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1.
Biochim Biophys Acta Mol Basis Dis ; 1865(9): 2475-2489, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31121247

RESUMO

Due to its pivotal role in NADH oxidation and ATP synthesis, mitochondrial complex I (CI) emerged as a crucial regulator of cellular metabolism. A functional CI relies on the sequential assembly of nuclear- and mtDNA-encoded subunits; however, whether CI assembly status is involved in the metabolic adaptations in CI deficiency still remains largely unknown. Here, we investigated the relationship between CI functions, its structure and the cellular metabolism in 29 patient fibroblasts representative of most CI mitochondrial diseases. Our results show that, contrary to the generally accepted view, a complex I deficiency does not necessarily lead to a glycolytic switch, i.e. the so-called Warburg effect, but that this particular metabolic adaptation is a feature of CI assembly defect. By contrast, a CI functional defect without disassembly induces a higher catabolism to sustain the oxidative metabolism. Mechanistically, we demonstrate that reactive oxygen species overproduction by CI assembly intermediates and subsequent AMPK-dependent Pyruvate Dehydrogenase inactivation are key players of this metabolic reprogramming. Thus, this study provides a two-way-model of metabolic responses to CI deficiencies that are central not only in defining therapeutic strategies for mitochondrial diseases, but also in all pathophysiological conditions involving a CI deficiency.

2.
Epilepsia ; 60(5): 845-856, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31026061

RESUMO

OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. RESULTS: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. SIGNIFICANCE: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.

4.
Ann Neurol ; 84(5): 788-795, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30269351

RESUMO

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.

6.
J Inherit Metab Dis ; 41(1): 129-139, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28924877

RESUMO

BACKGROUND AND AIM: To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns. METHODS: Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified. RESULTS: We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified. CONCLUSION: We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.

8.
Am J Hum Genet ; 101(5): 716-724, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100085

RESUMO

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.


Assuntos
Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto/genética , RNA Helicases/genética , Adenosina Trifosfatases/genética , Adolescente , Aminoácidos/genética , Linhagem Celular , Linhagem Celular Tumoral , Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Deficiência Intelectual/genética , Masculino , RNA/genética
9.
Neuropediatrics ; 48(3): 166-184, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28561207

RESUMO

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Interferon Tipo I/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Fenótipo , Adulto Jovem
10.
Clin Chim Acta ; 471: 101-106, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28532786

RESUMO

BACKGROUND: Despite ACADS (acyl-CoA dehydrogenase, short-chain) gene susceptibility variants (c.511C>T and c.625G>A) are considered to be non-pathogenic, encoded proteins are known to exhibit altered kinetics. Whether or not, they might affect overall fatty acid ß-oxidation still remains, however, unclear. METHODS: De novo biosynthesis of acylcarnitines by whole blood samples incubated with deuterated palmitate (16-2H3,15-2H2-palmitate) is suitable as a fluxomic exploration to distinguish between normal and disrupted ß-oxidation, abnormal profiles and ratios of acylcarnitines with different chain-lengths being indicative of the site for enzymatic blockade. Determinations in 301 control subjects of ratios between deuterated butyrylcarnitine and sum of deuterated C2 to C14 acylcarnitines served here as reference values to state specifically functional SCAD impairment in patients addressed for clinical and/or biological suspicion of a ß-oxidation disorder. RESULTS: Functional SCAD impairment was found in 39 patients. The 27 patients accepting subsequent gene studies were all positive for ACADS mutations. Twenty-six of 27 patients were positive for c.625G>A variant. Twenty-three of 27 patients harbored susceptibility variants as sole ACADS alterations (18 homozygous and 3 heterozygous for c.625G>A, 2 compound heterozygous for c.625G>A/c.511C>T). CONCLUSION: Our present fluxomic assessment of SCAD suggests a link between ACADS susceptibility variants and abnormal ß-oxidation consistent with known altered kinetics of these variants.


Assuntos
Acil-CoA Desidrogenase/genética , Predisposição Genética para Doença/genética , Análise do Fluxo Metabólico , Mitocôndrias/metabolismo , Ácido Palmítico/metabolismo , Polimorfismo de Nucleotídeo Único , Acil-CoA Desidrogenase/deficiência , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Oxirredução , Fenótipo
11.
Biochim Biophys Acta Mol Basis Dis ; 1863(1): 284-291, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27815040

RESUMO

Ketogenic Diet used to treat refractory epilepsy for almost a century may represent a treatment option for mitochondrial disorders for which effective treatments are still lacking. Mitochondrial complex I deficiencies are involved in a broad spectrum of inherited diseases including Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes syndrome leading to recurrent cerebral insults resembling strokes and associated with a severe complex I deficiency caused by mitochondrial DNA (mtDNA) mutations. The analysis of MELAS neuronal cybrid cells carrying the almost homoplasmic m.3243A>G mutation revealed a metabolic switch towards glycolysis with the production of lactic acid, severe defects in respiratory chain activity and complex I disassembly with an accumulation of assembly intermediates. Metabolites, NADH/NAD+ ratio, mitochondrial enzyme activities, oxygen consumption and BN-PAGE analysis were evaluated in mutant compared to control cells. A severe complex I enzymatic deficiency was identified associated with a major complex I disassembly with an accumulation of assembly intermediates of 400kDa. We showed that Ketone Bodies (KB) exposure for 4weeks associated with glucose deprivation significantly restored complex I stability and activity, increased ATP synthesis and reduced the NADH/NAD+ ratio, a key component of mitochondrial metabolism. In addition, without changing the mutant load, mtDNA copy number was significantly increased with KB, indicating that the absolute amount of wild type mtDNA copy number was higher in treated mutant cells. Therefore KB may constitute an alternative and promising therapy for MELAS syndrome, and could be beneficial for other mitochondrial diseases caused by complex I deficiency.

12.
Pediatrics ; 138(3)2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27581854

RESUMO

Hemolytic anemia (HA) of the newborn should be considered in cases of rapidly developing, severe, or persistent hyperbilirubinemia. Several causes of corpuscular hemolysis have been described, among which red blood cell enzyme defects are of particular concern. We report a rare case of red blood cell enzyme defect in a male infant, who presented during his first months of life with recurrent and isolated neonatal hemolysis. All main causes were ruled out. At 6.5 months of age, the patient presented with gastroenteritis requiring hospitalization; fortuitously, urine organic acid chromatography revealed a large peak of 5-oxoproline. Before the association between HA and 5-oxoprolinuria was noted, glutathione synthetase deficiency was suspected and confirmed by a low glutathione synthetase concentration and a collapse of glutathione synthetase activity in erythrocytes. Moreover, molecular diagnosis revealed 2 mutations in the glutathione synthetase gene: a previously reported missense mutation (c.[656A>G]; p.[Asp219Gly]) and a mutation not yet described in the binding site of the enzyme (c.[902T>C]; p.[Leu301Pro]). However, 15 days later, a control sample revealed no signs of 5-oxoprolinuria and the clinical history discovered administration of acetaminophen in the 48 hours before hospitalization. Thus, in this patient, acetaminophen exposure allowed the diagnosis of a mild form of glutathione synthetase deficiency, characterized by isolated HA. Early diagnosis is important because treatment with bicarbonate, vitamins C and E, and elimination of trigger factors are recommended to improve long-term outcomes. Glutathione synthetase deficiency should be screened for in cases of unexplained newborn HA.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Anemia Hemolítica/etiologia , Glutationa Sintase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Humanos , Recém-Nascido , Masculino , Recidiva
13.
Orphanet J Rare Dis ; 10: 158, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26666653

RESUMO

BACKGROUND: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations. METHODS: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. RESULTS: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response. CONCLUSIONS: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.


Assuntos
Biopterina/análogos & derivados , Estudos de Associação Genética/métodos , Genótipo , Fenótipo , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/genética , Biopterina/uso terapêutico , Estudos de Coortes , Feminino , França/epidemiologia , Humanos , Masculino , Fenilcetonúrias/epidemiologia , Resultado do Tratamento
14.
Ann Neurol ; 78(6): 871-86, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26288984

RESUMO

OBJECTIVE: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment. METHODS: A total of 321 index patients with spastic ataxia selected from the SPATAX network were analyzed by direct sequencing of the SACS gene, and 156 patients from the ATAXIC project presenting with congenital ataxia were investigated either by targeted or whole exome sequencing. For functional analyses, primary cultures of fibroblasts were obtained from 11 patients carrying either mono- or biallelic variants, including 1 case harboring a large deletion encompassing the entire SACS gene. RESULTS: We identified biallelic SACS variants in 33 patients from SPATAX, and in 5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent alteration of the mitochondrial network was observed in 10 of the 11 patients tested. INTERPRETATION: Our results permit extension of the clinical and mutational spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial network anomalies could be used as a trait biomarker for the diagnosis of ARSACS when SACS molecular results are difficult to interpret (ie, missense variants and heterozygous truncating variant). Based on our findings, we propose new diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria.


Assuntos
Biomarcadores , Proteínas de Choque Térmico/fisiologia , Mitocôndrias , Espasticidade Muscular/diagnóstico , Ataxias Espinocerebelares/congênito , Adolescente , Adulto , Técnicas de Cultura de Células , Criança , Estudos de Coortes , Feminino , Fibroblastos , Proteínas de Choque Térmico/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/fisiologia , Espasticidade Muscular/genética , Espasticidade Muscular/patologia , Espasticidade Muscular/fisiopatologia , Mutação , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/fisiopatologia , Adulto Jovem
15.
Int J Biochem Cell Biol ; 65: 91-103, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26024641

RESUMO

Complex I (CI) deficiency is the most common respiratory chain defect representing more than 30% of mitochondrial diseases. CI is an L-shaped multi-subunit complex with a peripheral arm protruding into the mitochondrial matrix and a membrane arm. CI sequentially assembled into main assembly intermediates: the P (pumping), Q (Quinone) and N (NADH dehydrogenase) modules. In this study, we analyzed 11 fibroblast cell lines derived from patients with inherited CI deficiency resulting from mutations in the nuclear or mitochondrial DNA and impacting these different modules. In patient cells carrying a mutation located in the matrix arm of CI, blue native-polyacrylamide gel electrophoresis (BN-PAGE) revealed a significant reduction of fully assembled CI enzyme and an accumulation of intermediates of the N module. In these cell lines with an assembly defect, NADH dehydrogenase activity was partly functional, even though CI was not fully assembled. We further demonstrated that this functional N module was responsible for ROS production through the reduced flavin mononucleotide. Due to the assembly defect, the FMN site was not re-oxidized leading to a significant oxidative stress in cell lines with an assembly defect. These findings not only highlight the relationship between CI assembly and oxidative stress, but also show the suitability of BN-PAGE analysis in evaluating the consequences of CI dysfunction. Moreover, these data suggest that the use of antioxidants may be particularly relevant for patients displaying a CI assembly defect.


Assuntos
Complexo I de Transporte de Elétrons/deficiência , Doenças Mitocondriais/metabolismo , Estresse Oxidativo/fisiologia , Trifosfato de Adenosina/metabolismo , Estudos de Casos e Controles , Células Cultivadas , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Fibroblastos/metabolismo , Humanos , Doenças Mitocondriais/genética , Modelos Moleculares , Mutação , Espécies Reativas de Oxigênio/metabolismo
16.
Am J Med Genet A ; 167A(2): 296-312, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25604658

RESUMO

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.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Exodesoxirribonucleases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Estudos de Associação Genética , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon , Interferons/sangue , Interferons/líquido cefalorraquidiano , Pterinas/líquido cefalorraquidiano , Proteína 1 com Domínio SAM e Domínio HD
17.
J Med Genet ; 51(11): 724-36, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25167861

RESUMO

BACKGROUND: Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. METHODS: We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. RESULTS: We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. CONCLUSIONS: With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Técnicas de Diagnóstico Molecular/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Análise de Sequência de DNA/métodos , Adulto Jovem
19.
Paediatr Drugs ; 16(5): 407-15, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24962711

RESUMO

OBJECTIVES: The aim of this study was to describe a nationwide system for pre-marketing follow-up (cohort temporary utilization authorization [ATU] protocol; i.e., 'therapeutic utilization') of a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane(®)) in France and to analyze safety and efficacy in this treated cohort of patients with urea cycle disease (UCD). METHODS: In October 2012, a cohort ATU was established in France to monitor the use of Pheburane(®) on a named-patient basis. All treated UCD patients were included in a follow-up protocol developed by the Laboratory (Lucane Pharma) and the French Medicines Agency (ANSM), which recorded demographics, dosing characteristics of NaPB, concomitant medications, adverse events, and clinical outcome during the period of treatment. Following the granting of the Marketing Authorization in Europe, the cohort ATU was terminated approximately 1 year after its initiation, as the product was launched on the French market. RESULTS: The ease of administration and acceptability were much better with the new taste-masked formulation than with the previous treatment. No episodes of metabolic decompensation were observed over a treatment period ranging from 3 to 11 months with Pheburane(®) and the range of ammonia and glutamine plasma levels improved and remained within the normal range. In all, no adverse events were reported with Pheburane(®) treatment. CONCLUSIONS: The recently developed taste-masked formulation of NaPB granules improved the quality of life for UCD patients. This may translate into improved compliance, efficacy, and safety, which may be demonstrated either in further studies or in the post-marketing use of the product.


Assuntos
Fenilbutiratos/administração & dosagem , Paladar , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , França , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento , Adulto Jovem
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