Doriette Soler - Academia.edu (original) (raw)

Papers by Doriette Soler

Research paper thumbnail of Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response

Nature Genetics, Jun 14, 2009

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap wi... more Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response. Aicardi-Goutières syndrome (AGS, MIM225750) is a genetically determined encephalopathy whose clinical importance is magnified because it closely mimics (and hence is often misdiagnosed as) the sequelae of congenital infection 1. AGS and congenital virus infection are both associated with an increased production of interferon alpha (IFNα) 2. Furthermore, a disturbance of IFN-α homeostasis is considered central to the pathogenesis of the autoimmune disorder systemic lupus erythematosus (SLE) 3. In keeping with this, some children with AGS also develop an early-onset form of SLE 4-7. These related clinical observations led us to predict in 2003 that elucidation of the genetic basis of AGS would identify cellular components with key roles in the pathogenesis of acquired autoimmune disease 8. In 2006 we reported that recessive mutations in any of the genes encoding the 3′→5′ exonuclease TREX1 (TREX1, previously known as AGS1) 9 or the three nonallelic components of the RNASEH2 endonuclease complex (RNASEH2B, RNASEH2C and RNASEH2A, also known as AGS2, AGS3 and AGS4, respectively) 10 result in AGS. We further showed that heterozygous TREX1 mutations can cause both a dominant form of AGS and a cutaneous subtype of SLE, called familial chilblain lupus (CHBL, MIM610448) 11 .

Research paper thumbnail of International NewsSpecial Educational Needs Teams (SENT) Project

Research paper thumbnail of Genetic landscape of ALS in Malta based on a quinquennial analysis

Neurobiology of Aging, Nov 1, 2022

Research paper thumbnail of Paroxysmal limb dystonias associated with GABBR2 pathogenic variant: A case-based literature review

Brain and Development

BACKGROUND De novo mutations in the GABBR2 (Gamma-Aminobutyric acid Type B Receptor Subunit 2) ge... more BACKGROUND De novo mutations in the GABBR2 (Gamma-Aminobutyric acid Type B Receptor Subunit 2) gene have recently been reported to be associated with a form of early-infantile epileptic encephalopathy (EIEE59; OMIM# 617904), as well as a Rett syndrome (RTT)-like disorder defined as a neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS; OMIM# 617903). METHODS We describe a pediatric case carrying a de novo GABBR2 pathogenic variant and showing a phenotype encompassing RTT, epilepsy, generalized hypotonia with a paroxysmal limb dystonia. RESULTS A 11-year-old girl, born to non-consanguineous parents after an uneventful pregnancy, had developmental delay and generalized hypotonia. At age 3.5 months she presented with infantile spasms with an electroencephalographic pattern of hypsarrhythmia. After treatment with clonazepam and prednisolone, she became seizure-free with a slow background electrical activity. Brain magnetic resonance imaging was normal. Paroxysmal dystonic posturing of the extremities, especially the upper limbs, have been observed since the age of 3 years. Motor stereotypies, non-epileptic episodes of hyperventilation and breath-holding were also reported. The girl suffered from feeding difficulties requiring gastrostomy at the age of 8. Exome sequencing (ES) revealed a de novo GABBR2 pathogenic variant (NM_005458:c.G2077T:p.G693W). CONCLUSION Paroxysmal limb dystonias, especially in the context of neurodevelopmental disorder featuring epilepsy, generalized hypotonia and RTT-like features should lead to the suspect of GABBR2 mutations.

Research paper thumbnail of ARTICLE Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those... more Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′r5 ′ exonuclease

Research paper thumbnail of Cerebral function monitoring in term or near term neonates at MDH : preliminary experience and proposal of a guideline

technical and clinical particulars of these cases was then compiled, analyzed and discussed. Resu... more technical and clinical particulars of these cases was then compiled, analyzed and discussed. Results: Amplitude aEEG traces were recorded from a total of 14 patients, 4 of whom were normal term or near term infants, and 10 were infants with a neurological abnormality. All records were of satisfactory quality, and all showed very high impedance levels. Five out of 11 neurologically-abnormal patients had signs of seizure activity on CFM. A technical fault

Research paper thumbnail of The clinical bank of BBMRI.mt

Vella, J., Borg, J., Grech, L., Galdies, R., Scerri, J., Cassar, W., Scerri, C.A., Camilleri, A.,... more Vella, J., Borg, J., Grech, L., Galdies, R., Scerri, J., Cassar, W., Scerri, C.A., Camilleri, A., Bezzina-Wettinger, S., Farrugia, R., Camilleri, G., Pace, N.P., Zammit, E., Said Conti, V., Grech, G., Saliba, C., Soler, D., Vella, N.R., Borg, I., Said, E., Camilleri Podesta, M.T., Ellul, B., Felice, T., Grima, D., Ebejer, J.P., Felice, A.E. Centre for Molecular Medicine and BioBanking, University of Malta www.um.edu.mt/biobank Contact: joanna.vella@um.edu.mt

Research paper thumbnail of Using antiepileptic drugs in children : recent developments and recommendations

Epilepsy is one of the most common neurological disorders, with approximately 45 per 100,000 chil... more Epilepsy is one of the most common neurological disorders, with approximately 45 per 100,000 children developing new-onset epilepsy every year. Children are a vulnerable population with unique health needs and a correct diagnosis and thus correct treatment of epilepsy in children, particularly a diagnosis of early onset epilepsy, is important in order to ensure better quality of life, neurodevelopmental outcomes, cognition, education, improved level of function and future employment. Therapy with antiepileptic drugs (AEDs) aims to minimize the frequency of epileptic seizures with minimal side effects. The first generation AEDs (such as phenytoin, carbamazepine and valproic acid) are still widely used, although they are associated with serious side effects and pharmacokinetic problems (narrow therapeutic indices, nonlinear kinetics, and drug-drug interactions due to enzyme inhibition and enzyme induction properties). The novel AEDs (such as lamotrigine, levetiracetam, rufinamide, and...

Research paper thumbnail of Video-EEG long term monitoring as a new service at Mater Dei Hospital

Malta Medical Journal Volume 28 Issue 02 2016 Abstract Introduction: Video-EEG long-term monitori... more Malta Medical Journal Volume 28 Issue 02 2016 Abstract Introduction: Video-EEG long-term monitoring (LTM) was introduced into Mater Dei Hospital (MDH) in May 2012. The audit aims to evaluate LTM in terms of diagnostic outcomes and impact on patient management. Methods: Analysis was carried out after retrospective review of 30 inpatients who underwent LTM at MDH between May 2012 and May 2014. 31 LTM sessions were performed. Referrals were made by 3 consultant neurologists. LTM and medical records were compared to evaluate whether LTM determined a change in diagnosis and how this affected management outcomes. Results: Patient ages ranged from 3 months to 73 years (35.5% paediatric cases) (16 male , 15 female studies). The most common indication was for uncontrolled seizures (54.8%), followed by suspected non-epileptic seizures (NES) (29%). The average hospital stay was 2 days for paediatric patients and 5 for adult cases. Major monitoring interruptions were recorded in 5 paediatric an...

Research paper thumbnail of International consensus recommendations on the diagnostic work-up for malformations of cortical development

Nature Reviews Neurology, 2020

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from ab... more Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians an...

Research paper thumbnail of Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity

The Journal of Molecular Diagnostics, 2020

Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant ... more Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)eConnect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelines.

Research paper thumbnail of MODELLING PHARMACOKINETICs FOR SPARSE LAMOTRIGINE DATA IN PAEDIATRICS

Research paper thumbnail of Rice,Crow.ThelancetNeurol.2013

Research paper thumbnail of Vici sy Nature Cullup et al. (Supplemental Information)

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

American journal of medical genetics. Part A, 2015

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1,... more 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, h...

Research paper thumbnail of Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response

Nature Genetics, 2009

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap wi... more Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response. Aicardi-Goutières syndrome (AGS, MIM225750) is a genetically determined encephalopathy whose clinical importance is magnified because it closely mimics (and hence is often misdiagnosed as) the sequelae of congenital infection 1. AGS and congenital virus infection are both associated with an increased production of interferon alpha (IFNα) 2. Furthermore, a disturbance of IFN-α homeostasis is considered central to the pathogenesis of the autoimmune disorder systemic lupus erythematosus (SLE) 3. In keeping with this, some children with AGS also develop an early-onset form of SLE 4-7. These related clinical observations led us to predict in 2003 that elucidation of the genetic basis of AGS would identify cellular components with key roles in the pathogenesis of acquired autoimmune disease 8. In 2006 we reported that recessive mutations in any of the genes encoding the 3′→5′ exonuclease TREX1 (TREX1, previously known as AGS1) 9 or the three nonallelic components of the RNASEH2 endonuclease complex (RNASEH2B, RNASEH2C and RNASEH2A, also known as AGS2, AGS3 and AGS4, respectively) 10 result in AGS. We further showed that heterozygous TREX1 mutations can cause both a dominant form of AGS and a cutaneous subtype of SLE, called familial chilblain lupus (CHBL, MIM610448) 11 .

Research paper thumbnail of Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Nature Genetics, 2012

Users may view, print, copy, download and text and data-mine the content in such documents, for t... more Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Research paper thumbnail of Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

The Lancet Neurology, 2013

Background-Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in an... more Background-Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods-In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2•466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings-74 (90%) of 82 patients had a positive interferon score (median 12•90, IQR 6•14-20•41) compared with two (7%) of 29 controls (median 0•93, IQR 0•57-1•30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=−0•604; serum, r=−0•289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that

Research paper thumbnail of Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations

Journal of Neurology, 2011

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inher... more Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic V. Guergueltcheva and J. S. Müller contributed equally to the study.

Research paper thumbnail of Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

Journal of Neurology, 2012

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neu... more The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

Research paper thumbnail of Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response

Nature Genetics, Jun 14, 2009

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap wi... more Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response. Aicardi-Goutières syndrome (AGS, MIM225750) is a genetically determined encephalopathy whose clinical importance is magnified because it closely mimics (and hence is often misdiagnosed as) the sequelae of congenital infection 1. AGS and congenital virus infection are both associated with an increased production of interferon alpha (IFNα) 2. Furthermore, a disturbance of IFN-α homeostasis is considered central to the pathogenesis of the autoimmune disorder systemic lupus erythematosus (SLE) 3. In keeping with this, some children with AGS also develop an early-onset form of SLE 4-7. These related clinical observations led us to predict in 2003 that elucidation of the genetic basis of AGS would identify cellular components with key roles in the pathogenesis of acquired autoimmune disease 8. In 2006 we reported that recessive mutations in any of the genes encoding the 3′→5′ exonuclease TREX1 (TREX1, previously known as AGS1) 9 or the three nonallelic components of the RNASEH2 endonuclease complex (RNASEH2B, RNASEH2C and RNASEH2A, also known as AGS2, AGS3 and AGS4, respectively) 10 result in AGS. We further showed that heterozygous TREX1 mutations can cause both a dominant form of AGS and a cutaneous subtype of SLE, called familial chilblain lupus (CHBL, MIM610448) 11 .

Research paper thumbnail of International NewsSpecial Educational Needs Teams (SENT) Project

Research paper thumbnail of Genetic landscape of ALS in Malta based on a quinquennial analysis

Neurobiology of Aging, Nov 1, 2022

Research paper thumbnail of Paroxysmal limb dystonias associated with GABBR2 pathogenic variant: A case-based literature review

Brain and Development

BACKGROUND De novo mutations in the GABBR2 (Gamma-Aminobutyric acid Type B Receptor Subunit 2) ge... more BACKGROUND De novo mutations in the GABBR2 (Gamma-Aminobutyric acid Type B Receptor Subunit 2) gene have recently been reported to be associated with a form of early-infantile epileptic encephalopathy (EIEE59; OMIM# 617904), as well as a Rett syndrome (RTT)-like disorder defined as a neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS; OMIM# 617903). METHODS We describe a pediatric case carrying a de novo GABBR2 pathogenic variant and showing a phenotype encompassing RTT, epilepsy, generalized hypotonia with a paroxysmal limb dystonia. RESULTS A 11-year-old girl, born to non-consanguineous parents after an uneventful pregnancy, had developmental delay and generalized hypotonia. At age 3.5 months she presented with infantile spasms with an electroencephalographic pattern of hypsarrhythmia. After treatment with clonazepam and prednisolone, she became seizure-free with a slow background electrical activity. Brain magnetic resonance imaging was normal. Paroxysmal dystonic posturing of the extremities, especially the upper limbs, have been observed since the age of 3 years. Motor stereotypies, non-epileptic episodes of hyperventilation and breath-holding were also reported. The girl suffered from feeding difficulties requiring gastrostomy at the age of 8. Exome sequencing (ES) revealed a de novo GABBR2 pathogenic variant (NM_005458:c.G2077T:p.G693W). CONCLUSION Paroxysmal limb dystonias, especially in the context of neurodevelopmental disorder featuring epilepsy, generalized hypotonia and RTT-like features should lead to the suspect of GABBR2 mutations.

Research paper thumbnail of ARTICLE Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those... more Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′r5 ′ exonuclease

Research paper thumbnail of Cerebral function monitoring in term or near term neonates at MDH : preliminary experience and proposal of a guideline

technical and clinical particulars of these cases was then compiled, analyzed and discussed. Resu... more technical and clinical particulars of these cases was then compiled, analyzed and discussed. Results: Amplitude aEEG traces were recorded from a total of 14 patients, 4 of whom were normal term or near term infants, and 10 were infants with a neurological abnormality. All records were of satisfactory quality, and all showed very high impedance levels. Five out of 11 neurologically-abnormal patients had signs of seizure activity on CFM. A technical fault

Research paper thumbnail of The clinical bank of BBMRI.mt

Vella, J., Borg, J., Grech, L., Galdies, R., Scerri, J., Cassar, W., Scerri, C.A., Camilleri, A.,... more Vella, J., Borg, J., Grech, L., Galdies, R., Scerri, J., Cassar, W., Scerri, C.A., Camilleri, A., Bezzina-Wettinger, S., Farrugia, R., Camilleri, G., Pace, N.P., Zammit, E., Said Conti, V., Grech, G., Saliba, C., Soler, D., Vella, N.R., Borg, I., Said, E., Camilleri Podesta, M.T., Ellul, B., Felice, T., Grima, D., Ebejer, J.P., Felice, A.E. Centre for Molecular Medicine and BioBanking, University of Malta www.um.edu.mt/biobank Contact: joanna.vella@um.edu.mt

Research paper thumbnail of Using antiepileptic drugs in children : recent developments and recommendations

Epilepsy is one of the most common neurological disorders, with approximately 45 per 100,000 chil... more Epilepsy is one of the most common neurological disorders, with approximately 45 per 100,000 children developing new-onset epilepsy every year. Children are a vulnerable population with unique health needs and a correct diagnosis and thus correct treatment of epilepsy in children, particularly a diagnosis of early onset epilepsy, is important in order to ensure better quality of life, neurodevelopmental outcomes, cognition, education, improved level of function and future employment. Therapy with antiepileptic drugs (AEDs) aims to minimize the frequency of epileptic seizures with minimal side effects. The first generation AEDs (such as phenytoin, carbamazepine and valproic acid) are still widely used, although they are associated with serious side effects and pharmacokinetic problems (narrow therapeutic indices, nonlinear kinetics, and drug-drug interactions due to enzyme inhibition and enzyme induction properties). The novel AEDs (such as lamotrigine, levetiracetam, rufinamide, and...

Research paper thumbnail of Video-EEG long term monitoring as a new service at Mater Dei Hospital

Malta Medical Journal Volume 28 Issue 02 2016 Abstract Introduction: Video-EEG long-term monitori... more Malta Medical Journal Volume 28 Issue 02 2016 Abstract Introduction: Video-EEG long-term monitoring (LTM) was introduced into Mater Dei Hospital (MDH) in May 2012. The audit aims to evaluate LTM in terms of diagnostic outcomes and impact on patient management. Methods: Analysis was carried out after retrospective review of 30 inpatients who underwent LTM at MDH between May 2012 and May 2014. 31 LTM sessions were performed. Referrals were made by 3 consultant neurologists. LTM and medical records were compared to evaluate whether LTM determined a change in diagnosis and how this affected management outcomes. Results: Patient ages ranged from 3 months to 73 years (35.5% paediatric cases) (16 male , 15 female studies). The most common indication was for uncontrolled seizures (54.8%), followed by suspected non-epileptic seizures (NES) (29%). The average hospital stay was 2 days for paediatric patients and 5 for adult cases. Major monitoring interruptions were recorded in 5 paediatric an...

Research paper thumbnail of International consensus recommendations on the diagnostic work-up for malformations of cortical development

Nature Reviews Neurology, 2020

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from ab... more Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians an...

Research paper thumbnail of Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity

The Journal of Molecular Diagnostics, 2020

Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant ... more Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)eConnect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelines.

Research paper thumbnail of MODELLING PHARMACOKINETICs FOR SPARSE LAMOTRIGINE DATA IN PAEDIATRICS

Research paper thumbnail of Rice,Crow.ThelancetNeurol.2013

Research paper thumbnail of Vici sy Nature Cullup et al. (Supplemental Information)

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

American journal of medical genetics. Part A, 2015

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1,... more 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, h...

Research paper thumbnail of Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response

Nature Genetics, 2009

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap wi... more Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response. Aicardi-Goutières syndrome (AGS, MIM225750) is a genetically determined encephalopathy whose clinical importance is magnified because it closely mimics (and hence is often misdiagnosed as) the sequelae of congenital infection 1. AGS and congenital virus infection are both associated with an increased production of interferon alpha (IFNα) 2. Furthermore, a disturbance of IFN-α homeostasis is considered central to the pathogenesis of the autoimmune disorder systemic lupus erythematosus (SLE) 3. In keeping with this, some children with AGS also develop an early-onset form of SLE 4-7. These related clinical observations led us to predict in 2003 that elucidation of the genetic basis of AGS would identify cellular components with key roles in the pathogenesis of acquired autoimmune disease 8. In 2006 we reported that recessive mutations in any of the genes encoding the 3′→5′ exonuclease TREX1 (TREX1, previously known as AGS1) 9 or the three nonallelic components of the RNASEH2 endonuclease complex (RNASEH2B, RNASEH2C and RNASEH2A, also known as AGS2, AGS3 and AGS4, respectively) 10 result in AGS. We further showed that heterozygous TREX1 mutations can cause both a dominant form of AGS and a cutaneous subtype of SLE, called familial chilblain lupus (CHBL, MIM610448) 11 .

Research paper thumbnail of Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Nature Genetics, 2012

Users may view, print, copy, download and text and data-mine the content in such documents, for t... more Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Research paper thumbnail of Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

The Lancet Neurology, 2013

Background-Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in an... more Background-Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods-In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2•466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings-74 (90%) of 82 patients had a positive interferon score (median 12•90, IQR 6•14-20•41) compared with two (7%) of 29 controls (median 0•93, IQR 0•57-1•30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=−0•604; serum, r=−0•289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that

Research paper thumbnail of Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations

Journal of Neurology, 2011

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inher... more Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic V. Guergueltcheva and J. S. Müller contributed equally to the study.

Research paper thumbnail of Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

Journal of Neurology, 2012

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neu... more The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.