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1.
Brain ; 2024 May 02.
Article in English | MEDLINE | ID: mdl-38696726

ABSTRACT

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years (SD = 15.1). Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit (ICU) admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved.

2.
Acta Neuropathol ; 148(1): 43, 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39283487

ABSTRACT

Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.


Subject(s)
Amyotrophic Lateral Sclerosis , Forkhead Box Protein O1 , Muscle, Skeletal , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Humans , Animals , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Forkhead Box Protein O1/metabolism , Forkhead Box Protein O1/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Male , RNA-Binding Protein FUS/genetics , RNA-Binding Protein FUS/metabolism , Female , Drosophila , Muscle Development/physiology , Middle Aged , Aged , Motor Neurons/metabolism , Motor Neurons/pathology , Myoblasts/metabolism
3.
Am J Hum Genet ; 107(6): 1078-1095, 2020 12 03.
Article in English | MEDLINE | ID: mdl-33217308

ABSTRACT

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/physiology , Molecular Chaperones/genetics , Molecular Chaperones/physiology , Muscular Diseases/genetics , Mutation, Missense , Adolescent , Adult , Alleles , Animals , Caenorhabditis elegans , Female , Genetic Variation , Humans , Loss of Function Mutation , Male , Muscle, Skeletal/pathology , Myofibrils , Myosins , Sarcomeres/metabolism , Sequence Analysis, RNA , Transgenes , Exome Sequencing , Young Adult
4.
Neuropathol Appl Neurobiol ; : e12952, 2023 Dec 20.
Article in English | MEDLINE | ID: mdl-38124360

ABSTRACT

AIMS: Limb-girdle congenital myasthenic syndrome (LG-CMS) is a genetically heterogeneous disorder characterized by muscle weakness and fatigability. The LG-CMS gene DPAGT1 codes for an essential enzyme of the glycosylation pathway, a posttranslational modification mechanism shaping the structure and function of proteins. In DPAGT1-related LG-CMS, reduced glycosylation of the acetylcholine receptor (AChR) reduces its localization at the neuromuscular junction (NMJ), and results in diminished neuromuscular transmission. LG-CMS patients also show tubular aggregates on muscle biopsy, but the origin and potential contribution of the aggregates to disease development are not understood. Here, we describe two LG-CMS patients with the aim of providing a molecular diagnosis and to shed light on the pathways implicated in tubular aggregate formation. METHODS: Following clinical examination of the patients, we performed next-generation sequencing (NGS) to identify the genetic causes, analysed the biopsies at the histological and ultrastructural levels, investigated the composition of the tubular aggregates, and performed experiments on protein glycosylation. RESULTS: We identified novel pathogenic DPAGT1 variants in both patients, and pyridostigmine treatment quantitatively improved muscle force and function. The tubular aggregates contained proteins of the sarcoplasmic reticulum (SR) and structurally conformed to the aggregates observed in tubular aggregate myopathy (TAM). TAM arises from overactivation of the plasma membrane calcium channel ORAI1, and functional studies on muscle extracts from our LG-CMS patients evidenced abnormal ORAI1 glycosylation. CONCLUSIONS: We expand the genetic variant spectrum of LG-CMS and provide a genotype/phenotype correlation for pathogenic DPAGT1 variants. The discovery of ORAI1 hypoglycosylation in our patients highlights a physiopathological link between LG-CMS and TAM.

6.
Eur J Neurol ; 30(3): 745-748, 2023 03.
Article in English | MEDLINE | ID: mdl-36403110

ABSTRACT

BACKGROUND AND PURPOSE: Amyloid myopathy is a rare and severe manifestation of systemic light chain (AL) amyloidosis. Early diagnosis and staging are mandatory for optimal therapy, given the rapid progression of muscle weakness. Despite the efficacy of bortezomib-based treatment regimens, there is a lack of therapeutic alternatives in non-responsive patients. METHOD: The case report of a patient with systemic AL amyloidosis myopathy treated with daratumumab is presented. RESULTS: A 70-year-old man displayed severe proximal muscle weakness which had developed over a 10-month period. Blood tests revealed an immunoglobulin A lambda monoclonal gammopathy, whilst muscle biopsy showed amyloid deposits within the arteriolar walls, confirming the diagnosis of amyloid myopathy associated with AL amyloidosis. Initial treatment with a bortezomib-based regimen showed no clinical or hematological improvement. After switching to daratumumab monotherapy, our patient achieved a favorable evolution with respect to functional muscle scoring and a complete hematological response. CONCLUSION: To our knowledge, this is the first case report of an amyloid myopathy showing a remarkable clinical improvement in response to daratumumab monotherapy. It thereby highlights the potential of daratumumab as a monotherapeutical approach to the treatment of amyloid myopathy complicating AL amyloidosis.


Subject(s)
Amyloidosis , Immunoglobulin Light-chain Amyloidosis , Muscular Diseases , Male , Humans , Aged , Immunoglobulin Light-chain Amyloidosis/complications , Immunoglobulin Light-chain Amyloidosis/drug therapy , Immunoglobulin Light-chain Amyloidosis/diagnosis , Bortezomib/therapeutic use , Amyloidosis/complications , Amyloidosis/drug therapy , Amyloidosis/diagnosis , Muscular Diseases/complications , Muscular Diseases/drug therapy , Muscular Diseases/diagnosis , Muscle Weakness
7.
Int J Mol Sci ; 24(13)2023 Jul 06.
Article in English | MEDLINE | ID: mdl-37446359

ABSTRACT

Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene (DES) result in a variety of diseases, including cardiomyopathies and myofibrillar myopathy, collectively called desminopathies. Here we describe the clinical, histological and radiological features of a Greek patient with a myofibrillar myopathy and cardiomyopathy linked to the c.734A>G,p.(Glu245Gly) heterozygous variant in the DES gene. Moreover, through ribonucleic acid sequencing analysis in skeletal muscle we show that this variant provokes a defect in exon 3 splicing and thus should be considered clearly pathogenic.


Subject(s)
Cardiomyopathies , Muscular Diseases , Myopathies, Structural, Congenital , Humans , Desmin/genetics , Desmin/metabolism , Greece , Cardiomyopathies/metabolism , Myopathies, Structural, Congenital/metabolism , Muscle, Skeletal/metabolism , Mutation , Muscular Diseases/metabolism
8.
Neuropathol Appl Neurobiol ; 48(1): e12761, 2022 02.
Article in English | MEDLINE | ID: mdl-34405429

ABSTRACT

AIMS: Several neurodegenerative and neuromuscular disorders are characterised by storage of polyglucosan, consisting of proteins and amylopectin-like polysaccharides, which are less branched than in normal glycogen. Such diseases include Lafora disease, branching enzyme deficiency, glycogenin-1 deficiency, polyglucosan body myopathy type 1 (PGBM1) due to RBCK1 deficiency and others. The protein composition of polyglucosan bodies is largely unknown. METHODS: We combined quantitative mass spectrometry, immunohistochemical and western blot analyses to identify the principal protein components of polyglucosan bodies in PGBM1. Histologically stained tissue sections of skeletal muscle from four patients were used to isolate polyglucosan deposits and control regions by laser microdissection. Prior to mass spectrometry, samples were labelled with tandem mass tags that enable quantitative comparison and multiplexed analysis of dissected samples. To study the distribution and expression of the accumulated proteins, immunohistochemical and western blot analyses were performed. RESULTS: Accumulated proteins were mainly components of glycogen metabolism and protein quality control pathways. The majority of fibres showed depletion of glycogen and redistribution of key enzymes of glycogen metabolism to the polyglucosan bodies. The polyglucosan bodies also showed accumulation of proteins involved in the ubiquitin-proteasome and autophagocytosis systems and protein chaperones. CONCLUSIONS: The sequestration of key enzymes of glycogen metabolism to the polyglucosan bodies may explain the glycogen depletion in the fibres and muscle function impairment. The accumulation of components of the protein quality control systems and other proteins frequently found in protein aggregate disorders indicates that protein aggregation may be an essential part of the pathobiology of polyglucosan storage.


Subject(s)
Glycogen Storage Disease , Proteomics , Glucans/metabolism , Glycogen Storage Disease/metabolism , Glycogen Storage Disease/pathology , Humans , Muscle, Skeletal/pathology , Transcription Factors , Ubiquitin-Protein Ligases/metabolism
9.
Neuropathol Appl Neurobiol ; 48(1): e12743, 2022 02.
Article in English | MEDLINE | ID: mdl-34164833

ABSTRACT

Rare pathogenic variants in TOR1AIP1 (OMIM 614512), coding the inner nuclear membrane protein lamin-associated protein 1 (LAP1), have been associated with a spectrum of disorders including limb girdle muscular dystrophy with cardiac involvement and a severe multisystem phenotype. Recently, Cossins et al reported two siblings with limb girdle muscular dystrophy and impaired transmission of the neuromuscular synapse, demonstrating that defective LAP1 may lead to a congenital myasthenic syndrome. Herein, we describe the association of TOR1AIP1 deficiency with congenital myasthenic syndrome in three siblings.


Subject(s)
Muscular Dystrophies, Limb-Girdle , Myasthenic Syndromes, Congenital , Cytoskeletal Proteins/genetics , Humans , Lamins/genetics , Membrane Proteins/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Mutation , Myasthenic Syndromes, Congenital/genetics , Phenotype
10.
Article in English | MEDLINE | ID: mdl-35896379

ABSTRACT

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

11.
Ann Neurol ; 88(2): 332-347, 2020 08.
Article in English | MEDLINE | ID: mdl-32403198

ABSTRACT

OBJECTIVE: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. METHODS: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done. RESULTS: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. INTERPRETATION: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332-347.


Subject(s)
Dimethylallyltranstransferase/genetics , Farnesyltranstransferase/genetics , Geranyltranstransferase/genetics , Hearing Loss/genetics , Muscular Dystrophies/genetics , Mutation/genetics , Primary Ovarian Insufficiency/genetics , Adolescent , Adult , Animals , Female , Gene Knock-In Techniques/methods , Hearing Loss/diagnostic imaging , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Muscular Dystrophies/diagnostic imaging , Pedigree , Primary Ovarian Insufficiency/diagnostic imaging , Protein Structure, Secondary , Sequence Analysis, DNA/methods , Exome Sequencing/methods , Young Adult
12.
J Med Genet ; 56(9): 617-621, 2019 09.
Article in English | MEDLINE | ID: mdl-30327447

ABSTRACT

BACKGROUND: The activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder. OBJECTIVE: We aim to contribute to a better understanding of the ASCC1-related disorder. METHODS: Here, we provide a clinical, histological and genetic description of three additional ASCC1 families. RESULTS: All patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations. CONCLUSION: Overall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.


Subject(s)
Arthrogryposis/diagnosis , Arthrogryposis/genetics , Carrier Proteins/genetics , Fractures, Bone/congenital , Fractures, Bone/diagnosis , Muscle Weakness/genetics , Mutation , Alleles , Amino Acid Substitution , Biopsy , DNA Mutational Analysis , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Infant , Pedigree , Phenotype , Severity of Illness Index , Exome Sequencing
13.
Ann Neurol ; 83(2): 269-282, 2018 02.
Article in English | MEDLINE | ID: mdl-29328520

ABSTRACT

OBJECTIVE: Nemaline myopathy (NM) is one of the most common congenital nondystrophic myopathies and is characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause of NM (ie, NEM3). ACTA1 encodes alpha-actin 1, the main constituent of the sarcomeric thin filament. The mechanisms by which mutations in ACTA1 contribute to muscle weakness in NEM3 are incompletely understood. We hypothesized that sarcomeric dysfunction contributes to muscle weakness in NEM3 patients. METHODS: To test this hypothesis, we performed contractility measurements in individual muscle fibers and myofibrils obtained from muscle biopsies of 14 NEM3 patients with different ACTA1 mutations. To identify the structural basis for impaired contractility, low angle X-ray diffraction and stimulated emission-depletion microscopy were applied. RESULTS: Our findings reveal that muscle fibers of NEM3 patients display a reduced maximal force-generating capacity, which is caused by dysfunctional sarcomere contractility in the majority of patients, as revealed by contractility measurements in myofibrils. Low angle X-ray diffraction and stimulated emission-depletion microscopy indicate that dysfunctional sarcomere contractility in NEM3 patients involves a lower number of myosin heads binding to actin during muscle activation. This lower number is not the result of reduced thin filament length. Interestingly, the calcium sensitivity of force is unaffected in some patients, but decreased in others. INTERPRETATION: Dysfunctional sarcomere contractility is an important contributor to muscle weakness in the majority of NEM3 patients. This information is crucial for patient stratification in future clinical trials. Ann Neurol 2018;83:269-282.


Subject(s)
Actins/genetics , Muscle Contraction/physiology , Muscle Weakness/genetics , Myopathies, Structural, Congenital/physiopathology , Sarcomeres/pathology , Adult , Female , Humans , Male , Middle Aged , Muscle Weakness/physiopathology , Muscle, Skeletal/pathology , Myopathies, Structural, Congenital/genetics , Sarcomeres/physiology , Young Adult
14.
Acta Neuropathol ; 137(3): 501-519, 2019 03.
Article in English | MEDLINE | ID: mdl-30701273

ABSTRACT

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.


Subject(s)
Actinin/genetics , Muscle, Skeletal/pathology , Myotonia Congenita/genetics , Myotonia Congenita/pathology , Animals , Female , Humans , Male , Mice , Mutation , Zebrafish
15.
Muscle Nerve ; 59(1): 137-141, 2019 01.
Article in English | MEDLINE | ID: mdl-30025162

ABSTRACT

INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified. METHODS: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described. RESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies. CONCLUSIONS: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.


Subject(s)
Exosome Multienzyme Ribonuclease Complex/genetics , Muscle, Skeletal/pathology , Mutation/genetics , Olivopontocerebellar Atrophies/genetics , Olivopontocerebellar Atrophies/pathology , RNA-Binding Proteins/genetics , Sarcoma/pathology , Biopsy , Child, Preschool , Cohort Studies , Female , Humans , Infant, Newborn , Male , Muscle, Skeletal/ultrastructure , Myopathies, Nemaline , Sarcoma/ultrastructure
16.
J Inherit Metab Dis ; 42(5): 803-808, 2019 09.
Article in English | MEDLINE | ID: mdl-30887539

ABSTRACT

Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic disorder caused by mutations in the PGK1 gene. Patients usually develop various combinations of nonspherocytic hemolytic anemia (NSHA), myopathy, and central nervous system disorders. In this national multicenter observational retrospective study, we recorded all known French patients with PGK deficiency, and 3 unrelated patients were identified. Case 1 was a 32-year-old patient with severe chronic axonal sensorimotor polyneuropathy resembling Charcot-Marie-Tooth (CMT) disease, mental retardation, microcephaly, ophthalmoplegia, pes cavus, and the new c.323G > A PGK1 hemizygous mutation. Case 2 was a 71-year-old patient with recurrent exertional rhabdomyolysis, and a c.943G > A PGK1 hemizygous mutation. Case 3 was a 48-year-old patient with NSHA, retinitis pigmentosa, mental retardation, seizures, stroke, parkinsonism, and a c.491A > T PGK1 hemizygous mutation. This study confirms that PGK deficiency is an extremely rare disorder with a wide phenotypic spectrum, and demonstrates for the first time that PGK deficiency may affect the peripheral nervous system and present as a CMT-like disorder.


Subject(s)
Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Phosphoglycerate Kinase/deficiency , Adult , Aged , France , Humans , Male , Middle Aged , Mutation , Phosphoglycerate Kinase/genetics , Retrospective Studies
17.
Mol Ther ; 26(3): 890-901, 2018 03 07.
Article in English | MEDLINE | ID: mdl-29396266

ABSTRACT

Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by a deficiency of glycogen-debranching enzyme (GDE), which results in profound liver metabolism impairment and muscle weakness. To date, no cure is available for GSDIII and current treatments are mostly based on diet. Here we describe the development of a mouse model of GSDIII, which faithfully recapitulates the main features of the human condition. We used this model to develop and test novel therapies based on adeno-associated virus (AAV) vector-mediated gene transfer. First, we showed that overexpression of the lysosomal enzyme alpha-acid glucosidase (GAA) with an AAV vector led to a decrease in liver glycogen content but failed to reverse the disease phenotype. Using dual overlapping AAV vectors expressing the GDE transgene in muscle, we showed functional rescue with no impact on glucose metabolism. Liver expression of GDE, conversely, had a direct impact on blood glucose levels. These results provide proof of concept of correction of GSDIII with AAV vectors, and they indicate that restoration of the enzyme deficiency in muscle and liver is necessary to address both the metabolic and neuromuscular manifestations of the disease.


Subject(s)
Genetic Therapy , Glycogen Debranching Enzyme System/genetics , Glycogen Storage Disease Type III/genetics , Glycogen Storage Disease Type III/metabolism , Liver/metabolism , Muscle, Skeletal/metabolism , Phenotype , Animals , Biomarkers , Blood Glucose , Dependovirus/genetics , Disease Models, Animal , Enzyme Activation , Gene Expression , Gene Transfer Techniques , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Glycogen/metabolism , Glycogen Debranching Enzyme System/metabolism , Glycogen Storage Disease Type III/diagnosis , Glycogen Storage Disease Type III/therapy , Hepatocytes/metabolism , Male , Mice , Mice, Knockout , Organ Specificity
18.
Ann Neurol ; 81(3): 467-473, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28220527

ABSTRACT

Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.


Subject(s)
Muscle Proteins/genetics , Myopathies, Structural, Congenital/genetics , Adult , Consanguinity , Exome , Female , Humans , Male , Mutation , Myopathies, Structural, Congenital/pathology , Myopathies, Structural, Congenital/physiopathology , Pedigree
19.
Muscle Nerve ; 57(2): 330-334, 2018 02.
Article in English | MEDLINE | ID: mdl-28224639

ABSTRACT

INTRODUCTION: Bcl-2-associated athanogene-3 (BAG3) mutations have been described in rare cases of rapidly progressive myofibrillar myopathies. Symptoms begin in the first decade with axial involvement and contractures and are associated with cardiac and respiratory impairment in the second decade. Axonal neuropathy has been documented but usually not as a key clinical feature. METHODS: We report a 24-year-old woman with severe rigid spine syndrome and sensory-motor neuropathy resembling Charcot-Marie-Tooth disease (CMT). RESULTS: Muscle MRI showed severe fat infiltration without any specific pattern. Deltoid muscle biopsy showed neurogenic changes and discrete myofibrillar abnormalities. Electrocardiogram and transthoracic echocardiography results were normal. Genetic analysis of a panel of 45 CMT genes showed no mutation. BAG3 gene screening identified the previously reported c.626C>T, pPro209Leu, mutation. DISCUSSION: This case indicates that rigid spine syndrome and sensory-motor axonal neuropathy are key clinical features of BAG3 mutations that should be considered even without cardiac involvement. Muscle Nerve, 57: 330-334, 2018.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Apoptosis Regulatory Proteins/genetics , Charcot-Marie-Tooth Disease/genetics , Hereditary Sensory and Motor Neuropathy/genetics , Mallory Bodies/pathology , Muscular Dystrophies/genetics , Scoliosis/genetics , Biopsy , Charcot-Marie-Tooth Disease/complications , Charcot-Marie-Tooth Disease/diagnostic imaging , Electrodiagnosis , Female , Heart Diseases/complications , Hereditary Sensory and Motor Neuropathy/complications , Hereditary Sensory and Motor Neuropathy/diagnostic imaging , Humans , Magnetic Resonance Imaging , Mallory Bodies/genetics , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Muscular Dystrophies/complications , Muscular Dystrophies/diagnostic imaging , Mutation/genetics , Scoliosis/complications , Scoliosis/diagnostic imaging , Young Adult
20.
Muscle Nerve ; 58(2): 224-234, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29624713

ABSTRACT

INTRODUCTION: MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies. METHODS: We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations. RESULTS: Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration ("inverted-collagen-VI sign") in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles. DISCUSSION: Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7-related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes. Muscle Nerve 58: 224-234, 2018.


Subject(s)
Cardiac Myosins/genetics , Muscular Diseases/diagnostic imaging , Muscular Diseases/genetics , Myosin Heavy Chains/genetics , Adolescent , Adult , Biopsy , Child , Electrodiagnosis , Female , Humans , Magnetic Resonance Imaging , Male , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Muscular Diseases/physiopathology , Mutation , Mutation, Missense , Spine/diagnostic imaging , Young Adult
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