Introduction: Antenatal presentation of hypertrophic cardiomyopathy (HCM) is rare. We describe familial recurrence of antenatal HCM associated with intrauterine growth restriction and the diagnostic process undertaken. Methods: Two pregnancies with antenatal HCM were followed up. Biological assessment including metabolic analyses, genetic analyses, and respiratory chain study was performed. We describe the clinical course of these two pregnancies, antenatal manifestations as well as specific histopathological findings, and review the literature. Results: The assessment revealed a deficiency in complex I of the respiratory chain and two likely pathogenic variations in the ACAD9 gene. Discussion and Conclusion: Antenatal HCM is rare and a diagnosis is not always made. In pregnancies presenting with cardiomyopathy and intrauterine growth restriction, ACAD9 deficiency should be considered as one of the potential underlying diagnoses, and ACAD9 molecular testing should be included among other prenatal investigations.

Purpose Diseases caused by defects in mitochondrial DNA (mtDNA) maintenance machinery, leading to mtDNA deletions, form a specific group of disorders. However, mtDNA deletions also appear during aging, interfering with those resulting from mitochondrial disorders. Methods Here, using next-generation sequencing (NGS) data processed by eKLIPse and data mining, we established criteria distinguishing age-related mtDNA rearrangements from those due to mtDNA maintenance defects. MtDNA deletion profiles from muscle and urine patient samples carrying pathogenic variants in nuclear genes involved in mtDNA maintenance (n = 40) were compared with age-matched controls (n = 90). Seventeen additional patient samples were used to validate the data mining model. Results Overall, deletion number, heteroplasmy level, deletion locations, and the presence of repeats at deletion breakpoints were significantly different between patients and controls, especially in muscle samples. The deletion number was significantly relevant in adults, while breakpoint repeat lengths surrounding deletions were discriminant in young subjects. Conclusion Altogether, eKLIPse analysis is a powerful tool for measuring the accumulation of mtDNA deletions between patients of different ages, as well as in prioritizing novel variants in genes involved in mtDNA stability.

To address the frequency of complex V defects, we systematically sequenced MT-ATP6/8 genes in 512 consecutive patients. We performed functional analysis in muscle or fibroblasts for 12 out of 27 putative homoplasmic mutations and in cybrids for four. Fibroblasts, muscle and cybrids with known deleterious mutations underwent parallel analysis. It included oxidative phosphorylation spectrophotometric assays, western blots, structural analysis, ATP production, glycolysis and cell proliferation evaluation. We demonstrated the deleterious nature of three original mutations. Striking gradation in severity of the mutations consequences and differences between muscle, fibroblasts and cybrids implied a likely under-diagnosis of human complex V defects.

Othello syndrome (OS) is a type of delusional jealousy, characterized by the false absolute certainty of the infidelity of a partner. This syndrome is not uncommon in Parkinson's Disease (PD), appearing as side effect of Dopaminergic Agonists (DA) therapy. We analyze the observations of five patients with OS, diagnosed in a series of 250 consecutive PD patients during two years. All patients are men, with a particularly young age at onset of PD. The mean duration of DA therapy at OS onset was 3 years. One patient had hypersexuality and another had punding. Significant cognitive impairment was present in two patients. All patients were treated with DA: two with Pramipexol and three with Piribedil. At the time of the management of the OS, three patients had already divorced their spouse. It is imperative for clinicians to know this underestimated syndrome in order to identify it early and approach it adequately to avoid irreversible negative prejudice.

Objective. - While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations. Research design and methods. - We performed a post-hoc analysis of a prospective multicenter cohort of 743 patients with mitochondrial disorder (previously published by the French Network of Mitochondrial Diseases), associated to a literature review of the PubMed database from 1992 to May 2016. We extracted all reported patients with diabetes and identified rare mtDNA mutations and described their clinical and metabolic phenotypes. Results. - The 50 identified patients (10 from the princeps study; 40 from the review of the literature) showed a heterogeneous metabolic phenotype in terms of age, symptoms prior to diagnosis, treatments, and associated clinical and biological signs. However, neurological symptoms were more frequent in case of rare mtDNA mutations compared to the classical m.3243 A> G mutation (A=0.024). In contrast, deafness (65% vs. 95%, P= 3.7E-5), macular pattern dystrophy (20% vs. 86%, P= 1.6E-10) and nephropathy (8% vs. 28%, P= 0.018) were significantly less frequent than in case of the classical m.3243 A>G mutation. Conclusion. - Although no specific metabolic phenotype could be identified suggesting or eliminating implication of rare mtDNA mutations in diabetes, clinical phenotypes featured more frequent neurological signs. (C) 2020 Elsevier Masson SAS. All rights reserved.

Objectives: To report two novel DNA2 gene mutations causing early onset myopathy with cardiac involvement and late onset mitochondriopathy with rhabdomyolysis. Methods: We performed detailed clinical, muscle histopathology and molecular studies including mitochondrial gene NGS analysis in two patients (Patient 1 and 2), a mother and her son, belonging to a Mexican family, and a third sporadic French patient. Results: Patient 1 and 2 presented with an early onset myopathy associated with ptosis, velopharyngeal weakness, and cardiac involvement. Patient 3 presented rhabdomyolysis unmasking a mitochondrial disease characterized by a sensorineural hearing loss, ptosis, and lipomas. Muscle biopsies performed in all patients showed variable mitochondrial alterations. Patient 3 had multiple mtDNA deletion in his muscle. Genetic studies revealed a novel heterozygous frameshift mutation in DNA2 gene (c.2346delT p.Phe782Leufs*3) in P1 and P2, and a novel heterozygous missense mutation in DNA2 gene (c.578T>C p.Leu193Ser) in the P3. Conclusions: To date only few AD cases presenting either missense or truncating DNA2 variants have been reported. None of them presented with a cardiac involvement or rhabdomyolysis. Here we enlarge the genetic and phenotypic spectrum of DNA2-related mitochondrial disorders.

Mutations in the gene encoding polymerase gamma (POLG) are a common cause of mitochondrial diseases in adults. We retrospectively analyzed volumetric and diffusion tensor imaging data from 20 adult POLG-mutated patients compared to healthy controls. We used an original clinical binary load score and electro-neuromyography to evaluate disease severity. Patients showed atrophy in the basal ganglia, amygdala, and brainstem (p < 0.05) compared to controls, as well as decreased fractional anisotropy (FA) in the cingulate gyrus, the internal capsule and the corona radiata (p < 0.05). Clinical scores correlated with decreased FA and increased radial diffusivity in several brain regions (p < 0.05).

Mitochondrial disease is concerning with rapid infantile liver failure. Two sibling pairs with variants in QIL1, a gene important for mitochondrial contact site and cristae organizing system (MICOS) function, were recently reported. They had intermittent liver disease, mild cardiac hypertrophy, cerebellar atrophy, acquired microcephaly, neurologic impairment and death before age 5 (12mo-5yo). Patients also had lactic acidosis and urinary excretion of 3-methylglutaconic acid (3MCGA) (1, 2). An additional case had renal stones, liver failure and progressive neurologic decline with death at 22mo (3). We discuss 7 unreported patients. This article is protected by copyright. All rights reserved.

Although relatively common in children, severe acute lactic acidosis is rare in adults with mitochondrial myopathies. We report here three cases, aged 27, 32 and 32 years, who developed life-threatening metabolic crisis with severe lactic acidosis, requiring hospitalisation in intensive care unit. Plasma lactates were elevated 10 to 15 fold normal values, necessitating extra-renal dialysis. By contrast CK levels were moderately increased (3 to 5N). No triggering factor was identified, but retrospectively all patients reported long-lasting mild muscle fatigability and weakness before their acute metabolic crisis. All of them recovered after prolonged intensive care but resting lactate levels remained elevated. Muscle biopsy showed ragged-red and COX-negative fibers in two patients and mild lipidosis in the third one. Heteroplasmic pathogenic point mutations were detected in MT-TL1 (m.3280G>A;m.3258C>T) and MT-TK (m.8363A>G). Life-threatening lactic acidosis may thus be a major inaugural clinical manifestation in adults with mitochondrial myopathies. Prolonged intensive care may lead to a dramatic and sustained improvement and is mandatory in such cases.

Le SANDO (Sensory Ataxic Neuropathy with Dysarthria and Ophthalmoplegia) est une mithochandriopathie rare, caractérisée par une neuropathie ataxiante au 1er plan, et liée à des mutations sur le gène POLG1. Nous rapportons le cas d’un jeune patient de 25 ans, ayant un syndrome de « SANDO » avec présentation clinique prédominante sur le versant moteur type « CMT-like » et compliqué de troubles psychiatrique (idées noires, accès psychotiques, dépression…). Le bilan électrophysiologique a objectivé une neuropathie sensitivomotrice, plus marquée aux deux membres inférieurs avec abolition des potentiels moteurs et sensitifs. L’étude génétique a conclu à une nouvelle mutation type c. 1789C > T, à l’état homozygote chez le patient et hétérozygote chez les parents. La grande hétérogénéité du phénotype « syndrome SANDO » lié à la mutation POLG1 nous a permis chez notre patiente de discuter plutôt un SMANDOP (Sensori-Motor Ataxic Neuropathy with Dysarthria Ophthalmoplegia and psychiatricdisorders) vu le phénotype plus moteur et le profil évolutif rapidement handicapant et amyotrophiant ainsi que les troubles psychiatriques majeurs qui ont marqué le stade final de l’évolution. Les auteurs proposent, à travers cette observation unique, une nouvelle entité le « SMANDOP » qui peut rejoindre hétérogénéité du phénotype « syndrome SANDO ».

Assessing long-term mortality and identifying predictors of death in adults with mitochondrial diseases. We retrospectively included adult patients with genetically proven mitochondrial diseases referred to our centre between January 2000 and June 2016, and collected information relative to their genetic testing, clinical assessments, and vital status. We performed single and multiple variable analyses in search of predictors of total mortality, and calculated hazard ratios (HR) and 95% confidence intervals (CI). We included 267 patients (women 59%; median age 43.3 [31.3-54.2] years), including 111 with mitochondrial DNA (mtDNA) single large-scale deletions, 65 with m.3243A>G, 24 with m.8344A>G, 32 with other mtDNA point mutations, and 36 patients with nuclear genes mutations. Over a median follow-up of 8.9 years (0.3 to 18.7), 61 patients (22.8%) died, at a median age of 50.7 (37.9-51.9) years. Primary cause of death was cardiovascular disease in 16 patients (26.2%), respiratory in 11 (18.0%), and gastrointestinal in 5 (8.1%). By multiple variable analysis, diabetes (HR 2.75; 95% CI 1.46-5.18), intraventricular cardiac conduction defects (HR 3.38; 95% CI 1.71-6.76) and focal brain involvement (HR 2.39; 95% CI 1.25-4.57) were independent predictors of death. Adult patients with mitochondrial diseases present high morbidity that can be independently predicted by the presence of diabetes, intraventricular cardiac conduction defects, and focal brain involvement.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Vers une harmonisation du diagnostic par séquençage haut débit des maladies neuromusculaires Aurélien Perrin, Philippe Latour, Vincent Procaccio, Claude Jardel, Mathieu Cerino, Gisèle Bonne, Emmanuelle Salort-Campana, J. Andoni Andoni Urtizberea, Jean Pouget, Martin Krahn, et al.

Purpose: Accurate detection of mitochondrial DNA (mtDNA) alterations is essential for the diagnosis of mitochondrial diseases. The development of high-throughput sequencing technologies has enhanced the detection sensitivity of mtDNA pathogenic variants, but the detection of mtDNA rearrangements, especially multiple deletions, is still poorly processed. Here, we present eKLIPse, a sensitive and specific tool allowing the detection and quantification of large mtDNA rearrangements from single and paired-end sequencing data. Methods: The methodology was first validated using a set of simulated data to assess the detection sensitivity and specificity, and second with a series of sequencing data from mitochondrial disease patients carrying either single or multiple deletions, related to pathogenic variants in nuclear genes involved in mtDNA maintenance. Results: eKLIPse provides the precise breakpoint positions and the cumulated percentage of mtDNA rearrangements at a given gene location with a detection sensitivity lower than 0.5% mutant. eKLIPse software is available either as a script to be integrated in a bioinformatics pipeline, or as user-friendly graphical interface to visualize the results through a Circos representation (https://github.com/dooguypapua/eKLIPse). Conclusion: Thus, eKLIPse represents a useful resource to study the causes and consequences of mtDNA rearrangements, for further genotype/phenotype correlations in mitochondrial disorders.

Les maladies mitochondriales, définies comme les affections dues à un défaut de la chaîne des oxydations phosphorylantes (OXPHOS), sont les plus fréquentes des maladies héréditaires du métabolisme. Ce sont des maladies de présentation clinique très variée et de diagnostic difficile. Elles sont essentiellement génétiques, dues à l'altération de gènes très divers localisés soit sur l'ADN mitochondrial (ADNmt), soit sur le génome nucléaire. Les avancées technologiques récentes (NGS) avec le séquençage de l'exome (WES) ont permis la découverte de nombreux gènes impliqués et de mieux comprendre les mécanismes physiopathologiques de ces maladies. La démarche diagnostique repose sur la présentation clinique, des explorations biochimiques, d'imagerie, d'histopathologie et génétiques communes. Les investigations génétiques portent sur la totalité de l'ADNmt puis en cas de négativité sur des panels larges de gènes nucléaires. Seule la mise en évidence du gène causal permet d'affirmer le diagnostic de maladie mitochondriale ; en l'absence de traitement de ces maladies elle permet un conseil génétique et la possibilité pour les parents de mettre au monde des enfants non atteints.