M Rio

Université Paris-Sorbonne - Paris IV, Lutetia Parisorum, Île-de-France, France

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Publications (38)116.45 Total impact

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    ABSTRACT: Pyruvate carboxylase (PC) is a biotin-containing mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby being involved in gluconeogenesis and in energy production through replenishment of the tricarboxylic acid (TCA) cycle with oxaloacetate. PC deficiency is a very rare metabolic disorder. We report on a new patient affected by the moderate form (the American type A). Diagnosis was nearly fortuitous, resulting from the revision of an initial diagnosis of mitochondrial complex IV (C IV) defect. The patient presented with severe lactic acidosis and pronounced ketonuria, associated with lethargy at age 23 months. Intellectual disability was noted at this time. Amino acids in plasma and organic acids in urine did not show patterns of interest for the diagnostic work-up. In skin fibroblasts PC showed no detectable activity whereas biotinidase activity was normal. We had previously reported another patient with the severe form of PC deficiency and we show that she also had secondary C IV deficiency in fibroblasts. Different anaplerotic treatments in vivo and in vitro were tested using fibroblasts of both patients with 2 different types of PC deficiency, type A (patient 1) and type B (patient 2). Neither clinical nor biological effects in vivo and in vitro were observed using citrate, aspartate, oxoglutarate and bezafibrate. In conclusion, this case report suggests that the moderate form of PC deficiency may be underdiagnosed and illustrates the challenges raised by energetic disorders in terms of diagnostic work-up and therapeutical strategy even in a moderate form.KeywordsPC deficiencyLactic acidosisSecondary mitochondrial respiratory chain defectsBezafibrate
    Full-text · Article · Mar 2015 · Molecular Genetics and Metabolism Reports
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    ABSTRACT: 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. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Barth syndrome associates cardiomyopathy, myopathy and neutropenia in boys. This genetic disease is inherited as an X-linked trait and is associated to mutations in the TAZ gene. The disease is extremely rare (incidence at birth in France: 1–3 cases). Here, we propose guidelines for diagnosis and medical management associating cardiological, metabolic and hematological expertise. We also propose the use of prophylaxis of infections by intravenous immunoglobulin during infancy as mortality in Barth syndrome mainly occurs in infants and is usually the consequence of acute heart failure at the time of apparently common viral infection.
    Full-text · Article · Sep 2014
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    ABSTRACT: The Behr syndrome (MIM#210000) is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay (Behr, 1909). Although the disorder is believed to be inherited in an autosomal recessive manner, it may be clinically heterogeneous, encompassing several genetic aetiologies and patterns of inheritance. Recently, an adult-onset Behr-like syndrome, including optic atrophy and ataxia, was reported in two brothers carrying a heterozygous mutation in the optic atrophy type 1 gene (OPA1, p.Cys551Tyr) (Marelli et al., 2011). Heterozygous mutations in OPA1, a gene encoding for a dynamin-related GTPase involved in mitochondrial dynamics and mtDNA maintenance, are the main causes of autosomal dominant optic atrophy (DOA). In DOA, the optic neuropathy occurs insidiously in the first decade of life leading to various levels of visual impairment. As many as 20% of patients with DOA exhibit extra-ocular neuromuscular signs including deafness (Amati-Bonneau et al., 2005), chronic progressive external ophthalmoplegia, ataxia, peripheral neuropathy and mitochondrial myopathy with multiple mtDNA deletions, also called the ‘DOA plus’ phenotype (Amati-Bonneau et al., 2008; Yu-Wai-Man et al., 2010). The ‘DOA plus’ phenotype, which is similar to that observed in multi-systemic mitochondrial disorders (Amati-Bonneau et al., 2005), is often associated with missense mutations in OPA1 (Yu-Wai-Man et al., 2010). Apart from these autosomal dominant forms, only a few syndromic cases have so far been reported with compound heterozygous OPA1 mutations suggestive of either recessive or semi-dominant patterns of inheritance (Pesch et al., 2001; Yu-Wai-Man et al., 2010; Schaaf et al., 2011). However, the clinical spectrum of these emerging double-mutant OPA1-related disorders remains to be characterized. We here report four cases of children affected by the Behr syndrome associated with compound heterozygous OPA1 mutations.
    Full-text · Article · Jul 2014 · Brain
  • I Desguerre · M Hully · M Rio · R Nabbout
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    ABSTRACT: Mitochondrial respiratory chain defects (RCD) often exhibit multiorgan involvement, affecting mainly tissues with high-energy requirements such as the brain. Epilepsy is frequent during the evolution of mitochondrial disorders (30%) with different presentation in childhood and adulthood in term of type of epilepsy, of efficacy of treatment and also in term of prognosis. Mitochondrial disorders can begin at any age but the diseases with early onset during childhood have generally severe or fatal outcome in few years. Four age-related epileptic phenotypes could be identified in infancy: infantile spasms, refractory or recurrent status epilepticus, epilepsia partialis continua and myoclonic epilepsy. Except for infantile spasms, epilepsy is difficult to control in most cases (95%). In pediatric patients, mitochondrial epilepsy is more frequent due to mutations in nDNA-located than mtDNA-located genes and vice versa in adults. Ketogenic diet could be an interesting alternative treatment in case of recurrent status epilepticus or pharmacoresistant epilepsy. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death.
    No preview · Article · May 2014 · Revue Neurologique
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    ABSTRACT: Mitochondrial diseases are characterised by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is difficult and genotype/phenotype correlations remain elusive. Brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we summarise the various combinations of MRI lesions observed in the most frequent mitochondrial respiratory chain deficiencies so as to direct molecular genetic test in patients at risk of such diseases. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.
    No preview · Article · May 2014 · Journal of Medical Genetics
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    ABSTRACT: Mitochondrial diseases are due to deficiency of the respiratory chain and are characterized by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Some clinical presentations are highly suggestive of given gene mutations, allowing rapid genetic diagnosis. However, owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is frequently difficult and genotype/phenotype correlations remain elusive. For this reason, brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we report the most frequent neuroradiological signs in mitochondrial respiratory chain deficiency and we propose a diagnostic algorithm based on neuroimaging features, so as to direct molecular genetic tests in patients at risk of mitochondrial respiratory chain deficiency. This algorithm is based on the careful analysis of five areas on brain MRI: (1) basal ganglia (hyperintensities on T2 or calcifications); (2) cerebellum (hyperintensities on T2 or atrophy); (3) brainstem (hyperintensities on T2 or atrophy); (4) white matter (leukoencephalopathy); (5) cortex (sub-tentorial atrophy); (6) stroke-like episodes. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.
    No preview · Article · May 2014 · Revue Neurologique
  • A. Rötig · M. Rio · A. Munnich

    No preview · Article · May 2014 · Archives de Pédiatrie
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    ABSTRACT: Mitochondrial diseases are due to deficiency of the respiratory chain and are characterized by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Some clinical presentations are highly suggestive of given gene mutations, allowing rapid genetic diagnosis. However, owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is frequently difficult and genotype/phenotype correlations remain elusive. For this reason, brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we report the most frequent neuroradiological signs in mitochondrial respiratory chain deficiency and we propose a diagnostic algorithm based on neuroimaging features, so as to direct molecular genetic tests in patients at risk of mitochondrial respiratory chain deficiency. This algorithm is based on the careful analysis of five areas on brain MRI: (1) basal ganglia (hyperintensities on T2 or calcifications); (2) cerebellum (hyperintensities on T2 or atrophy); (3) brainstem (hyperintensities on T2 or atrophy); (4) white matter (leukoencephalopathy); (5) cortex (sub-tentorial atrophy); (6) stroke-like episodes. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.
    No preview · Article · Apr 2014 · Revue Neurologique
  • M. Rio · A.-S. Lebre · A. Rötig · A. Munnich
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    ABSTRACT: Le citopatie mitocondriali raggruppano delle patologie eterogenee clinicamente e geneticamente, il cui denominatore comune è una disfunzione della catena respiratoria mitocondriale. La catena respiratoria mitocondriale ha, come ruolo essenziale, la sintesi dell’energia necessaria a tutte le cellule dell’organismo. Così, un malfunzionamento della catena respiratoria può manifestarsi con qualsiasi sintomo e interessare qualsiasi organo o tessuto, ad ogni età e con tutte le modalità di eredità possibili, tenuto conto della doppia origine genetica della catena respiratoria mitocondriale. L’indagine diagnostica delle malattie mitocondriali si esegue in diversi passaggi. Le indagini cliniche, paracliniche e metaboliche ricercheranno degli argomenti a favore della malattia, che permetteranno di ipotizzare la diagnosi. Le indagini enzimatiche e molecolari hanno lo scopo di confermare la diagnosi. La grande variabilità di espressione clinica, la necessità di procedure diagnostiche invasive e la grande eterogeneità genetica fanno della diagnosi delle citopatie mitocondriali una sfida importante per il medico e richiedono una collaborazione stretta tra medici e laboratori di diagnosi con esperienza biochimica e molecolare di queste patologie.
    No preview · Article · Feb 2014
  • I. Desguerre · M. Hully · M. Rio · R. Nabbout
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    ABSTRACT: Introduction Les maladies mitochondriales chez l’enfant et chez l’adulte ont fréquemment une expression neurologique et l’épilepsie est un symptôme fréquent (30 %). L’expression de l’épilepsie est différente chez l’enfant et chez l’adulte témoignant du rôle de la maturation cérébrale. État des connaissances La survenue d’une épilepsie en particulier chez l’enfant est souvent un tournant de la maladie et un critère de gravité avec 40 % de décès à 6 mois dans notre série. Les pathologies mitochondriales chez l’enfant sont souvent liées à des mutations de gènes nucléaires en dehors de MTAP6 et MTTPK, que l’épilepsie soit une épilepsie myoclonique, des états de mal convulsifs réfractaires (syndrome d’Alpers) ou sous forme d’épilepsie partielle continue lors d’épisodes de stroke-like. Les spasmes en flexion, épilepsie du nourrisson peuvent aussi être révélateur d’une maladie mitochondriale. Chez l’adulte, la sévérité de l’épilepsie et du pronostic paraît moindre. L’épilepsie est souvent myoclonique ou partielle et liée à des mutations de l’ADN mitochondrial. L’épilepsie est donc plus fréquemment pharmaco-résistante chez l’enfant et les choix thérapeutiques limités (en évitant le valproate de sodium en particulier en cas de suspicion de syndrome d’Alpers avec mutation PolG) avec un intérêt croissant du régime cétogène comme traitement anticomitial adjuvant. Conclusion La gravité du pronostic de l’épilepsie est liée au fait qu’un cercle vicieux s’installe entre la survenue d’une épilepsie témoin d’une souffrance cellulaire cérébrale énergétique et l’aggravation de la souffrance mitochondriale cérébrale par l’état de mal épileptique lui-même.
    No preview · Article · Jan 2014 · Revue Neurologique
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    ABSTRACT: STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, has been reported in Ohtahara syndrome, a rare epileptic encephalopathy with suppression burst pattern on EEG, in patients with infantile spasms and in a few patients with non syndromic mental retardation without epilepsy. We report a patient who presented late onset infantile spasms. Epilepsy was controlled but the patient developed severe mental delay. A first diagnosis of mitochondrial disease was based on clinical presentation and on a partial deficit of respiratory chain complex IV, but molecular screening for mitochondrial genes was negative. The sequencing of STXBP1 gene found a de novo nonsense mutation (c.585C>G/p.Tyr195X). This observation widens the clinical spectrum linked to STXBP1 mutations with the description of a patient with late onset infantile spasms. It raises the question of the value of epilepsy genes screening in patients with uncertain, partial or unconfirmed mitochondrial dysfunction.
    No preview · Article · Oct 2013 · European journal of medical genetics
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    ABSTRACT: The aetiology of mental impairment is highly heterogeneous and as new investigative techniques evolve, an increasing number of different causes are being reported. Establishing an aetiological diagnosis should, however, follow a well-defined strategy, in which brain MRI plays a fundamental role. Here, we present the four types of lesion most frequently revealed by brain MRI in mentally impaired patients: (1) spectroscopic anomaly, (2) accumulation of iron, (3) cortical malformations, and (4) leukodystrophy. By precisely characterising and classifying each lesion, MRI may be used to guide and target more extensive investigative molecular techniques, thus leading to aetiological diagnosis. MRI plays a two-fold role; on the one hand, it improves the cost-effectiveness of this exploratory procedure, and on the other, based on the classification of groups of patients with homogeneous radiological phenotypes and combined use of exome investigation techniques, may facilitate the discovery of novel genes implicated in mental impairment.
    No preview · Article · Jul 2013 · Medecine Therapeutique Pediatrie
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    ABSTRACT: Background This study describes the natural history of Barth syndrome (BTHS). Methods The medical records of all patients with BTHS living in France were identified in multiple sources and reviewed. Results We identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2–2.3). The median age at presentation was 3.1 weeks (range, 0–1.4 years), and the median age at last follow-up was 4.75 years (range, 3–15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients ≥3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 × 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000. Conclusions This survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation.
    Full-text · Article · May 2013 · Orphanet Journal of Rare Diseases
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    ABSTRACT: Although discordant phenotypes in monozygotic twins with developmental disorder are not an exception, underlying genetic discordance is rarely reported. Here, we report on the clinical and cytogenetic details of 4-year-old female monozygotic twins with discordant phenotypes. Twin 1 exhibited global developmental delay, overweight and hyperactivity. Twin 2 had an autistic spectrum disorder. Molecular karyotyping in twin 1 identified a 2p25.3 deletion, further confirmed by FISH analysis on leukocytes. Interestingly, array-CGH was normal in twin 2 but FISH analysis using the same probe as twin 1 showed mosaicism with 1/3 of cells with a 2p25.3 deletion, 1/3 of cells with a 2p25.3 duplication, and 1/3 of normal cells. Genotyping with microsatellite markers confirmed the monozygosity of the twins. We propose that the chromosome imbalance may be due to a mitotic non-allelic recombination occurring during blastomeric divisions of a normal zygote. Such event will result in three distinct cell populations, whose proportion in each embryo formed after separation from the zygote may differ, leading to discordant chromosomal anomalies between twins. We also discuss that the MYTL1L and the SNTG2 genes within the reported region could probably relate to the phenotypic discordance of the monozygotic twins.
    No preview · Article · Oct 2012 · Clinical Genetics
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    Preview · Article · Jul 2012 · Neurology
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    ABSTRACT: Isolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population.
    Preview · Article · Feb 2012 · Biochimica et Biophysica Acta
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    ABSTRACT: Developmental disability/mental retardation is a major public health problem and a common cause of consultation in pediatrics, neuropediatrics, and genetics. Etiologies of mental retardation are highly heterogeneous. Diagnostic strategies have been explored in a small number of consensus publications, essentially from English-speaking countries. In these publications, the utility of the conventional karyotype, fragile X screening, metabolic workup, and brain imaging were discussed. Recently, investigations in mental disabilities have been dramatically modified by molecular cytogenetics and the emergence of new metabolic pathologies. Based on the published experiments, the Reference centers for rare disease network "mental deficiencies with rare causes" elaborated an updated protocol for the investigation of nonsyndromal mental disability that takes into account recent innovations in genetics and genomics. Whenever local facilities make it possible, we recommend array CGH investigation as the first step or, when CGH is not available, a combination of classic karyotype with systematic screening of telomeric and interstitial rearrangements by MLPA, fragile X screening in both sexes, and a reorientation of metabolic screening toward certain diseases that have recently been described: congenital disorders of glycosylation (CDG), thyroid hormone carrier deficiency, and creatine metabolism deficiency. We recommend MRI imaging only if head size is abnormal, if neurological examination is abnormal, or regression occurs if walking is not achieved by 2 years, or if development is severely delayed.
    Full-text · Article · Feb 2012 · Archives de Pédiatrie

  • No preview · Article · Feb 2012 · Archives de Pédiatrie
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    ABSTRACT: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.
    Full-text · Article · Dec 2011 · Journal of Medical Genetics

Publication Stats

935 Citations
116.45 Total Impact Points

Institutions

  • 2014
    • Université Paris-Sorbonne - Paris IV
      Lutetia Parisorum, Île-de-France, France
  • 2011-2014
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2004-2010
    • Unité Inserm U1077
      Caen, Lower Normandy, France