cause of AS was identified (n = 16), of which tectal plate thickening (n = 7) was most frequently observed. The remaining 8 patients had multiple causes of AS, in which tectal plate thickening (n = 7) and aqueductal webs (n = 5) were the most common observations. Surgery was performed on all patients with evidence of raised pressure (n = 8) by performing endoscopic third ventriculostomy (ETV) (n = 5) or ventriculoperitoneal (VP)-shunting (n = 3). Tectal plate thickening was most frequently observed in patients who underwent ETV (n = 3), followed by aqueductal web (n = 1) and T2-signal changes in the tectal plate (n = 1). Patients treated with VP-shunt had 4th ventricle outflow obstruction (n = 2) and a tectal plate tumour (n = 1). Conclusion This study identifies that AS is more prevalent amongst the paediatric complex NF-1 population than previously reported, occurring in 10 % of cases. Our findings demonstrate that AS is most commonly symptomatic in presentation but can be asymptomatic in 25 % of paediatric complex NF1 patients. In this population, AS can occur both in the presence and absence of ventriculomegaly and therefore requires careful monitoring for development of hydrocephalus. In this study, over one third of patients (9 of 24 patients) with AS eventually required treatment.

AimThis study describes the prevalence and severity of perceived fatigue in a young neurofibromatosis type 1 (NF1) population.MethodsEthical approval was obtained and NF1 affected Individuals aged 2–18 years from the Manchester's NF1 clinic invited along with any unaffected siblings. The PedsQL Multidimensional Fatigue Scale Parental and child report was used. This validated measure explores cognitive, physical and sleep/rest domains on a 0–100 scale. Higher scores indicate less fatigue. Fatigue scores in affected children were compared to unaffected siblings after adjusting for age, sex and Index of Multiple Deprivation and with published population standards using z‐scores.ResultsA total of 286 families were invited and 75 affected and 16 siblings participated. There were significant differences between NF1 and controls in the aggregated fatigue core (child report 55 ± 19 vs. 75 (14), P P = 0.001) and the three sub‐domains: cognitive (child 48 ± 27 vs. 75 ± 23, P P P = 0.018). Similar differences were seen when compared with published controls (aggregated child z‐score −1.9 ± 1.4, P P ConclusionThis study suggests that children with NF1 are affected by perceived fatigue when compared with healthy children who do not have NF1.

To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant.This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

AimsThe aim of this study is to systematically investigate the demographic and disease predictors of cognitive and behavioural phenotype in the largest cohort of children with NF1 published to date. Based on previously published research, we examine the potential role of demographic predictors such as age, sex, SES, parental NF1 status as well as the neurological complications such as epilepsy and brain tumours in NF1 associated cognitive/ behavioural impairments.MethodIn this cross-sectional study design, participant data were drawn from two large databases which included (i) A clinical database of all patients with NF1 seen in a clinical psychological service from 2010 to 2019 and (ii) A research dataset from two previously published studies (2,8). The complex National NF1 service based within Manchester regional genetic services is set up for individuals with complex NF1 (https://www.mangen.co.uk/healthcare-professionals/clinical-genomic-services/nf1/) in the North of the UK. Children were referred to the psychological services by NF1 clinicians if psychological assessment was warranted based on parental reports. In order to reduce clinic referral bias, the clinical sample was supplemented by including participants that were seen solely for the purposes of research studies within our centre.ResultRelative to population norms, 90% of the NF1 sample demonstrated significantly lower scores in at least one cognitive or behavioral domain. Family history of NF1 and lower SES were independently associated with poorer cognitive, behavioral and academic outcomes. Neurological problems such as epilepsy and hydrocephalus were associated with lower IQ and academic skills.ConclusionCognitive and behavioural phenotypes commonly emerge via a complex interplay between genes and environmental factors, and this is true also of a monogenic condition such as NF1. Early interventions and remedial education may be targeted to risk groups such those with familial NF1, families with lower SES and those with associated neurological comorbidities.

Objectives The goal of this study was to review and present neurosurgical related activity within a multidisciplinary nationally commissioned specialty neurofibromatosis type I (NF1) center. Patients & methods We reviewed all NF1 Neurosurgical MDTs, NF1 Neurosurgical clinics and all neurosurgical procedures carried out in NF1 patients over an 8-year period. Results Since the inception of the service in 2009, 1505 cases were discussed at our NF-1 multidisciplinary meeting, 171 clinic appointments in complex NF1 patients with neurosurgical pathologies and 43(cranial and spinal) operations were performed. Conclusions The formation of a supraregional multidisciplinary team allows for a better understanding of the disease, a comprehensive evaluation of neuroimaging findings and a steep learning curve in the management of NF1 surgical conditions. We provide holistic treatment for these patients via direct care, specialist advice and liaison with local units.

Childhood onset neurofibromatosis type 2 can be severe and genotype dependent. We present a retrospective phenotypic analysis of all ascertained children in Englandage 18 (N = 87; male 61%). Mean age at last review was 13.9 years with mean follow-up 6.5 years. Patients were stratified using a validated score (1A/1B:no NF2 pathogenic_variant in blood; 2A/2B:mild/moderate NF2 constitutional or mosaic pathogenic_variant in blood; 3: constitutional truncating exon 2-13 pathogenic_variant. A total of 91% patients had a constitutional NF2 pathogenic_variant (44% de novo). Mean age at first manifestation was 4.3 and 8.8 years in groups 3 and 2A, respectively. Bilateral vestibular schwannoma, intracranial meningioma and spinal schwannoma occurred in 77%, 52% and 65% of group 3 patients, respectively, and 58%, 26% and 33% in 2A. A total of 43% group 3 and 18% 2A had severe unilateral visual loss (logmar1.0). Focal cortical dysplasia occurred in 26% group 3 and 4% 2A. A total of 48% of group 3 underwent ≥1 major intervention (intracranial/spinal surgery/Bevacizumab/radiotherapy) compared to 35% of 2A; with 23% group 3 undergoing spinal surgery (schwannoma/ependymoma/meningioma resection) compared to 4% of 2A. Mean age starting Bevacizumab was 12.7 in group 3 and 14.9 years in 2A. In conclusion, group 3 phenotype manifests earlier with greater tumour load, poorer visual outcomes and more intervention.

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], pINTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.

Aims Paediatric acute ischaemic stroke (AIS) is a neurological emergency. The Royal College of Physician guidelines (2004) focus on imaging and basic treatment. The understanding of AIS has improved therefore we aimed to investigate current management. Methods Notes of children ( Results Forty-three cases (28 boys) were identified. The median age was 4 years 11 months (5 days – 16 years 5 months). Aetiologies included: 14 unknown; 8 infectious (5 varicella; 3 meningitis); 7 secondary to cardiac pathology; 7 Moya Moya disease; 5 arterial dissection; 1 fibromuscular dysplasia, 1 sickle cell anaemia. All had MRI [27 (63%) also had MRA] in keeping with the guideline although there was a>48 hour delay in imaging in three (7%) due to atypical presentation. Bloods undertaken included: Routine 43 (100%); Basic clotting 35 (81%); Advanced clotting 20 (46.5%); Full vasculitis screen 12 (28%); prothrombin gene mutation 14 (32.5%) (all negative). Thirty-two received anticoagulation appropriately (aspirin 27; other 5). None received inappropriate anticoagulation. Eleven (25%) had neurological sequelae with the median (range) GOS (n=32) being 5 (3–5). Conclusions The incidence of stroke in the 2 catchment areas was 2.1/100 000. No patients died but a quarter had neurological sequelae. No cause was identified in a third of cases but a wide variation in the investigations undertaken existed: less than a third had a vasculitis and half had an advanced clotting screen. Imaging and anticoagulation were in keeping with current guidelines. New AIS guidelines to include investigations for treatable causes such as vasculitis are needed. This may help determine more aetiologies and improve management. Reference Royal College of Physicians. Stroke in Childhood: clinical guidelines for diagnosis, management and rehabilitation. 2004. Available from: [http://www.rcpch.ac.uk/system/files/protected/page/RCP%20-%20Stroke%20in%20childhood%2020015_0.pdf]

Complex regional pain syndrome (CRPS) is a condition of unknown etiology characterized by autonomic, sensory, and motor disturbance. CRPS usually follows an injury in the affected limb, which is often trivial in nature. CRPS involving the facial region is rare, and there have been no previous descriptions in children. We describe a 13-year-old girl with CRPS involving the face, which developed after being struck by a snowball. The clinical characteristics were similar to those of CRPS elsewhere in the body involving burning pain, hyperalgesia, and hyperesthesia. This was later accompanied by skin edema, fluctuating color, and temperature changes, as well as loss of eyebrow hair. Following detailed but inconclusive investigations, a clinical diagnosis of CRPS was made in line with Budapest diagnostic criteria. Over the next year, her condition gradually improved with ongoing comprehensive multidisciplinary input. We present this patient to alert clinicians to consider CRPS in the differential diagnosis of similar cases who present with chronic facial pain and skin changes.

Cerebral palsy (CP) is primarily a non-progressive disorder of movement and posture affecting the developing brain, but many children with CP have other impairments which may affect their quality of life and life expectancy. It is the most common childhood physical disability and affects 2 to 2.5 children per 1,000 born in the developing world. The differential diagnosis of cerebral palsy includes metabolic and genetic disorders. The diagnostic strategy is based on the clinical picture, pattern of development of symptoms, family history, and other factors influencing the probability of specific diagnoses. Targeted laboratory tests and cerebral imaging using magnetic resonance imaging are useful diagnostic tools. Surveillance for associated disabilities such as hearing impairment can help determine the goals of treatment and to improve functionality and quality of life. Children with CP being evaluated for cochlear implant should have assessment by paediatric neurologists to establish the correct d...

Aim: we aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms. Method: retrospective review and brain MRI analysis of children enrolled in the International Collaborative Infantile Spasms Study (ICISS) who developed a movement disorder on vigabatrin therapy. Comparisons were made with controls within ICISS who had no movement disorder. Results: ten of 124 infants had a movement disorder and in eight it had developed on vigabatrin therapy. Two had a movement disorder that resolved on dose-reduction of vigabatrin, one had improvement on withdrawing vigabatrin, two had resolution without any dose change, and in three it persisted despite vigabatrin withdrawal. The typical brain MRI changes associated with vigabatrin therapy were noted in two infants. Ten control infants were identified. Typical MRI changes noted with vigabatrin were noted in three controls. Interpretation: it is possible that in two out of eight cases, vigabatrin was associated with the development of a movement disorder. In six out of eight cases a causal relationship was less plausible. The majority of infants treated with vigabatrin did not develop a movement disorder. MRI changes associated with vigabatrin do not appear to be specifically related to the movement disorder

We present an 11-year-old girl with sudden, severe, sequential optic neuropathy. Investigations revealed severe vitamin B12 deficiency, and identified a novel mitochondrial ND5 variant. She was treated with steroids followed by plasma exchange, but the vision continued to deteriorate to eventual bilateral blindness over the next few months. Vitamin B12 deficiency can rarely cause severe irreversible visual loss secondary to optic neuropathy. The significance of the concurrent mitochondrial ND5 variant remains undetermined.

Aim To define better the phenotype and genotype of familial and sporadic cases of paroxysmal kinesigenic dyskinesia (PKD) caused by mutations in the PRRT2 gene presenting in the paediatric age group. Method We report the detailed clinical and molecular genetic features of 11 patients (six females, five males) with childhood-onset PRRT2-mutation-positive PKD. Results Mean age at disease onset was 8 years 7.5 months (range 5–11y), and clinical presentation was characterized by daily short paroxysmal episodes of dystonia/dyskinesia. Most patients also had non-kinesigenic attacks in addition to the classical movement-induced paroxysmal episodes. One family demonstrated great phenotypic variability with PKD, infantile convulsions, and/or hemiplegic migraine affecting different family members with the same mutation. All patients in whom antiepileptics (carbamazepine/phenytoin) were tried showed a dramatic improvement with complete abolition of dyskinetic episodes. Interpretation Our case series provides a detailed clinical description of patients with PRRT2-PKD, and reports a spectrum of disease-causing mutations, thereby expanding both the clinical phenotype and mutation spectrum of disease.

Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. (c) 2015 Wiley Periodicals, Inc

Idiopathic brachial neuritis (idiopathic neuralgic amyotrophy) in children is a well-recognized but rare condition. Although the precise aetiology is unknown, its usual occurrence after an infection suggests an immunological process. There is no specific test for brachial neuritis, and the diagnosis is one of exclusion with supportive evidence from nerve conduction studies, electromyography (EMG), and, in adults, changes in affected muscles on magnetic resonance imaging. Young children are often unable to tolerate EMG.

IMPORTANCE: Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Patients with multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intra-mitochondrial protein synthesis, with many not yet linked to human disease. OBJECTIVE: To determine the molecular basis of multiple respiratory chain complex deficiencies. DESIGN: We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005-2012. All had biochemical evidence of multiple respiratory chain complex defects, and no primary pathogenic mitochondrial DNA mutation. Whole exome sequencing was performed using 62Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family. PARTICIPANTS: 53 patients with biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. RESULTS: Presumptive causal variants were identified in 28 patients (53%, 95% CI=39-67), and possible causal variants were identified in 4 (8%, 95% CI=2-18). Together these account for 32 patients (60%, 95% CI=46-74), and involved 18 different genes. These included recurrent mutations in RMND1, AARS2 and MTO1, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1 and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1, and cardiomyopathy with AARS2, and MTO1. However, “classical” features were absent in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations, and no cardiomyopathy with founder SCO2 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%, 95% CI=26-54). CONCLUSIONS AND RELEVANCE: Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically-defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study will be required in independent patient populations to determine the utility of this approach in comparison to traditional diagnostic methods.

Guillain–Barre syndrome (GBS) causes acute motor, sensory and autonomic dysfunction. There is a relative paucity of published data regarding the autonomic features of GBS. The aims of this study were to describe the incidence, management and outcome of bladder dysfunction and hypertension in GBS and to ascertain whether these features relate to muscle weakness severity. Twenty-seven patients with a median (interquartile range) age of 5.7 (3.5–8.4) years were included, of whom 18 (67 %) were male and 14 (52 %) had autonomic dysfunction. One patient presented with and three subsequently developed urinary retention necessitating catheterisation for a median of 7.5 (7–14.5) days. Univariate analysis demonstrated that urinary retention was associated with weakness in all four limbs [retention: MRC muscle grade 2 (2–2.75); no retention: MRC grade 4 (3–4); p = 0.02], possibly reflecting more severe disease. Patients with hypertension (12 patients, 44 %) had a longer hospital stay [median 32.5 (15.5–53.5) days; rho = 0.65; p = 0.02], and those with worse muscle weakness required more anti-hypertensive medications (upper limb rho = −0.71, p = 0.03; lower limb rho = −0.72, p = 0.03]. The majority of blood pressure treatments involved calcium channel and beta blockers. In children with GBS, bladder dysfunction and hypertension are common. The presence of severe muscle weakness may predict those at greatest risk of these complications.

Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus β subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.

Objectives Children with hypoxic brain injuries have been considered to make poorer recovery than children with traumatic brain injuries. We aim to highlight that early rehabilitation may contribute to better outcomes than widely appreciated. Methods Retrospective study. Setting: two hospitals in the UK with paediatric intensive care units (ICU) and neurorehabilitation wards. Inclusion criteria: children under 16 years; admitted to ICU for ventilation; encephalopathy following cardiorespiratory arrest January 2010 to December 2014; survived to discharge from ICU. Exclusion criteria: children under 1 year of age; cardiorespiratory arrest following trauma. Results 16 children (8 male) were identified. Mean age: 99 months. Causes of cardiorespiratory arrest: strangulation (3); hypovolaemia (2); near-drowning (2); peri-operative (2); cardiac arrhythmia or unexplained (3); asthmatic arrest (2); other (2). Return of spontaneous cardiac output was 15 min or more in 11 out of 16 children. Mean length (SD) of stay on ICU: 11.5 (12.4) days. Eleven children had bilateral basal ganglia injury with varying cortical involvement; no imaging abnormality was identified in one child. Six children required prolonged parenteral nutrition or gastrostomy; two required ileo-colectomy; three children required tracheostomy. Four children required re-admission to ICU or high dependency care. Movement disorders requiring medications (baclofen, diazepam, L-Dopa) were common. Discharge from hospital occurred at median (range) 107 (9–706) days after injury. Ten children were discharged home directly. Discharge KOSCHI score was 3B (severe disability) or worse in nine children; four children were at 5A or 5B (good recovery). 60% of children were sitting independently 150 days and walking independently 500 days post injury. Duration of cardiac arrest did not alter outcomes but mode of injury played a more significant role in predicting outcome. Conclusions Severe disability or vegetative state after hypoxic encephalopathy is a frequent, but not inevitable outcome in children who survive to discharge from ICU. This group of children often require several months of inpatient admission to achieve medical stability during which time they are capable of active participatory rehabilitation. There is some potential for continued improvement following discharge.

Introduction An initial manifestation of isolated facial weakness is commonly due to Bell’s palsy. We describe three cases of paediatric stroke presenting as facial weakness, posing a challenge to medical practitioners in interpreting clinical signs and delaying diagnosis. Cases Patient 1 is 15 year old boy who presented to his local emergency department with a right-sided facial droop and was discharged with a diagnosis of Bell’s palsy. The pattern of facial nerve weakness was not documented. Over the next 48 h during a camping trip, his parents noticed weakness of his right arm and he was rushed to a different emergency department. Brain imaging confirmed a left MCA infarct secondary to left ICA dissection. Patient 2 is a 4 year old boy who presented to his local emergency department with a four day history of right-sided facial weakness. He was diagnosed with Bell’s palsy and discharged with prednisolone and aciclovir. Over the next 24 h, he became encephalopathic with right arm weakness and re-presented. Urgent brain imaging demonstrated an acute left MCA infarct. Patient 3 is a 4 year old girl who presented to her GP with mild encephalopathy a few days after the onset of a viral illness. She developed an asymmetrical smile, which was presumed to be due to Bell’s palsy. Over the next week, it was noted that the use of her right arm was suboptimal and subsequent brain imaging confirmed a left MCA infarct. Discussion In all cases, the diagnosis of stroke was not contemplated and the facial weakness was dismissed as the much commoner Bell’s palsy. Documentation on the pattern of weakness was absent in all three cases. Careful examination differentiating upper and lower motor neurone features will help distinguish stroke from Bell’s palsy. Conclusion Our cases illustrate that stroke is an important condition to consider in children presenting with any form of acute neurological deficit, including facial weakness. Increased awareness amongst primary and secondary healthcare professionals is needed to ensure that the diagnosis of stroke is not delayed in these situations.

Neurological complications in paediatric patients with inflammatory bowel disease (IBD) are rare. Most previous reports involve cerebral venous thrombosis, central nervous system vasculitis, or peripheral nerve inflammation. We report a child with active inflammatory bowel disease complicated by acute disseminated encephalomyelitis (ADEM). The child presented with acute neurological deficits following an exacerbation of colitis with evidence of lesions in the central nervous system white matter on magnetic resonance imaging. Ancillary investigations did not provide evidence of systemic infection, coagulation disorders, or vasculitis. In our case the colitis improved with immunosuppressive therapy, with a similar improvement in the white matter lesions showing almost complete resolution of the MR scan changes and no evidence of infarction. This case suggests that ADEM may be another extra intestinal manifestation of inflammatory bowel disease, probably associated with an autoimmune pathogenic mechanism.

Item does not contain fulltext Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.

The epileptic encephalopathies of infancy and childhood are a collection of epilepsy disorders characterized by refractory, severe seizures and poor neurological outcome, in which the mechanism of disease is poorly understood. We report the clinical presentation and evolution of epileptic encephalopathy in a patient, associated with a loss-of-function mutation in the phospholipase C-β 1 gene. We ascertained a consanguineous family containing a male infant who presented with early-onset epileptic encephalopathy for detailed clinical phenotyping and molecular genetic investigation. In addition, a cohort of 12 consanguineous families of children with infantile spasms were analysed for linkage to the phospholipase C-β 1 gene locus. The male infant presented with tonic seizures in early infancy and subsequently developed infantile spasms. Over time, he developed drug-resistant epilepsy associated with severe neurological regression and failure to thrive. Molecular genetic investigation revealed a homozygous loss-of-function 0.5-Mb deletion, encompassing the promoter element and exons 1, 2 and 3 of phospholipase C-β 1 in the index case. Linkage to the phospholipase C-β 1 locus was excluded in the 12 other consanguineous families, consistent with genetic heterogeneity in this disorder. Although phospholipase C-β 1 deficiency has not previously been reported in humans, the Plcb1 homozygote knockout mouse displays early-onset severe tonic seizures and growth retardation, thus recapitulating the human phenotype. Phospholipase C-β 1 has important functions in both hippocampal muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C-β 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy.

Idiopathic brachial neuritis (idiopathic neuralgic amyotrophy) in children is a well-recognized but rare condition. Although the precise aetiology is unknown, its usual occurrence after an infection suggests an immunological process. There is no specific test for brachial neuritis, and the diagnosis is one of exclusion with supportive evidence from nerve conduction studies, electromyography (EMG), and, in adults, changes in affected muscles on magnetic resonance imaging. Young children are often unable to tolerate EMG.

Degos disease, or malignant atrophic papulosis, is a rare vasculopathy of uncertain aetiology manifesting as a primary dermatological disorder in most cases, but with widespread systemic involvement developing in an undefined proportion of patients. Reported neurological features of Degos disease include ischaemic and haemorrhagic stroke, subdural effusion, seizures, neuropathy, transverse myelitis, and optic atrophy. The description of contrast enhancement of the leptomeninges possibly indicates a defect of blood vessel integrity likely explaining the pleiotropic neurological manifestations. Degos disease is usually considered a disorder of adulthood, although a small number of infantile cases have been described. Here, we report a female who demonstrated a neonatal onset of Degos disease, eventually showing the highly characteristic skin lesions together with ptosis and a generalized weakness as part of her systemic disorder. Subsequent exacerbations led to an inexorable neurodevelopmental and physical decline. CT scan revealed intracranial calcification, a feature described in two previous cases. Our report highlights the need to consider Degos disease in the differential diagnosis of childhood neurological disease with skin involvement.

OBJECTIVES: C1q deficiency is a rare inherited defect in the early part of the complement cascade. In this report, we describe the varied clinical features of patients with this condition as well as the characteristic autoantibody profile. METHODS: A large Pakistani family with a high degree of consanguinity is described in which the father and five sons have C1q deficiency, all with different clinical manifestations. RESULTS: Clinical features of C1q deficiency can vary from almost no disease to fulminant bacterial infection and localized lupus-like skin, renal or CNS disease. Autoantibodies to ribonucleoproteins such as anti-Sm and Ro, but not dsDNA, were present. CONCLUSIONS: Awareness of the spectrum of clinical disease, autoantibody profiles and tests required to confirm the diagnosis of C1q deficiency are important if this life-threatening immunodeficiency disease is to be managed correctly.

Introduction Kingella kingae endocarditis is an extremely rare but severe infection in childhood which may occur following chickenpox. It is associated with neurological complications and high morbidity, especially if not recognised promptly. Case A previously healthy 11 month old boy presented very unwell with fever and lethargy 7 days after the development of chickenpox. He was covered with IV ceftriaxone for suspected secondary bacterial sepsis. As he improved with the antibiotics, he was noted to have asymmetrical crawling with extension of his right leg. A soft grade 1/6 murmur was present on examination. Brain MRI demonstrated multiple bilateral cerebral abscesses, which appeared embolic in nature. CSF analysis was normal but blood cultures isolated the growth of Kingella kingae. An urgent cardiac ECHO revealed a large embolic mitral valve vegetation requiring rapid surgical intervention. His immunodeficiency screen was unremarkable. He is now neurologically back to his normal self but has significant residual mitral valve regurgitation, and remains under cardiac surveillance. Discussion Kingella kingae is a gram negative bacillus which is part of the normal upper respiratory tract flora. Pathogenic cases are starting to be identified over recent times, especially in children. The risk of severe bacterial infections following chickenpox has been established in literature previously. Endocarditis is a rare complication of Kingella and there are less than 10 reported cases in literature of Kingella endocarditis affecting a native valve in children under the age of 2 years. The detection of Kingella in the bloodstream should therefore never be discounted without further investigations. Conclusion Our case highlights the importance of recognising Kingella kingae endocarditis in a child presenting with fever and neurological complications following recent chickenpox. A cardiac ECHO should be considered despite normal cardiac examination to look specifically for endocarditis secondary to this pathogen, and urgent management tailored accordingly.