The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Surgical revascularizations for pediatric moyamoya: a systematic review, meta-analysis, and meta-regression analysis.

INTRODUCTION: There is no clear consensus regarding the technique of surgical revascularization for moyamoya disease and syndrome (MMD/MMS) in the pediatric population. Previous meta-analyses have attempted to address this gap in literature but with methodological limitations that affect the reliability of their pooled estimates. This meta-analysis aimed to report an accurate and transparent comparison between studies of indirect (IB), direct (DB), and combined bypasses (CB) in pediatric patients with MMD/MMS. METHODS: In accordance with PRISMA guidelines, systematic searches of Medline, Embase, and Cochrane Central were undertaken from database inception to 7 October 2022. Perioperative adverse events were the primary outcome measure. Secondary outcomes were rates of long-term revascularization, stroke recurrence, morbidity, and mortality. RESULTS: Thirty-seven studies reporting 2460 patients and 4432 hemispheres were included in the meta-analysis. The overall pooled mean age was 8.6 years (95% CI: 7.7; 9.5), and 45.0% were male. Pooled proportions of perioperative adverse events were similar between the DB/CB and IB groups except for wound complication which was higher in the former group (RR = 2.54 (95% CI: 1.82; 3.55)). Proportions of post-surgical Matsushima Grade A/B revascularization favored DB/CB over IB (RR = 1.12 (95% CI 1.02; 1.24)). There was no significant difference in stroke recurrence, morbidity, and mortality. After meta-regression analysis, year of publication and age were significant predictors of outcomes. CONCLUSIONS: IB, DB/CB are relatively effective and safe revascularization options for pediatric MMD/MMS. Low-quality GRADE evidence suggests that DB/CB was associated with better long-term angiographic revascularization outcomes when compared with IB, although this did not translate to long-term stroke and mortality benefits.

Management of haemorrhagic stroke secondary to arteriovenous malformations in childhood.

AIMS: The aim of this study is to describe the outcome and management of all children who have presented with haemorrhagic stroke (HS) secondary to an arteriovenous malformation (AVM) at a single UK centre over a 13-year period. METHODS: All children with HS managed at our institution (2005-2018) were identified and those with underlying AVMs were studied. Clinical and imaging data were obtained from medical records. Outcome was scored using the Recovery and Recurrence Questionnaire. RESULTS: Ninety-three children (median age 8.8 years; 56 males; 8 neonates) presented with both global and focal features (28 had Glasgow Coma Score < 8). Haemorrhage was intraparenchymal in 72; prior risk factors present in 14. An underlying vascular lesion was identified in 68/93, most commonly AVM (n = 48). A systemic cause was found in 10, cerebral venous thrombosis in three, and 9 remain unidentified despite neuroradiological investigation. Median follow-up was 2.4 years, six died, and one was lost to follow-up. Outcome was rated as good in 60/86. Of the 48 AVMs, 3 were Spetzler-Martin (SM) grade 1, 21 SM 2, 21 SM3 and 3 SM4. One patient was treated conservatively as the AVM was too high risk to treat. At follow-up, 19 with AVM were angiographically cured, all with low SM grade and with the use of a single modality in 9 cases (all low SM grade). CONCLUSION: Although children with acute HS are extremely unwell at presentation, supportive care results in a good outcome in the majority. Complete obliteration for childhood AVMs is challenging even with low-grade lesions with multimodal treatment.

Diagnostic algorithm for children presenting with epilepsia partialis continua.

OBJECTIVE: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. METHODS: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. RESULTS: Fifty-four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6-15), with median follow-up of 4.3 years (range 0.2-16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion-positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3-15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole-exome sequencing on blood-derived DNA should be performed. SIGNIFICANCE: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis.

A child in shock: carotid blowout syndrome.

Paediatricians commonly encounter neck lumps during their routine clinical practice; vascular abnormalities, such as (pseudo)aneurysms, are a rare cause of these. Pseudoaneurysms of the carotid artery in children are usually the result of blunt or penetrating trauma, infection or vasculitis/connective tissue disorders. They can present with a variety of symptoms including neck pain, as a pulsatile neck mass or with compressive symptoms (for example, cranial nerve palsies or dyspnoea). Pseudoaneurysms carry a risk of rupture in which case they are fatal, unless immediate treatment is provided.We report a 17-month-old male child with idiopathic carotid artery blowout syndrome presenting with acute oropharyngeal haemorrhage leading to asystolic cardiac arrest. He was successfully resuscitated and emergency embolisation controlled the bleeding. Despite extensive left hemispheric infarct, he has survived.Carotid artery blowout syndrome needs to be recognised as a potential cause of major haemorrhage in childhood. The purpose of this case report is to remind readers of the differential diagnosis and work-up of a child presenting with a neck lump, to highlight important aspects of the acute management of major haemorrhage and massive blood transfusion in paediatrics, to describe the aetiology, presentation and management of carotid artery pseudoaneurysm in children and to discuss long term rehabilitation in patients with consequent neurological sequelae (including the need for input from multiple specialty teams).

Cross-sectional study of a United Kingdom cohort of neonatal vein of galen malformation.

OBJECTIVE: Describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation identified before 28 days of life. METHODS: Neonates with angiographically confirmed vein of Galen malformation presenting to 1 of 2 UK treatment centers (2006-2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomized into "good" and "poor" categories. Cross-sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors. RESULTS: Of 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty-four participated in neurocognitive assessment. Outcomes were approximately evenly split between "good" and "poor" categories across all domains, namely, neurological status, general cognition, neuromotor skills, adaptive behavior, and emotional and behavioral development. Important predictors of poor cognitive outcome were initial Bicêtre score ≤ 12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariate analysis, only Bicêtre score ≤ 12 remained significant. INTERPRETATION: Despite modern supportive and endovascular treatment, more than one-third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous as well as arterial circulation are important in the pathophysiology of brain injury. Ann Neurol 2018;84:547-555.

Presentation, course, and outcome of postneonatal presentations of vein of Galen malformation: a large, single-institution case series.

AIM: To describe presentation, clinical course, and outcome in postneonatal presentations of vein of Galen malformation (VGM). METHOD: Children older than 28 days presenting with VGM (from 2006-2016) were included. Notes/scans were reviewed. Outcome was dichotomized into 'good' or 'poor' using the Recovery and Recurrence Questionnaire. Logistic regression was performed to explore relationships between clinico-radiological features and outcome. RESULTS: Thirty-one children (18 males, 13 females) were included, presenting at a median age of 9.6 months (range 1.2mo-11y 7mo), most commonly with macrocrania (n=24) and prominent facial veins (n=9). Seven had evidence of cardiac failure. VGM morphology was choroidal in 19. Hydrocephalus (n=24) and loss of white matter volume (n=15) were the most common imaging abnormalities. Twenty-nine patients underwent glue embolization (median two per child). Angiographic shunt closure was achieved in 21 out of 28 survivors. Three children died of intracranial haemorrhage (1y, 6y, and 30d after embolization). Ten patients underwent neurosurgical procedures; to treat haemorrhage in four, and hydrocephalus in the rest. Outcome was categorized as good in 20 out of 28 survivors, but this was not predictable on the basis of the variables listed above. INTERPRETATION: Postneonatally presenting VGM has distinctive clinico-radiological features, attributable to venous hypertension. Endovascular treatment is associated with good outcomes, but more specific prognostic prediction was not possible within this cohort. WHAT THIS PAPER ADDS: Clinical and radiological features in older children with vein of Galen malformation relate to venous hypertension. Outcome is good in most cases with endovascular therapy. Mortality is low but is related to intracranial haemorrhage.

Anticoagulation in the management of neonatal cerebral sinovenous thrombosis: a systematic review and meta-analysis.

AIM: To determine whether anticoagulation therapy (ACT) in the treatment of neonatal cerebral sinovenous thrombosis (CSVT) improves outcomes, in the presence or absence of pre-existing intracerebral haemorrhage (ICH). METHOD: We searched CENTRAL, MEDLINE, Embase, CINAHL, the Web of Science, and clinical trial databases. We considered data from retrospective and prospective cohort studies, case series, and randomized controlled studies evaluating outcomes of CSVT treated with anticoagulation or no anticoagulation. Studies were included if they involved infants either younger than 28 days of age or younger than 44 weeks postmenstrual age at the time of diagnosis of CSVT in which ACT was considered. RESULTS: Seven non-randomized studies were included in meta-analysis. ACT had no significant effect on mortality before discharge either in the presence or absence of pre-existing ICH, nor on the incidence of extension of pre-existing ICH. ACT was associated with a reduced risk of propagation of thrombus (risk ratio 0.14, 95% confidence interval 0.03-0.72). INTERPRETATION: There are no randomized trials assessing the safety and efficacy of ACT in the treatment of neonatal CSVT. The results of this meta-analysis would justify a position of equipoise and support the need for well-designed randomized controlled trials of ACT in this population. WHAT THIS PAPER ADDS: No randomized studies have evaluated anticoagulation therapy (ACT) in neonatal cerebral sinovenous thrombosis. ACT may reduce thrombus propagation. No evidence of increased morbidity or mortality with ACT was demonstrated. A position of equipoise is justified, supporting the need for placebo-controlled randomized trials.

A practical approach to acute hemiparesis in children.

Acute hemiparesis in children is a common clinical syndrome presenting to a variety of care settings. The recognition and the differential diagnosis is challenging, particularly in young children. Arterial ischaemic stroke (AIS) is the primary diagnosis to be considered as this requires emergency investigations and management; however, there are several conditions collectively described as 'stroke mimics' that need consideration. Accurate diagnosis is essential for appropriate management. Clinical data combined with neuroimaging are important for accurate diagnosis and management. This review and the accompanying illustrative case vignettes suggest a practical approach to differential diagnosis and management of children presenting with acute hemiparesis.

Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum.

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

Neurosurgical management of proton beam therapy-induced moyamoya syndrome.

OBJECTIVE: Proton beam therapy (PBT) is an increasingly used treatment modality for pediatric patients with brain tumors. Moyamoya syndrome (MMS) is well recognized as a complication of traditional photon radiotherapy, however its association with PBT is less well described. The authors discuss their initial experience with the neurosurgical management of MMS secondary to PBT in a large-volume pediatric neurovascular service. METHODS: The authors performed a retrospective case review of consecutive children referred for neurosurgical management of MMS after PBT between 2009 and 2022. Patient demographic characteristics, oncological history and treatment, interval between PBT and MMS diagnosis, and MMS management were recorded. Clinical outcome at last review was classified as good if the modified Rankin Scale (mRS) score was ≤ 2 and/or the patient attended mainstream education without additional assistance. Poor outcome was defined as mRS score ≥ 3 and/or the patient received additional educational support. The recorded radiological outcomes included angiographic analysis of stenosis, evidence of brain ischemia/infarction on MRI, and postsurgical angiographic revascularization. RESULTS: Ten patients were identified. Oncological diagnosis included craniopharyngioma (n = 6), optic pathway glioma (1), ependymoma (1), Ewing sarcoma (1), and rhabdosarcoma (1). The median (interquartile range [IQR]) age at PBT was 5.1 (2.7-7.9) years. The median (IQR) age at MMS diagnosis was 7.8 (5.7-9.3) years. The median time between PBT and diagnosis of MMS was 20 (15-41) months. Six patients had poor functional status after initial oncological treatment and prior to diagnosis of MMS. All 10 patients had endocrine dysfunction, 8 had visual impairment, and 4 had behavioral issues prior to MMS diagnosis. Four patients had a perioperative ischemic event: 2 after tumor surgery, 1 after MMS surgical revascularization, and 1 after receiving a general anesthetic for an MRI scan during oncological surveillance. Seven children were treated with surgical revascularization, whereas 3 were managed medically. The incidence of ischemic events per cerebral hemisphere was reduced after surgical revascularization: only 1 patient of 7 had an ischemic event during the follow-up period after surgery. No children moved from good to poor functional status after MMS diagnosis. CONCLUSIONS: MMS can occur after PBT. Magnetic resonance angiography sequences should be included in surveillance MRI scans to screen for MMS, and families should be counseled about this complication. Management at a high-volume pediatric neurovascular center, including selective use of revascularization surgery, appears to maintain functional status in these children.

Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia.

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1, encoding the most abundant dopamine receptor (D1) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1-T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D1 agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D1 agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D1 receptor in motor control.

Surgical revascularization for pediatric moyamoya: the role of surgical mentorship in sustaining and developing a neurovascular service.

OBJECTIVE: Obtaining operative experience for the treatment of rare conditions in children represents a challenge for pediatric neurosurgeons. Starting in November 2017, a surgeon was mentored in surgical revascularization (SR) for pediatric moyamoya with a view to service development and sustainability. The aim of this audit was to evaluate early outcomes of SR for pediatric moyamoya during and following a surgical mentorship. METHODS: A retrospective cohort study with chart/database review of consecutive moyamoya surgeries performed by a new attending surgeon (between November 2017 and March 2020) was compared to a previously published cohort from the authors' institution in terms of clinical and angiographic outcomes, complications, operating time, and length of stay. A standardized technique of encephaloduroarteriomyosynangiosis with the superficial temporal artery was used. RESULTS: Twenty-two children underwent 36 indirect SRs during the study period. Patient demographics were similar between cohorts. The first group of 6 patients had 11 SRs performed jointly by the new attending surgeon mentored by an established senior surgeon (group A), followed by 10 patients with 16 SRs performed independently by the new attending surgeon (group B). The last 6 patients had 9 SRs with the new attending surgeon mentoring a senior fellow (group C) in performing SR. Good angiographic collateralization (Matsushima grades A and B) was observed in 80% of patients, with similar proportions across all 3 groups. A total of 18/19 symptomatic patients (95%) derived symptomatic benefit. There was no perioperative death and, compared to the historical cohort, a similar proportion had a recurrent arterial ischemic event (i.e., acute ischemic stroke) necessitating a second SR (1/22 vs 3/73). Operative times were longest in group C, with no difference in length of hospital stay among the 3 groups. CONCLUSIONS: Early outcomes demonstrate the feasibility of mentorship for safely incorporating new neurosurgeons in sustaining and developing a tertiary-level surgical service.

Diagnosing Mitochondrial Disorders Remains Challenging in the Omics Era.

OBJECTIVE: We hypothesized that novel investigative pathways are needed to decrease diagnostic odysseys in pediatric mitochondrial disease and sought to determine the utility of clinical exome sequencing in a large cohort with suspected mitochondrial disease and to explore whether any of the traditional indicators of mitochondrial disease predict a confirmed genetic diagnosis. METHODS: We investigated a cohort of 85 pediatric patients using clinical exome sequencing and compared the results with the outcome of traditional diagnostic tests, including biochemical testing of routine parameters (lactate, alanine, and proline), neuroimaging, and muscle biopsy with histology and respiratory chain enzyme activity studies. RESULTS: We established a genetic diagnosis in 36.5% of the cohort and report 20 novel disease-causing variants (1 mitochondrial DNA). Counterintuitively, routine biochemical markers were more predictive of mitochondrial disease than more invasive and elaborate muscle studies. CONCLUSIONS: We propose using biochemical markers to support the clinical suspicion of mitochondrial disease and then apply first-line clinical exome sequencing to identify a definite diagnosis. Muscle biopsy studies should only be used in clinically urgent situations or to confirm an inconclusive genetic result. CLASSIFICATION OF EVIDENCE: This is a Class II diagnostic accuracy study showing that the combination of CSF and plasma biochemical tests plus neuroimaging could predict the presence or absence of exome sequencing confirmed mitochondrial disorders.

Two Cases of Guillain-Barré Syndrome Variants Presenting With Dysautonomia.

We describe 2 pediatric cases presenting with posterior reversible encephalopathy syndrome secondary to autonomic dysfunction preceding the onset of motor symptoms in Guillain-Barré syndrome variants. Patient 1 presented acutely with encephalopathy, cerebellar signs, hypertension, lower limb weakness, and respiratory decompensation. Magnetic resonance imaging (MRI) brain showed occipital lesions consistent with posterior reversible encephalopathy syndrome. Nerve conduction studies were consistent with Miller-Fisher syndrome. After intravenous immunoglobulin and plasmapheresis, he improved clinically with radiological resolution. Patient 2 presented with headache, leg pain, seizures, and significant hypertension. Brain MRI was normal but spine MRI revealed enhancement of the cauda equina ventral nerve roots. She was areflexic with lower limb weakness a few days after intensive care unit admission and made a significant improvement after treatment with intravenous immunoglobulin. In children presenting with posterior reversible encephalopathy syndrome in the absent of other causes of primary hypertension, Guillain-Barré syndrome variants are an important differential etiology, presenting with autonomic dysfunction, even before signs of motor weakness become evident.

Quantifying the Intra-Operative Hemodynamic Effects of Glue Embolization in Vein of Galen Malformations.

Vein of Galen malformation is a rare congenital pathological intracranial arteriovenous shunt which carries 30% risk of death before 28 days-of-age. Treatment is by high risk minimally invasive endovascular glue embolization of shunt feeding arteries under angiographic control. A tool to support intra-operative decision making would be useful. We present a novel method for visualizing angiography data to demonstrate the effect of the intervention based upon change the after embolization in the delay in time of peak contrast density relative to the injected artery and a novel method for quantifying the immediate effect of embolization on the hemodynamics of the shunt. The method is demonstrated on the angiograms of five neonates who underwent embolization. We show consistent results including a post-embolization increase in the delay in time of peak contrast density relative to the injected artery at the venous outflow in keeping with reduced shunting and redistribution of blood following embolization.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Multiple causes of apnea in 1p36 deletion syndrome include seizures.

INTRODUCTION: Apneic episodes have not previously been described in children with 1p36 deletion syndrome with seizures. Having encountered one such patient, we reviewed our experience of breathing difficulties in this syndrome, with particular attention to evidence of ictal apnea. We describe four children with 1p36 deletion syndrome, seizures and apneic episodes. METHOD: Retrospective analysis of clinical features, seizure semiology and video-EEG data. RESULTS: All patients showed characteristic craniofacial features, mental retardation, and diffuse hypotonia and apnea. Seizure semiology included focal motor, ± secondary generalized tonic clonic and tonic events. All had histories of status epilepticus; three showed clustering of their habitual seizures. Assessment of apnea was complicated by the presence of multiple other potential causes including obesity, reflux, respiratory, and cardiac problems Epileptic apneas were confirmed in one child by video-telemetry. In three other children, an epileptic basis for apneas was inferred from their clinical histories and treatment response supported by EEG findings. In three children, epileptiform discharges occurred over fronto-centro-temporal regions. CONCLUSION: Epileptic apnea is a feature of 1p36 deletion syndrome, though episodic apnea is multifactorial in these children, and may need repeated re-appraisal.

Taylor-type focal cortical dysplasia in infants: some MRI lesions almost disappear with maturation of myelination.

Identification of focal cortical dysplasia (FCD) on magnetic resonance (MR) images of young children with refractory focal epilepsy is important, as surgical resection may offer improvement of seizure control and subsequent developmental progress. However, the MR appearances of malformations of cortical development may change during brain maturation. We report 4 children with refractory focal epilepsy, whose MR images in infancy showed localized cortical and subcortical signal abnormalities (hypointense on T(2)-weighted and hyperintense on T(1)-weighted images), suggestive of abnormal cortical development. The visibility of these lesions was significantly reduced on later MR images. Subtle blurring of the gray-white matter junction in these areas was the only indicator of cortical abnormality in 3 patients, which was recognized only after comparison with earlier images. Taylor-type FCD was subsequently confirmed in all patients, following surgical cortical resection of the lesions. MR images performed early within the first year of life in children with epilepsy are important to identify areas of FCD. The appearances of FCD on later scans can be very subtle escaping recognition, and conclusions may be misleading with respect to diagnosis and appropriateness of surgical treatment.