Truncating mutations on myofibrillar myopathies causing genes as prevalent molecular explanations on patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. More than 40 genes have been reported to cause DCM. To provide new insights into the pathophysiology of dilated cardiomyopathy, a next-generation sequencing (NGS) workflow based on a panel of 48 cardiomyopathies-causing genes was used to analyze a cohort of 222 DCM patients. Truncating variants were detected on 63 unrelated DCM cases (28.4%). Most of them were identified, as expected, on TTN (29 DCM probands), but truncating variants were also identified on myofibrillar myopathies causing genes in 17 DCM patients (7.7% of the DCM cohort): 10 variations on FLNC and 7 variations on BAG3 . This study confirms that truncating variants on myofibrillar myopathies causing genes are frequently associated with dilated cardiomyopathies and also suggest that FLNC mutations could be considered as a common cause of dilated cardiomyopathy. Molecular approaches that would allow to detect systematically truncating variants in FLNC and BAG3 into genetic testing should significantly increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy.

Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease.

INTRODUCTION: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. METHODS AND RESULTS: Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. CONCLUSION: Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.

[Necrotizing autoimmune myopathies]. / Les myopathies nécrosantes auto-immunes.

Necrotizing autoimmune myopathies are included in the spectrum of inflammatory myopathies, together with polymyosis, dermatopolymyosis and inclusion body myositis, despite the characteristic feature of marked muscular necrosis without inflammatory infiltrates. The clinical presentation is highly variable, often similar to the other inflammatory myopathies. The most common finding is nevertheless the severe form with rhabdomyolysis. The creatine kinase level is elevated (around 10,000IU/l) and electromyography shows myopathic changes with increased spontaneous activities reflecting the importance of the muscular necrosis. Muscle biopsy is required for diagnosis, revealing active necrosis of the muscle fibers without inflammatory invasion by CDA+ or CD8+ T-cells. Deposition of a microvascular membrane attack complex (C5b9) is often noted, whereas the upregulation of MHC class 1 is rarely detected. Signs of endomysial microangiopathy are frequently reported. Necrotizing autoimmune myopathies can be associated with antisignal recognition particle (SRP) antibodies or more rarely with the usual inflammatory myopathy antibodies. Paraneoplasic forms are described but remain exceptional. Lastly, necrotizing autoimmune myopathies, sometimes associated with statin therapy, have been recently described. They are linked with an antibody directed against 3-hydroxy-3-methyglutaryl-coenzyme A. Treatment is based on corticosteroid therapy, immunosuppressive drugs or intravenous immunoglobulins. Response is variable, depending on the clinical form.

[Exercise-induced muscle pain due to phosphofrutokinase deficiency: Diagnostic contribution of metabolic explorations (exercise tests, 31P-nuclear magnetic resonance spectroscopy)]. / Intolérance musculaire à l'effort par déficit en phosphofructokinase : apport au diagnostic du bilan métabolique musculaire (tests d'effort, spectroscopie RMN du P31).

INTRODUCTION: Muscle phosphofructokinase deficiency, the seventh member of the glycogen storage diseases family, is also called Tarui's disease (GSD VII). METHODS: We studied two patients in two unrelated families with Tarui's disease, analyzing clinical features, CK level, EMG, muscle biopsy findings and molecular genetics features. Metabolic muscle explorations (forearm ischemic exercise test [FIET]; bicycle ergometer exercise test [EE]; 31P-nuclear magnetic resonance spectroscopy of calf muscle [31P-NMR-S]) are performed as appropriate. RESULTS: Two patients, a 47-year-old man and a 38-year-old woman, complained of exercise-induced fatigue since childhood. The neurological examination was normal or showed light weakness. Laboratory studies showed increased CPK, serum uric acid and reticulocyte count without anemia. There was no increase in the blood lactate level during the FIET or the EE although there was a light increase in the respiratory exchange ratio during the EE. 31P-NMR-S revealed no intracellular acidification or accumulated intermediates such as phosphorylated monoesters (PME) known to be pathognomic for GSD VII. Two new mutations were identified. DISCUSSION: FIET and EE were non-contributive to diagnosis, but 31P-NMR provided a characteristic spectra of Tarui's disease, in agreement with phosphofructokinase activity level in erythrocytes. Muscle biopsy does not always provide useful information for diagnosis. In these two cases, genetic studies failed to establish a genotype-phenotype correlation. CONCLUSION: The search for phosphofructokinase deficiency should be continued throughout life in adults experiencing fatigability or weakness because of the severe disability for daily life activities caused by the late onset form.

Brain immunohistopathological study in a patient with anti-NMDAR encephalitis.

BACKGROUND AND PURPOSE: Anti-N-methyl-D-asparate (NMDA) receptor encephalitis is thought to be antibody-mediated. To perform an immunohistopathological study of the inflammatory reaction in a brain biopsy performed before immunomodulatory treatments in a patient with anti-NMDA receptor encephalitis. METHODS: An immunohistochemical study was performed using CD3, CD68, CD20, CD138 and CD1a antibodies. RESULTS: Prominent B-cell cuffing was present around brain vessels accompanied by some plasma cells, while macrophages and T cells were scattered throughout the brain parenchyma. CONCLUSION: These findings suggest that the B cells interact with the T cells and are involved in antibody secretion by the plasma cells.

Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways.

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into two main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery, and radiotherapy. The 5-year survival rate has plateaued at 70% since 2000, despite several clinical trials. RMS cells are thought to derive from the muscle lineage. During development, myogenesis includes the expansion of muscle precursors, the elimination of those in excess by cell death and the differentiation of the remaining ones into myofibers. The notion that these processes may be hijacked by tumor cells to sustain their oncogenic transformation has emerged, with RMS being considered as the dark side of myogenesis. Thus, dissecting myogenic developmental programs could improve our understanding of RMS molecular etiology. We focused herein on ANT1, which is involved in myogenesis and is responsible for genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a dual functionality, as it is involved both in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore. Bioinformatics analyses of transcriptomic datasets revealed that ANT1 is expressed at low levels in RMS. Using the CRISPR-Cas9 technology, we showed that reduced ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects arise notably from an abnormal metabolic switch induced by ANT1 downregulation. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapy. Based on our results, modulation of ANT1 expression and/or activity appears as an appealing therapeutic approach in RMS management.

Primary angiitis of the central nervous system: response to mycophenolate mofetil.

Primary angiitis of the central nervous system (PACNS) is a rare inflammatory disease restricted to the CNS of unknown cause. Clinical presentation and evolution are highly variable with potentially fluctuating signs and symptoms. Brain imaging often shows supratentorial ischaemic lesions. Definite diagnosis is established by brain biopsy. Treatment usually combines glucocorticosteroids and cyclophosphamide. A case of PACNS is reported here, which was proved by a brain biopsy and characterised by unusually prominent involvement of the posterior cerebral fossa. Successful treatment with mycophenolate mofetil in combination with steroids is described.

[Structural anatomy of cranial nerves (V, VII, VIII, IX, X)]. / Anatomie structurelle des nerfs crâniens (V, VII, VIII, IX, X).

This study reports a review of the literature on the structural anatomy of the Vth, VIIth, VIIIth, IXth, and Xth cranial nerves, known to harbor dysfunction syndromes in humans. Because these dysfunctions are hypothesized to be caused by neurovascular conflicts at the root entry/exit zone and the transitional zone between central and peripheral myelinization, this investigation focused on the study and description of this junction. All the cranial nerves, except the optic and olfactory nerves, which are considered to be more a direct expansion of the central nervous system, have a transitional zone between central myelin (coming from oligodendrocytes) and peripheral myelin (produced by Schwann cells). The human studies reported in the literature argue in favor of a dome-shaped transitional zone directed to the periphery. It seems that this junctional region is situated more peripherally in sensory nerves than in motor nerves. The transitional zone is situated very peripherally for the cochlear and vestibular nerves, and on the contrary very close to its exit from the brain stem for the facial nerve.

Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene.

Deficiency of Dolichol-P-mannose synthase subunit 3 (DPM3) affects the N-glycosylation and O-mannosylation pathways that are respectively involved in congenital disorders of glycosylation (CDG) and alpha-dystroglycanopathies. Herein, we describe novel pathogenic variants in the DPM3 gene in two unrelated male patients. They developed dilated cardiomyopathy in their late teens, limb-girdle muscular dystrophy - one patient in childhood and the other in adulthood. In both patients, next generation sequencing found in the DPM3 gene a heterozygous deletion and a heterozygous pathogenic missense mutation in exon 2 (c.41T>C, p.Leu14Pro). Electrophoresis of serum transferrin found an abnormal N-glycosylation profile suggestive of CDG type 1 (decreased tetrasialotransferrin, increased disialo- and asialotransferrin). Only two cases of DPM3 gene mutations with limb-girdle muscular dystrophy-dystroglycanopathy have been reported previously. The present study highlights several aspects related to DPM3 gene mutations such as mild to moderately severe limb-girdle muscular dystrophy, dilated cardiomyopathy, and abnormal N-glycosylation profile suggestive of CDG type 1.

[Unilateral presentation of X-linked myotubular myopathy (XLMTM) in two out of three female carriers in a family with no affected male]. / Expression hémicorporelle d'une myopathie myotubulaire liée à l'X (XLMTM) chez deux des trois femmes conductrices d'une même famille sans cas masculin.

INTRODUCTION: X-linked myotubular myopathy (XLMTM), a recessive disorder, is caused by mutations affecting the myotubulatin (MTM1) gene located on the X chromosome. Most of the affected males die in the early postnatal period whereas female carriers are usually asymptomatic. CASE REPORTS: We report a family in which two females (45 and 27 years old) in two different generations, presented unilateral weakness which had worsened since adolescence, and one 48-year-old woman presented minimal symptoms. In agreement with the computed tomography and magnetic resonance imaging findings, the EMG was compatible with myopathy. Serum creatine kinase was elevated in the second patient. The histological study showed centronuclear myopathy aspects, more severe in the second patient. Both presented c.1420C>T, p.Arg474X in exon 13 of the MTM1 gene, whereas the third patients with less pronounced manifestation, had a skewed pattern of X chromosome inactivation. DISCUSSION: Symptomatic female carriers of XLMTM can present with asymmetric malformations, which must be distinguished from an autosomal-dominant centronuclear myopathy. CONCLUSION: Unilateral presentation of weakness cannot rule out a diagnosis of myopathy. Detection of symptomatic female carriers of an X linked recessive disease, with a severe presentation in males, is important for genetic counselling.

Diffusion-weighted imaging in brain aspergillosis.

Brain aspergillosis is a rare pathology, occurring mainly in immunocompromised patients, responsible for multiple cerebral septic infarctions. Some researchers have described magnetic resonance (MR) findings in cerebral invasive aspergillosis, but diffusion-weighted imaging (DWI) has rarely been reported, especially in typical non-enhancing lesions, while it may be helpful for early differential diagnosis and may allow earlier antifungal treatment. We describe three cases of patients presenting brain aspergillosis, with MR imaging including diffusion-weighted sequences and apparent diffusion coefficient (ADC) cartography. The three patients described in this study presented a total of 23 circular lesions, and one patient presented an infarction area in the territory of the right middle cerebral artery. Lesions were ring-enhancing for one patient, and presented no enhancement for the other two. Eleven lesions were very bright on DWI, with reduced ADC values. Twelve lesions, either enhancing or not enhancing, presented a 'target-like' aspect with central and peripheral hypointense areas on DWI, corresponding to higher ADC value areas, and intermediate marked hypersignal on DWI. This typical aspect of aspergillosis lesions on DWI may allow early diagnosis and treatment of cerebral aspergillosis, and is helpful for differentiating aspergillosis lesions from other infectious or malignant lesions affecting immunocompromised patients.

[Sarcoidosis demonstrated by fluorodeoxyglucose positron emission tomography in a case of granulomatous myopathy]. / Apport de la tomographie par émission de positons pour le diagnostic de sarcoïdose au cours d'une myopathie granulomateuse.

INTRODUCTION: Granulomatous myositis is a rare condition that has been described in association with sarcoidosis. In the absence of sarcoidosis or other underlying disease, a diagnosis of isolated granulomatous myositis is considered. OBSERVATION: A 61-year-old African man presented with progressive limitation in running and proximal atrophy of the lower limbs for the past year. Quadricipital muscle biopsy revealed non-caseating epithelioid granulomas and multinuclear giant cells. Whole body fluorodeoxyglucose positron emission tomography ((18)FDG-PET) revealed hypermetabolic activity of salivary and lachrymal glands, and mild hypermetabolism in the mediastinal lymph nodes. Minor salivary gland biopsy was consistent with sarcoidosis. CONCLUSION: To our knowledge, this is the first reported case of sarcoid myopathy demonstrating the diagnostic usefulness of (18)FDG-PET.

[Family study allows more optimistic prognosis and genetic counselling in a child with a deletion of exons 50-51 of the dystrophin gene]. / Impact de l'étude familiale sur le pronostic et le conseil génétique chez un enfant porteur d'une délétion des exons 50-51 du gène de la dystrophine.

INTRODUCTION: In frame deletions of exons encoding the central rod domain of dystrophin have been associated with a highly variable phenotype, including asymptomatic individuals. The lack of family history impairs accurate genetic counselling. OBSERVATION: We report on a 4-year-old child suffering from transient episodes of limping at the age of 2 and several episodes of fall since the age of 3. Clinical examination did not show muscle weakness. CPK levels were increased (1300 UI). EMG was normal. Muscle histology showed a rhabdomyolysis without features of muscular dystrophy. Immunolabelling for dystrophin, merosin and dysferlin were normal. Western blot analysis of muscular proteins showed reduced-size dystrophin bands and a slightly reduced intensity for dystrophin, alpha and gamma-sarcoglycan. Multiplex PCR of the dystrophin gene showed an in-frame deletion of exons 50-51, predicted to be associated to a Becker type of dystrophinopathy. Intragenic markers and quantitative PCR suggested maternal inheritance. This was confirmed by testing the maternal grand-parents, revealing that the asymptomatic 69-year-old grand father was a carrier. Three additional healthy males, whose ages ranged from 28 to 55 years and who were asymptomatic, also carried the mutation. The proband became spontaneously asymptomatic and cardiac echography was normal. In light of these data, genetic counselling was more reassuring and the mutation carrier maternal aunt, who was pregnant, decided to continue the pregnancy. CONCLUSION: This case report emphasizes the importance of family molecular analysis, especially in males from the maternal lineage, for genetic counselling of dystrophinopathies associated to atypical features or to an isolate increase of muscular enzymes level in a young boy with no positive family history.

[Focal myositis: An unknown disease]. / Myosite focale : une maladie méconnue.

Focal myositis are inflammatory muscle diseases of unknown origin. At the opposite from the other idiopathic inflammatory myopathies, they are restricted to a single muscle or to a muscle group. They are not associated with extramuscular manifestations, and they have a good prognosis without any treatment. They are characterized by a localized swelling affecting mostly lower limbs. The pseudo-tumor can be painful, but is not associated with a muscle weakness. Creatine kinase level is normal. Muscle MRI shows an inflammation restricted to a muscle or a muscle group. Muscle biopsy and pathological analysis remain necessary for the diagnosis, showing inflammatory infiltrates composed by macrophages and lymphocytes without any specific distribution within the muscle. Focal overexpression of HLA-1 by the muscle fibers is frequently observed. The muscle biopsy permits to rule out differential diagnosis such a malignancy (sarcoma). Spontaneous remission occurs within weeks or months after the first symptoms, relapse is unusual.

[Diffusion and perfusion MR imaging in cerebral lymphomas]. / IRM de diffusion-perfusion dans l'évaluation des lymphomes cérébraux.

Because of the increasing incidence of cerebral lymphoma, it is critical for patient management to recognize the MR features of this disease. We present the characteristic morphological and functional MRI features of this tumor. The findings on MRI studies, including morphological, diffusion and perfusion imaging, performed in 9 biopsy-proven cases of cerebral lymphoma with 13 lesions are presented and analyzed, and are discussed in comparison with published literature data. All patients underwent diffusion-weighted imaging with a single shot echo-planar pulse sequence. Dynamic susceptibility-contrast MRI was performed using a T2*-weighted gradient-echo echo-planar sequence after intravenous injection of chelates of gadolinium at the rate of 6 ml/s and a temporal resolution of 1 second. All cases of cerebral lymphoma appeared hypointense or isointense on T1-weighted images and in 75% of cases iso- or hypointense on T2-weighted images. All lesions enhanced except one in a patient receiving steroid therapy. On diffusion-weighted images, tumours were hyperintense with normal or decreased ADC values (0.717+/-0.152.10-3 mm2/sec, range: 0.550-1.014) and an ADC ratio tumour/normal white matter of 0.974+/-0.190 (range: 0.768-1.410). On perfusion, the signal intensity-time curve of each tumour showed a characteristic type of curve with a significant increase of the signal intensity above the baseline and a low maximum relative cerebral blood volume ratio (rCVBmax) of 1.43+/-0.64 (0.55-2.62). Due to their higher cellularity, the lack of neoangiogenesis, and the increased permeability of the blood-brain barrier related to the infiltration of blood vessels wall by lymphomatous cells, cerebral lymphoma presents characteristic diffusion and perfusion MRI features that should be useful for diagnosis and patient follow-up.

Focal myositis: A review.

Amongst the heterogeneous group of inflammatory myopathies, focal myositis stands as a rare and benign dysimmune disease. Although it can be associated with root and/or nerve lesions, traumatic muscle lesions and autoimmune diseases, its triggering factors remain poorly understood. Defined as an isolated inflammatory pseudotumour usually restricted to one skeletal muscle, clinical presentation of focal myositis is that of a rapidly growing solitary mass within a single muscle, usually in the lower limbs. Electromyography shows spontaneous activity associated with a myopathic pattern. MRI reveals a contrast enhanced enlarged muscle appearing hyper-intense on FAT-SAT T2 weighted images. Adjacent structures are spared and there are no calcifications. Serum creatine kinase (CK) levels are usually moderately augmented and biological markers of systemic inflammation are absent in most cases. Pathological histological features include marked variation in fibre size, inflammatory infiltrates mostly composed of T CD4+ lymphocytes and macrophages, degenerating/regenerating fibres and interstitial fibrosis. Differential diagnoses are numerous and include myositis of other origin with focal onset. Steroid treatment should be reserved for patients who present with major pain, nerve lesions, associated autoimmune disease, or elevated C reactive protein or CK.

[Autosomal dominant limb-girdle muscular dystrophy associated with conduction defects (LGMD1B): a description of 8 new families with the LMNA gene mutations]. / La dystrophie musculaire des ceintures autosomique dominante associée à des troubles de la conduction cardiaque (LGMD1B). Description de 8 nouvelles familles avec mutations du gène LMNA.

INTRODUCTION: Limb girdle muscular dystrophy type 1b (LGMD1B), due to LMNA gene mutations, is a relatively rare form of LGMD characterized by proximal muscle involvement associated with heart involvement comprising atrio-ventricular conduction blocks and dilated cardiomyopathy. Its clinical and genetic diagnosis is crucial for cardiac management and genetic counselling. Seven LMNA mutations have been previously reported to be responsible for LGMD1B. PATIENTS AND METHODS: We describe the neurological and cardiologic features of 14 patients belonging to 8 families in whom we identified 6 different LMNA mutations, 4 of them having never been reported. Results. Eleven patients had an LGMD1B phenotype with scapulohumeral and pelvic-femoral involvement. Thirteen patients had cardiac disease associating conduction defects (12 patients) or arrhythmias (9 patients). Seven patients needed cardiac device (pacemaker or implantable cardiac defibrillator) and two had heart transplantation. CONCLUSION: This study allowed us to specify the clinical characteristics of this entity and to outline the first phenotype/genotype relations resulting from these observations.

Significant response to immune therapies in a case of subacute necrotizing myopathy and FKRP mutations.

Necrotizing myopathies can be encountered in various conditions as acquired myopathies (toxic or autoimmune) or muscular dystrophies. We report a twenty-year-old Caucasian woman who presented with clinical findings suggestive of an inflammatory myopathy: subacute onset of lower limb muscle weakness, myalgia, weight loss and absence of family history. The serum creatine kinase level was elevated at 4738 IU/L (normal range, 25-175 IU/L). Muscle biopsy was consistent with necrotizing myopathy. The patient showed significant clinical improvement following corticosteroid, azathioprine and intravenous immunoglobulin treatments. Biological tests revealed no specific autoantibodies associated with necrotizing autoimmune myopathies. Immunohistochemical staining for sarcolemmal proteins in muscle biopsy samples finally led to a diagnosis of limb-girdle muscular dystrophy 2I (fukutin-related protein gene mutations). The response to immune therapies suggested a possible inflammatory component associated with the muscular dystrophy and highlighted the potential benefit of corticosteroid treatment in patients with LGMD2I and subacute onset.