Publications by authors named "Venkateswaran Ramesh"

22 Publications

  • Page 1 of 1

Severe cortical damage associated with COVID-19 case report.

Seizure 2021 Jan 23;84:66-68. Epub 2020 Nov 23.

Paediatric Neurology, Royal London Hospital, Barts Health NHS Trust, Whitechapel Road, Whitechapel, London, E1 1FR United Kingdom.

Symptoms of COVID-19, as reported during the SARS-CoV-2 pandemic in 2019-2020, are primarily respiratory and gastrointestinal, with sparse reports on neurological manifestations. We describe the case of a 17-year old female with Cornelia de Lange syndrome and well controlled epilepsy, who sustained significant cortical injury during a COVID-19 associated multi-inflammatory syndrome.
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http://dx.doi.org/10.1016/j.seizure.2020.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682480PMC
January 2021

The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset -related mitochondrial disease.

Epilepsia Open 2018 03 11;3(1):103-108. Epub 2018 Jan 11.

Department of Clinical Neurophysiology Royal Victoria Infirmary Newcastle United Kingdom.

Focal status epilepticus in -related mitochondrial disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re-emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full-time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by mitochondrial disease.
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http://dx.doi.org/10.1002/epi4.12094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839316PMC
March 2018

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

Genet Med 2018 10 8;20(10):1224-1235. Epub 2018 Mar 8.

Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Purpose: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.

Methods: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.

Results: The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.

Conclusion: Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.
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http://dx.doi.org/10.1038/gim.2017.251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004311PMC
October 2018

Clinical and molecular characterization of -related severe early-onset epilepsy.

Neurology 2018 01 1;90(1):e55-e66. Epub 2017 Dec 1.

From Molecular Neurosciences (A.M., E.M., A., A.N., M.A.K.), Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health; Department of Neurology (A.M., A., A.N., C.E., J.H.C., M.A.K.) and Neuroradiology (W.K.C.), Great Ormond Street Hospital for Children, London, UK; Florey Institute of Neuroscience and Mental Health (U.N., E.V.G., I.E.S., S.P.), Melbourne, Australia; Department of Biological Sciences (S.M., M.T.), Institute of Structural and Molecular Biology, Birkbeck College, University of London; Regional Molecular Genetics Laboratory (N.T., R.H.S.), North East Thames Regional Genetics Service, and Department of Clinical Genetics (A.V.K., R.H.S.), Great Ormond Street Hospital, London, UK; Department of Paediatric Neurology (S.A.), Red Cross War Memorial Children's Hospital, Cape Town, South Africa; Department of Paediatric Neurology (G.A.), Addenbrooke's Hospital, Cambridge; Roald Dahl EEG Unit (R.A.), Department of Neurology, and Department of Neurology (R.K.), Alder Hey Children's Hospital, Liverpool; Department of Paediatric Neurology (A.D.), Sheffield Children's Hospital; Clinical Neurosciences (C.E., J.H.C.), Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London; Institute of Infection and Global Health (R.K.), University of Liverpool; Department of Paediatric Neurology (K.L.), Evelina Children's Hospital, Guys and St. Thomas' NHS Foundation Trust, London; Department of Clinical Genetics (T.M.), Northern Genetics Service; Department of Pediatric Neurology (V.R.), Great North Children's Hospital, Newcastle Upon Tyne; Department of Paediatric Neurology (R.S.), University Hospital Leicester Children's Hospital; Department of Paediatric Neurology (J.T.), Royal Manchester Children's Hospital; Department of Paediatric Neurology (W.W.), Nottingham University Hospitals NHS Trust, UK; Epilepsy Genetics Program (A. Poduri), Department of Neurology, Boston Children's Hospital; Department of Neurology (A. Poduri), Harvard Medical School, Boston, MA; University of Melbourne (I.E.S.), Austin Health and Royal Children's Hospital, Australia; and Department of Medicine (S.P.), Royal Melbourne Hospital, University of Melbourne, Australia. Dr. Malhotra is currently at the Department of Biochemistry, University of Cambridge, UK.

Objective: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset epilepsy.

Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a oocyte model system.

Results: We identified pathogenic variants in in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine.

Conclusions: Gain-of-function pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.
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http://dx.doi.org/10.1212/WNL.0000000000004762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754647PMC
January 2018

Genetic heterogeneity of motor neuropathies.

Neurology 2017 Mar 1;88(13):1226-1234. Epub 2017 Mar 1.

From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.

Objective: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.

Methods: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).

Results: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy.

Conclusions: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.
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http://dx.doi.org/10.1212/WNL.0000000000003772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373778PMC
March 2017

FHF1 (FGF12) epileptic encephalopathy.

Neurol Genet 2016 Dec 28;2(6):e115. Epub 2016 Oct 28.

Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.

Voltage-gated sodium channels (Nas) are mainstays of neuronal function, and mutations in the genes encoding CNS Nas (Na1.1 [], Na1.2 [], Na1.3 [], and Na1.6 []) are causes of some of the most common and severe genetic epilepsies and epileptic encephalopathies (EE). Fibroblast-growth-factor homologous factors (FHFs) compose a family of 4 proteins that interact with the C-terminal tails of Nas to modulate the channels' fast, and long-term, inactivations. mutation is a rare cause of generalized epilepsy with febrile seizures plus (GEFS+). Recently, a de novo mutation (p.R52H) was reported in early-onset EE in 2 siblings. We report 3 patients from unrelated families with the same p.R52H mutation. The 5 cases together frame the FHF1 R52H EE from infancy to adulthood. As discussed below, this gain-of-function disease may be amenable to personalized therapy.
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http://dx.doi.org/10.1212/NXG.0000000000000115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087254PMC
December 2016

Mortality in Dravet syndrome.

Epilepsy Res 2016 12 26;128:43-47. Epub 2016 Oct 26.

Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia. Electronic address:

We measured the mortality rate and the rate of Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet Syndrome (DS). We studied a cohort of 100 consecutively recruited, unrelated patients with DS; 87 had SCN1A mutations. Living cases had a median follow-up of 17 years. Seventeen patients died, at a median age of seven years (inter-quartile range 3-11 years) with causes of death: 10 SUDEP, four status epilepticus, two drowning and one asphyxia. The SUDEP classification included three Definite, one Definite Plus and six Probable. The Dravet-specific mortality rate/1000-person-years was 15.84 (98% CI 9.01-27.85). The Dravet-specific SUDEP rate was 9.32/1000-person-years (98% CI 4.46-19.45). The Dravet-specific SUDEP rate is the only documented syndrome-specific SUDEP rate. SUDEP in DS occurs mainly in childhood. It is also the highest SUDEP rate, considerably higher than the recent 5.1 SUDEP rate/1000-person-years for adults with refractory epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.10.006DOI Listing
December 2016

Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood.

Neurol Genet 2016 Apr 3;2(2):e59. Epub 2016 Mar 3.

Wellcome Trust Centre for Mitochondrial Research (D.L.-S., H.G., J.D., A.P., R.W.T., P.Y.-W.-M., R.H., P.F.C.), Institute of Genetic Medicine (D.L.-S., H.G., J.D., A.P., P.Y.-W.-M., R.H.), and Institute of Neuroscience (R.W.T.), Newcastle University, Newcastle upon Tyne, United Kingdom; Howard Hughes Medical Institute (K.J.K., D.T., V.K.M.), Department of Molecular Biology, Massachusetts General Hospital, Boston, MA; Department of Paediatric Neurology (A.-M.C., K.P.), The General Infirmary, Leeds, United Kingdom; Department of Child Neurology (V.R.), The Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom; Department of Systems Biology (V.K.M.), Harvard Medical School, Boston, MA; Broad Institute (V.K.M.), Cambridge, MA; Department of Clinical Neurosciences (P.F.C.), University of Cambridge; and MRC Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus, United Kingdom.

Objective: To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy.

Methods: Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein.

Results: Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele.

Conclusions: MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1.
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http://dx.doi.org/10.1212/NXG.0000000000000059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830195PMC
April 2016

The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy.

Brain 2015 Nov 10;138(Pt 11):e391. Epub 2015 Jun 10.

1 The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 2 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

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http://dx.doi.org/10.1093/brain/awv159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620510PMC
November 2015

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Am J Med Genet A 2015 Feb 16;167A(2):296-312. Epub 2015 Jan 16.

INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes - Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.

Aicardi-Goutières 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-Goutières 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.
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http://dx.doi.org/10.1002/ajmg.a.36887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382202PMC
February 2015

Exome sequencing in undiagnosed inherited and sporadic ataxias.

Brain 2015 Feb 12;138(Pt 2):276-83. Epub 2014 Dec 12.

1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK

Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision.
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http://dx.doi.org/10.1093/brain/awu348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306819PMC
February 2015

Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.

JAMA 2014 Jul;312(1):68-77

Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.

Importance: Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. 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 intramitochondrial protein synthesis, with many not yet linked to human disease.

Objective: To determine the molecular basis of multiple respiratory chain complex deficiencies.

Design, Setting, And Participants: We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb 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.

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 accounted 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, atypical clinical features were present 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 is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods.
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http://dx.doi.org/10.1001/jama.2014.7184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558267PMC
July 2014

Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the Gene.

J Neuromuscul Dis 2014 ;1(1):55-63

Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Background: Behr's syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties.

Objective: Here we describe 4 patients with the classical Behr's syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the gene encoding a protein involved in mitochondrial translation.

Methods: Whole exome sequencing was performed in genomic DNA and oxygen consumption was measured in patient cell lines.

Results: We detected 2 different homozygous nonsense mutations in 4 patients with a homogeneous clinical presentation matching the historical description of Behr's syndrome. The first symptom in all patients was childhood-onset optic atrophy, followed by spastic paraparesis, distal weakness, motor neuropathy and ophthalmoparesis.

Conclusions: We think that mutations are more frequent than previously suggested and screening of this gene should be considered not only in patients with mitochondrial respiratory chain deficiencies, but also in inherited peripheral neuropathies, spastic paraplegias and ataxias, especially with pre-existing optic atrophy.
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http://dx.doi.org/10.3233/JND-140003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568311PMC
January 2014

Diagnostic lumbar puncture in suspected acute bacterial meningitis: avoiding catastrophe.

Dev Med Child Neurol 2013 Dec;55(12):1068

Paediatric Neurology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1111/dmcn.12333DOI Listing
December 2013

Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome.

Dev Med Child Neurol 2013 Sep;55(9):846-56

Neurosciences Unit, Great Ormond Street Hospital for Children NHS Trust and UCL-Institute of Child Health, London, UK.

Aim: Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities.

Method: We conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6-20y) with genetically proven EAST syndrome.

Results: All children presented with tonic-clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm.

Interpretation: The neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.
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http://dx.doi.org/10.1111/dmcn.12171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298033PMC
September 2013

Functional neurological disorders in children and young people.

Dev Med Child Neurol 2013 Jan;55(1):3-4

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http://dx.doi.org/10.1111/dmcn.12058DOI Listing
January 2013

TUBA1A mutation-associated lissencephaly: case report and review of the literature.

Pediatr Neurol 2012 Feb;46(2):127-31

Department of Pediatric Neurology, Great North Children's Hospital, Newcastle-upon-Tyne, UK.

Lissencephaly is a disorder of neuronal migration resulting in abnormal cerebral cortical sulcation and gyration. Affected children present with microcephaly, developmental delay, and early-onset epileptic seizures. Recently, de novo missense mutations in the tubulin α-1A (TUBA1A) gene were identified as causing a distinctive radiologic phenotype comprising of posteriorly predominant lissencephaly with dysgenetic corpus callosum, cerebellar and brainstem hypoplasia, and more recently, polymicrogyria. We describe a 14-month-old girl with TUBA1A mutation-associated lissencephaly, and summarize the clinical and neuroradiologic findings of 19 cases in the literature.
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http://dx.doi.org/10.1016/j.pediatrneurol.2011.11.017DOI Listing
February 2012

Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.

Dev Med Child Neurol 2010 Aug;52(8):725-32

Department of Paediatric Neurology, Newcastle General Hospital, Newcastle upon Tyne, UK.

Aim: To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1.

Method: We used clinical and radiological description and molecular analysis.

Results: Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin.

Interpretation: Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1.
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http://dx.doi.org/10.1111/j.1469-8749.2010.03727.xDOI Listing
August 2010

LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.

Hum Mutat 2010 Jul;31(7):E1564-73

Paris Descartes University, INSERM U781 and Ref Center of Metabolic Diseases, Necker Hospital, Paris, France.

Autosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement Delta pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy.
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http://dx.doi.org/10.1002/humu.21282DOI Listing
July 2010

Treatment of primary angiitis of the central nervous system in childhood with mycophenolate mofetil.

Rheumatology (Oxford) 2010 Apr 25;49(4):806-11. Epub 2010 Jan 25.

Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, UK.

Objective: To assess the use of mycophenolate mofetil (MMF) in the treatment of refractory primary angiitis of the CNS in childhood (cPACNS).

Methods: A retrospective chart review was performed in patients with cPACNS who were treated with MMF following failure of a combination of corticosteroids and another immunosuppressant.

Results: Three patients from two centres were included in this study. The age of onset of disease was 5, 6 and 9 years. All the patients improved when treated with MMF, such that the dose of corticosteroids could be weaned or stopped.

Conclusions: MMF should be considered for maintenance treatment in the management of patients with cPACNS refractory to the combination of corticosteroids and first-line immunosuppressive agents.
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http://dx.doi.org/10.1093/rheumatology/kep453DOI Listing
April 2010

Coma blisters in 2 children on anticonvulsant medication.

J Child Neurol 2009 Aug 8;24(8):1021-5. Epub 2009 Apr 8.

Department of Paediatric Neurology, Newcastle General Hospital, Newcastle Upon Tyne, United Kingdom.

Blister formation and eccrine sweat gland necrosis have been recognized to occur in states of impaired consciousness and were first reported following barbiturate intoxication. Their etiology is complex and cannot simply be explained by pressure effects. Now that barbiturates are less frequently used, clinicians are likely to be less aware of the phenomenon of coma blister formation; however, newer drugs have also been associated with the occurrence of coma blisters. We describe 2 new associations of coma blisters and anticonvulsants in children. In the first child, blisters recurred on multiple occasions along with obtundation and edema. Our aims are to alert clinicians to the occurrence of coma blisters in children sedated on anticonvulsant medications and to report the new finding of recurrent coma blisters.
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http://dx.doi.org/10.1177/0883073809332771DOI Listing
August 2009

Outcome of hematopoietic stem cell transplantation in severe combined immune deficiency with central nervous system viral infection.

Pediatr Infect Dis J 2007 Feb;26(2):129-33

Paediatric Immunology Department, Newcastle General Hospital, Newcastle upon Tyne, UK.

Background: Patients with severe combined immunodeficiency and preexisting viral pneumonitis formally had a poor outcome from hematopoietic stem cell transplantation. With inhaled steroid and antitumor necrosis factor alpha antibody treatment, results improved. The poor outcome of patients with viral central nervous system infection prompted this retrospective single center review.

Results: Eight of 71 patients with severe combined immunodeficiency transplanted since 1987 were identified with viral central nervous system infection (adenovirus [1], cytomegalovirus [2], Epstein-Barr virus [2], parvovirus [1], varicella zoster virus [1], human herpesvirus 6 [1]). Nonspecific neurologic symptoms included drowsiness, irritability, head lag, fisting and floppiness. Later symptoms included unresponsiveness, apnea, posturing, hypotonia, hyperreflexia and seizures. All had neuroradiologic investigations. Only one had an initially normal computed tomography scan. Magnetic resonance image abnormalities included cerebral atrophy, basal ganglia changes, diffuse leukoencephalopathy, and multifocal mass lesions. Five patients had virus identified from cerebrospinal fluid by polymerase chain reaction and brain tissue examination from 3 patients identified human herpesvirus 6, adenovirus type 41 and varicella zoster virus. Three children remain alive, 2 received replete marrow and one remains untransplanted. Others who received T cell depleted marrow died of neurologic sequelae.

Conclusion: Outcome of viral central nervous system infection after hematopoietic stem cell transplantation for severe combined immunodeficiency is poor, particularly associated with T cell depleted marrow.
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http://dx.doi.org/10.1097/01.inf.0000250621.46742.b5DOI Listing
February 2007
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