Marco Spinazzi

Centre Hospitalier Universitaire d'Angers | CHU Angers · Département de neurologie

Background Myasthenia gravis (MG) is an autoimmune disease treated with acetylcholinesterase inhibitors and immunosuppressant/immunomodulatory drugs. MG is frequently diagnosed in elderly patients, a fragile population in which treatment adverse effects (TAE) have not been evaluated until now. Methods We retrospectively analysed the files of all M...

Introduction: Patients with severe neuromuscular disease (sNMD) are considered at high risk of severe COVID-19. Muscle tissue is often replaced by fibroadipose tissue in these diseases whereas the new mRNA-based vaccines are injected intramuscularly. We aimed at evaluating the efficacy of two injections associated with a booster injection of mRNA...

Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of Leigh syndrome, develop early testicular atrophy caused by a complete arrest of sperm...

Background and Objectives Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients’ series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performa...

Background and objectives The French Pompe disease registry was created in 2004, for studies of the natural course of the disease in patients. It rapidly became a major tool for assessing the long-term efficacy of enzyme replacement therapy (ERT) following the market release of alglucosidase-alfa. Methods Almost 10 years after publication of the b...

The integrity of ER–mitochondria appositions ensures transfer of ions and phospholipids (PLs) between these organelles and exerts crucial effects on mitochondrial bioenergetics. Malfunctions within the ER–mitochondria contacts altering lipid trafficking homeostasis manifest in diverse pathologies, but the molecular effectors governing this process...

Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for PARL, the mitochondrial rhomboid protease, a recently reported model of Leigh syndrome, develop postpubertal testicular atrophy caused by arrested spermatogenesis and germ...

Duchenne muscular dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. Whereas mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. Here we demonstrate that in DMD and other muscular dystrophies, a large number of Dlk1-Dio3 clustered miRN...

Background Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE). Objectives We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population. Methods We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regre...

Background Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies and currently has no treatment. Clinical and genetic heterogeneity are the main challenges to a full comprehension of the physiopathological mechanism. Improving our knowledge of FSHD is crucial to the development of future therapeutic trials a...

Background Data on interruption of enzyme replacement therapy are scarce in late-onset Pompe disease. Due to the COVID-19 crisis, 8 neuromuscular reference centers in France were obligated to stop the treatment for 31 patients. Method We collected the motor and respiratory data from our French registry, before COVID-19 and at treatment restart. R...

Background Duchenne Muscular Dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. While mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. We recently identified in DMD and in other muscular dystrophies the upregulation of a large numbe...

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. Here, using next-generation sequencing (NGS) data processed by eKLIPse and data mining, we es...

Background To describe the clinical, pathological, and molecular characteristics of late onset (LO) dysferlinopathy patients. Methods Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS)...

Objective: To describe the clinical characteristics and outcomes of COVID-19 among patients with MG and identify factors associated with COVID-19 severity in MG patients. Methods: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS...

Importance: The tapering of prednisone therapy in generalized myasthenia gravis (MG) presents a therapeutic dilemma; however, the recommended regimen has not yet been validated. Objective: To compare the efficacy of the standard slow-tapering regimen of prednisone therapy with a rapid-tapering regimen. Design: From June 1, 2009, to July 31, 20...

Camptocormia is defined by a pathological involuntary flexion of the thoracic and lumbar spine that is fully reducible in the supine position. Although originally described as a manifestation of conversion disorder, it is more commonly caused by a wide range of neurological diseases, in particular movement and neuromuscular disorders. We describe h...

Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscl...

Fluorescein-derived fluorochromes and anionic dyes such as Fluoro-Jade (FJ) stains have been introduced to facilitate recognition of dying neurons in tissue sections. However, the definition of what is really detected by FJ-based stains and its sensitivity in the detection of neuronal cell death is unclear. In our work, we evaluated the outcome of...

Duchenne Muscular Dystrophy (DMD) is a muscle disease which is caused by the lack of dystrophin expression. MicroRNA profiling in DMD patients and animal models revealed a coordinated dysregulation of clustered miRNAs of the DLK1-DIO3 locus (DD-miRNAs), in both serum and muscles. DD-miRNA dysregulation was controled epigenetically by DNA and histon...

Objective Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme®), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stab...

Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene lin...

The T61I mutation in CHCHD2, a protein residing in the mitochondrial intermembrane space, causes an autosomal dominant form of Parkinson's disease (PD), but the underlying pathogenic mechanisms are not well understood. Here, we compared the subcellular localization and solubility of wild-type and T61I mutant CHCHD2 in human cells. We found that mit...

The T61I mutation in CHCHD2, a protein residing in the mitochondrial intermembrane space, causes an autosomal dominant form of Parkinson's disease (PD), but the underlying pathogenic mechanisms are not well understood. Here, we compared the subcellular localization and solubility of wild-type and T61I mutant CHCHD2 in human cells. We found that mit...

Genetically engineered mouse lines on a C57BL/6J background are widely employed as preclinical models to study neurodegenerative human disorders and brain tumors. However, because of the lack of comprehensive data on the spontaneous background neuropathology of the C57BL/6J strain, discriminating between naturally occurring changes and lesions caus...

The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that Parl ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with con...

The mitochondrial intramembrane rhomboid protease Parl has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that Parl ablation in mouse causes a striking necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice...

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and pat...

The rhomboid family comprises evolutionary conserved intramembrane proteases involved in a wide spectrum of biologically relevant activities. A mitochondrion-localized rhomboid, called PARL in mammals, and conserved in yeast and Drosophila as RBD1/PCP1 and rho-7, respectively, plays an indispensable role in cell homeostasis as illustrated by the se...

Focal amplifications of chromosome 3p13-3p14 occur in about 10% of melanomas and are associated with a poor prognosis. The melanoma-specific oncogene MITF resides at the epicentre of this amplicon. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-co...

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of lef...

Micronutrient deficiencies lead to under-recognized diseases affecting multiple systems, in particular the hematopoietic and nervous systems. The optic nerves can sometimes be affected, owing to their high energy requirements. The involved vitamins, as well as copper, are critical cofactors of mitochondrial enzymes involved in the production of ene...

Severe copper deficiency leads to a treatable multisystem disease characterized by anaemia and degeneration of spinal cord and nerves, but its mechanisms have not been investigated in humans. We tested whether copper deficit leads to alterations in fundamental copper dependent proteins and in iron metabolism in blood cells and muscles of patients a...

Objectives: Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial syndrome, mostly caused by the 8344A>G mitochondrial DNA mutation. Most of the previous studies have been based on single case/family reports or series with few patients. The primary aim of this study was the characterization of a large cohort of patients with th...

The assessment of mitochondrial respiratory chain (RC) enzymatic activities is essential for investigating mitochondrial function in several situations, including mitochondrial disorders, diabetes, cancer, aging and neurodegeneration, as well as for many toxicological assays. Muscle is the most commonly analyzed tissue because of its high metabolic...

The diagnosis of mitochondrial disorders is difficult due to clinical and genetic heterogeneity. Measurements of mitochondrial respiratory chain (RC) enzyme activities are essential for both clinical diagnoses and many basic research questions. Current protocols for RC analysis are not standardized, and so are prone to inter-laboratory variability,...

A 71 year-old man with a history of partial gastrectomy presented to the emergency department with subacute gait instability associated with painful dysesthesias and clumsiness in both hands. 10 years before presentation he had received a diagnosis of megaloblastic anemia, with no neurological involvement, as a result of vitamin B(12) and folate de...

Mitochondrial myopathies are regulated by two genomes: the nuclear DNA, and the mitochondrial DNA. While, so far, most studies have dealt with mitochondrial myopathies due to deletions or point mutations in the mitochondrial DNA, a new field of investigation is that of syndromes due to mutations in the nuclear DNA. These latter disorders have mende...

Ovarian carcinoma is a common gynecological malignancy. Distant metastases usually involve the liver and lung while neurological complications are rare. We describe the case of a 63-year-old woman diagnosed from an ovarian carcinoma with peritoneal seed, which was treated surgically and with chemotherapy. After 4 years she was admitted to our Depar...

Autosomal dominant optic atrophy (ADOA), the commonest cause of inherited optic atrophy, is caused by mutations in the ubiquitously expressed gene optic atrophy 1 (OPA1), involved in fusion and biogenesis of the inner membrane of mitochondria. Bioenergetic failure, mitochondrial network abnormalities and increased apoptosis have all been proposed a...

We observed a 42-year-old woman presenting with severe dysphagia secondary to paralysis of the lower cranial nerves and right phrenic nerve involvement, followed by respiratory failure. An EMG confirmed bilateral denervation of the 9th, 10th, 11th and 12th cranial nerves and right phrenic nerve. Videolaryngoscopy showed bilateral vocal fold immobil...

Limb girdle muscular dystrophy type 2A (LGMD2A) is characterised by wide variability in clinical features and rate of progression. Patients with two null mutations usually have a rapid course, but in the remaining cases (two missense mutations or compound heterozygote mutations) prognosis is uncertain. We conducted what is to our knowledge the firs...

Acquired copper deficiency has recently been recognized as a cause of myeloneuropathy mimicking subacute combined degeneration due to vitamin B-12 deficiency. A remote history of gastric surgery is frequently associated with this syndrome. However, the very limited prevalence of severe copper deficiency in patients with a history of gastric surgery...

Acquired copper deficiency has recently been recognized as a cause of myeloneuropathy mimicking subacute combined degeneration due to vitamin B-12 deficiency. A remote history of gastric surgery is frequently associated with this syndrome. However, the very limited prevalence of severe copper deficiency in patients with a history of gastric surger...

Hereditary mitochondrial fusion disorders like ADOA, due to OPA1 gene mutations, and CMT2A, due to MFN2 gene mutations, are recognized causes of optic atrophy, due to optic nerve fibers degeneration. CMT2 additional distinguishing and predominant feature includes axonal peripheral neuropathy. We studied the clinical, laboratory, electrophysiologica...

Danon disease is an X-linked dominant disorder due to mutations in the LAMP2 gene, presenting with hypertrophic cardiomyopathy, skeletal myopathy and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle...

Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and...

Limb girdle muscular dystrophy (LGMD) type 2A (LGMD2A) is caused by mutations in the CAPN3 gene encoding for calpain-3, a muscle specific protease. While a large number of CAPN3 gene mutations have already been described in calpainopathy patients, the diagnosis has recently shifted from molecular genetics towards biochemical assay of defective prot...

Limb girdle muscular dystrophy (LGMD) type 2A (LGMD2A) is caused by mutations in the CAPN3 gene encoding for calpain-3, a muscle specific protease. While a large number of CAPN3 gene mutations have already been described in calpainopathy patients, the diagnosis has recently shifted from molecular genetics towards biochemical assay of defective prot...