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1.
Hum Mol Genet ; 25(8): 1559-73, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-27008887

ABSTRACT

Despite recent progress in the genetic characterization of congenital muscle diseases, the genes responsible for a significant proportion of cases remain unknown. We analysed two branches of a large consanguineous family in which four patients presented with a severe new phenotype, clinically marked by neonatal-onset muscle weakness predominantly involving axial muscles, life-threatening respiratory failure, skin abnormalities and joint hyperlaxity without contractures. Muscle biopsies showed the unreported association of multi-minicores, caps and dystrophic lesions. Genome-wide linkage analysis followed by gene and exome sequencing in patients identified a homozygous nonsense mutation in TRIP4 encoding Activating Signal Cointegrator-1 (ASC-1), a poorly characterized transcription coactivator never associated with muscle or with human inherited disease. This mutation resulted in TRIP4 mRNA decay to around 10% of control levels and absence of detectable protein in patient cells. ASC-1 levels were higher in axial than in limb muscles in mouse, and increased during differentiation in C2C12 myogenic cells. Depletion of ASC-1 in cultured muscle cells from a patient and in Trip4 knocked-down C2C12 led to a significant reduction in myotube diameter ex vivo and in vitro, without changes in fusion index or markers of initial myogenic differentiation. This work reports the first TRIP4 mutation and defines a novel form of congenital muscle disease, expanding their histological, clinical and molecular spectrum. We establish the importance of ASC-1 in human skeletal muscle, identify transcriptional co-regulation as novel pathophysiological pathway, define ASC-1 as a regulator of late myogenic differentiation and suggest defects in myotube growth as a novel myopathic mechanism.


Subject(s)
Codon, Nonsense , Muscle Development , Muscular Diseases/congenital , Muscular Diseases/pathology , Transcription Factors/genetics , Adolescent , Animals , Cell Differentiation , Cell Line , Child , Female , Gene Expression Regulation, Developmental , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Infant , Male , Mice , Muscle, Skeletal/metabolism , Muscular Diseases/genetics , Pedigree , RNA Stability , Sequence Analysis, DNA , Transcription Factors/metabolism
2.
PLoS One ; 8(1): e53826, 2013.
Article in English | MEDLINE | ID: mdl-23326516

ABSTRACT

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation.


Subject(s)
Muscle Weakness , Muscle, Skeletal , Myasthenic Syndromes, Congenital , Neuromuscular Junction , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Cholinergic/genetics , Agrin/metabolism , Animals , Child , HEK293 Cells , Humans , Male , Mice , Muscle Proteins/genetics , Muscle Proteins/metabolism , Muscle Weakness/genetics , Muscle Weakness/metabolism , Muscle Weakness/physiopathology , Muscle, Skeletal/innervation , Muscle, Skeletal/physiopathology , Mutation, Missense , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/metabolism , Myasthenic Syndromes, Congenital/physiopathology , Neuromuscular Junction/genetics , Neuromuscular Junction/metabolism , Neuromuscular Junction/physiopathology , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Cholinergic/metabolism , Receptors, Growth Factor/genetics , Receptors, Growth Factor/metabolism , Signal Transduction , Synaptic Transmission/genetics
3.
J Neuropathol Exp Neurol ; 66(1): 57-65, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17204937

ABSTRACT

Central core disease (CCD) and multi-minicore disease (MmD) are muscle disorders characterized by foci of mitochondria depletion and sarcomere disorganization ("cores") in muscle fibers. Although core myopathies are the most frequent congenital myopathies, their pathogenesis remains elusive and specific diagnostic markers are lacking. Core myopathies are mostly caused by mutations in 2 sarcoplasmic reticulum proteins: the massive Ca-release channel RyR1 or the selenoprotein N (SelN) of unknown function. To search for distinctive markers and to obtain further pathophysiological insight, we identified the molecular defects in 12 core myopathy patients and analyzed the immunolocalization of 6 proteins of the Ca-release complex in their muscle biopsies. In 7 cases with RYR1 mutations (6 CCD, one MmD), RyR1 was depleted from the cores; in contrast, the other proteins of the sarcoplasmic reticulum (calsequestrin, SERCA1/2, and triadin) and the T-tubule (dihydropyridine receptor-alpha1subunit) accumulated within or around the lesions, suggesting an original modification of the Ca-release complex protein arrangement. Conversely, all Ca-related proteins were distributed normally in 5 MmD cases with SelN mutations. Our results provide an appropriate tool to orientate the differential and molecular diagnosis of core myopathies and suggest that different pathophysiological mechanisms lead to core formation in SelN- and in RyR1-related core myopathies.


Subject(s)
Muscle, Skeletal/metabolism , Muscular Diseases/metabolism , Mutation , Adolescent , Adult , Biomarkers/metabolism , Calsequestrin/metabolism , Carrier Proteins/metabolism , Child , DNA Mutational Analysis , Humans , Immunohistochemistry/methods , Microscopy, Electron, Transmission/methods , Models, Biological , Muscle Proteins/genetics , Muscle Proteins/metabolism , Muscle, Skeletal/pathology , Muscle, Skeletal/ultrastructure , Muscular Diseases/classification , Muscular Diseases/genetics , Myopathy, Central Core/genetics , Myopathy, Central Core/metabolism , Ryanodine Receptor Calcium Release Channel/genetics , Ryanodine Receptor Calcium Release Channel/metabolism , Sarcoplasmic Reticulum/metabolism , Sarcoplasmic Reticulum/pathology , Selenoproteins/genetics , Selenoproteins/metabolism
4.
Brain ; 129(Pt 5): 1249-59, 2006 May.
Article in English | MEDLINE | ID: mdl-16537564

ABSTRACT

Increased susceptibility to apoptosis has been shown in many models of mitochondrial defects but its relevance to human diseases is still discussed. We addressed the presence of apoptosis in muscle from patients with mitochondrial DNA (mtDNA) disorders. Taking advantage of the mosaic pattern of muscle morphological anomalies associated with heteroplasmic mtDNA alterations, we have used an in situ approach to address the relationship between apoptosis and respiratory defect, mitochondrial proliferation and mutation load. Different patterns of mitochondrial morphological alterations were provided by the analysis of muscles with large mtDNA deletion (16 cases) or with the MELAS mutation (4 cases). The patient's age at biopsy ranged from 0.4 to 66 years and the muscle mutant mtDNA proportion from 32 to 82%. Apoptotic muscle fibres were observed in a small proportion of muscle fibres of 16 out of the 20 biopsies by three different detection methods for different steps of apoptosis: caspase 3 activation, fragmentation of nuclear DNA [terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay] or overexpression of the pro-apoptotic factor Bax. Analysis of apoptotic features in parallel to cytochrome c oxidase (COX) and succinate dehydrogenase activity of more than 34,000 individual muscle fibres showed that apoptosis occurred only in muscle fibres with mitochondrial proliferation (ragged red fibres, RRF) irrespective of their COX activity. Molecular analyses of single muscle fibres evidenced that, as expected, the presence of COX defect was associated with higher proportion of mutant mtDNA and lower amount of normal mtDNA. Within COX-defective fibres, the presence of mitochondrial proliferation was associated with increase of the mtDNA content but without change in the ratio between normal and mutant mtDNA molecules, thus showing that mitochondrial proliferation was accompanied by similar amplification of normal and mutant mtDNA molecules. Within RRF, apoptosis was associated with higher mutation proportion, suggesting that it was provoked by severe respiratory defect in the same time as increased mitochondrial mass. In conclusion, apoptosis most probably contributes to mitochondrial pathology. It is tightly linked to mitochondrial proliferation and high mutation load. When considering training therapeutics, one will have to take into account the possibility to induce apoptosis in parallel to mitochondrial proliferation.


Subject(s)
Apoptosis , Mitochondria, Muscle/pathology , Mitochondrial Myopathies/pathology , Adolescent , Adult , Aged , Caspase 3 , Caspases/metabolism , Cell Nucleus/ultrastructure , Cell Respiration , Child , DNA, Mitochondrial/analysis , DNA, Mitochondrial/genetics , Electron Transport Complex IV/metabolism , Female , Gene Deletion , Humans , In Situ Nick-End Labeling , Infant , MELAS Syndrome/genetics , MELAS Syndrome/pathology , Male , Middle Aged , Mitochondria, Muscle/metabolism , Mitochondrial Myopathies/genetics , Mitochondrial Myopathies/metabolism , Muscle Fibers, Skeletal/enzymology , Muscle, Skeletal/ultrastructure , Point Mutation , bcl-2-Associated X Protein/metabolism
5.
Neuromuscul Disord ; 16(3): 178-82, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16487706

ABSTRACT

Mutations in the gene encoding the gamma2 subunit of AMP-activated protein kinase (PRKAG2) cause familial cardiac hypertrophy and electrophysiological abnormalities, with glycogen accumulation in the heart of affected patients. The authors describe a 38-year-old man with a new heterozygous PRKAG2 mutation (Ser548Pro) manifesting by hypertrophic cardiomyopathy, severe conduction system abnormalities, and skeletal muscle glycogenosis. Considering those results, PRKAG2 gene could be a potential candidate for unexplained muscle glycogenosis associated with cardiac abnormalities.


Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Glycogen Storage Disease/genetics , Heart Conduction System/physiopathology , Multienzyme Complexes/genetics , Muscle, Skeletal/pathology , Protein Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinases , Adult , DNA Mutational Analysis/methods , Exercise , Humans , Male , Mutation , Proline/genetics , Serine/genetics
7.
J Pathol ; 207(3): 313-23, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16178054

ABSTRACT

Tubular aggregates are morphological abnormalities characterized by the accumulation of densely packed tubules in skeletal muscle fibres. To improve knowledge of tubular aggregates, the formation and role of which are still unclear, the present study reports the electron microscopic analysis and protein characterization of tubular aggregates in six patients with 'tubular aggregate myopathy'. Three of the six patients also presented with myasthenic features. A large panel of immunochemical markers located in the sarcoplasmic reticulum, T-tubules, mitochondria, and nucleus was used. Despite differences in clinical phenotype, the composition of tubular aggregates, which contained proteins normally segregated differently along the sarcoplasmic reticulum architecture, was similar in all patients. All of these proteins, calsequestrin, RyR, triadin, SERCAs, and sarcalumenin, are involved in calcium uptake, storage, and release. The dihydropyridine receptor, DHPR, specifically located in the T-tubule, was also present in tubular aggregates in all patients. COX-2 and COX-7 mitochondrial proteins were not found in tubular aggregates, despite being observed close to them in the muscle fibre. The nuclear membrane protein emerin was found in only one case. Electron microscopy revealed vesicular budding from nuclei, and the presence of SAR-1 GTPase protein in tubular aggregates shown by immunochemistry, in all patients, suggests that tubular aggregates could arise from endoplasmic reticulum exit sites. Taken together, these results cast new light on the composition and significance of tubular aggregates.


Subject(s)
Muscle, Skeletal/pathology , Myopathies, Structural, Congenital/pathology , Adult , Calcium/metabolism , Calcium-Transporting ATPases/analysis , Cell Nucleus/pathology , Female , Humans , Immunohistochemistry/methods , Male , Microscopy, Electron/methods , Middle Aged , Mitochondria, Muscle/pathology , Mitochondrial Proteins/analysis , Muscle Fibers, Skeletal/pathology , Muscle Proteins/analysis , Myopathies, Structural, Congenital/physiopathology , Sarcoplasmic Reticulum/pathology , Sarcoplasmic Reticulum Calcium-Transporting ATPases
8.
J Soc Biol ; 199(1): 61-77, 2005.
Article in French | MEDLINE | ID: mdl-16114265

ABSTRACT

Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.


Subject(s)
Mutation , Myasthenic Syndromes, Congenital/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Cholinergic/genetics , Animals , Axons/pathology , Frameshift Mutation , Gene Expression , Humans , Male , Muscle, Skeletal/enzymology , Muscle, Skeletal/pathology , Mutation, Missense , Myasthenic Syndromes, Congenital/enzymology , Myasthenic Syndromes, Congenital/pathology , Neuromuscular Junction/chemistry , Neuromuscular Junction/enzymology , Neuromuscular Junction/pathology , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Cholinergic/analysis , Receptors, Cholinergic/metabolism , Synapses/chemistry , Synapses/pathology , Synapses/physiology , Transfection
9.
Article in English | MEDLINE | ID: mdl-15979370

ABSTRACT

AMP-deaminase activity was measured in white muscle from a wide range of fish, including one cyclostome, 13 chondrosteans, and one teleost to elucidate the pattern of the AMP-deaminase activity in white muscle of fish. Compared to a mammalian (rat) muscle extract, low enzyme activities are found in the cyclostome and two elasmobranchs from two families (Scyliorhinidae, Hexanchidae). In contrast, higher AMP-deaminase activities, similar to mammals, are expressed in Squalidae, all families of skates, Chimaeridae and in the teleostean fish. We then compared AMP-deaminase activities in red and white muscles from two representative elasmobranch fish, the dogfish (Scyliorhinus canicula) and the thornback ray (Raja clavata). The fibre type composition and distribution of the locomotory musculature were determined in these two elasmobranchs to establish a relationship between the morphology, the type of fibres of the locomotion-implicated muscles and the AMP-deaminase activity. Experimental data are discussed with respect to the layout of fibres in the myotome. In both species, three fibre types were identified. In the two fish myotomes, most of the axial muscles are white fibres while red fibres constitute a thin sheet. Some differences were observed between the two species in the distribution of intermediate fibres: in dogfish, these are located between the red and white fibres; in thornback ray, some are dispersed within the white fibre region, while others form an intermediary layer like in dogfish. These results suggest that in the course of evolution, an amplification of the AMP-deaminase activity in muscle was coupled with increase of complexity of the muscular structure.


Subject(s)
AMP Deaminase/analysis , Dogfish , Muscles/enzymology , Skates, Fish , AMP Deaminase/metabolism , Animals , Fishes , Histocytochemistry , Muscles/chemistry , Muscles/ultrastructure , Rats , Rats, Wistar , Species Specificity
10.
Hum Mol Genet ; 13(24): 3229-40, 2004 Dec 15.
Article in English | MEDLINE | ID: mdl-15496425

ABSTRACT

We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.


Subject(s)
Myasthenic Syndromes, Congenital/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Cholinergic/genetics , Adult , DNA Mutational Analysis , Female , Humans , Immunohistochemistry , Male , Muscles/metabolism , Mutation , Myasthenic Syndromes, Congenital/metabolism , Pedigree , Polymorphism, Genetic , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Cholinergic/metabolism
11.
Neuromuscul Disord ; 14(1): 24-32, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14659409

ABSTRACT

Congenital myasthenic syndromes are rare heterogeneous hereditary disorders, which lead to defective neuromuscular transmission resulting in fatigable muscle weakness. Post-synaptic congenital myasthenic syndromes are caused by acetylcholine receptor kinetic abnormalities or by acetylcholine receptor deficiency. Most of the congenital myasthenic syndromes with acetylcholine receptor deficiency are due to mutations in acetylcholine receptor subunit genes. Some have recently been attributed to mutations in the rapsyn gene. Here, we report the case of a 28-year-old French congenital myasthenic syndrome patient who had mild diplopia and fatigability from the age of 5 years. His muscle biopsy revealed a marked reduction in rapsyn and acetylcholine receptor at neuromuscular junctions together with a simplification of the subneural apparatus structure. In this patient, we excluded mutations in the acetylcholine receptor subunit genes and identified the homozygous N88K rapsyn mutation, which has already been shown by cell expression to impair rapsyn and acetylcholine receptor aggregation at the neuromuscular junction. The detection of the N88K mutation at the heterozygous state in five of 300 unrelated control subjects shows that this mutation is not infrequent in the healthy population. Electrophysiological measurements on biopsied intercostal muscle from this patient showed that his rapsyn mutation-induced fatigable weakness is expressed not only in a diminution in acetylcholine receptor membrane density but also in a decline of endplate potentials evoked at low frequency.


Subject(s)
Muscle Proteins/deficiency , Muscle, Skeletal/physiopathology , Myasthenic Syndromes, Congenital/genetics , Neuromuscular Junction/metabolism , Receptors, Nicotinic/deficiency , Adult , Biopsy , Chromosome Disorders/genetics , Chromosome Disorders/metabolism , Chromosome Disorders/physiopathology , DNA Mutational Analysis , Down-Regulation/genetics , Electrophysiology , Female , Gene Frequency , Genes, Recessive/genetics , Haplotypes/genetics , Homozygote , Humans , In Vitro Techniques , Male , Membrane Potentials/genetics , Muscle Proteins/genetics , Muscle, Skeletal/innervation , Muscle, Skeletal/pathology , Mutation/genetics , Myasthenic Syndromes, Congenital/metabolism , Myasthenic Syndromes, Congenital/physiopathology , Neuromuscular Junction/pathology , Neuromuscular Junction/ultrastructure , Pedigree , Receptor Aggregation/genetics , Receptors, Nicotinic/genetics , Synaptic Membranes/metabolism , Synaptic Membranes/pathology , Synaptic Membranes/ultrastructure , Synaptic Transmission/genetics
12.
Neuromuscul Disord ; 13(7-8): 545-53, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12921791

ABSTRACT

Muscle glycogen storage was measured by in vivo, natural abundance 13C nuclear magnetic resonance spectroscopy in distal and proximal lower limb segments of patients suffering from adult-onset acid maltase deficiency. Interleaved T1-weighted acquisitions of glycogen and creatine served to quantify glycogen excess. For acid maltase deficient patients (n=11), glycogen:creatine was higher than controls (n=12), (1.20+/-0.39 vs. 0.83+/-0.18, P=0.0005). Glycogen storage was above the normal 95% confidence limits in at least one site for 7/11 patients. The intra-individual coefficient of reproducibility was 12%. This totally atraumatic measurement of glycogen allows repeated measurement at different muscle sites of acid maltase deficient patients, despite selective fatty replacement of tissue. This could provide an additional parameter to follow the development of disease in individual patients, including in the perspective of forthcoming therapeutic trials. It may also offer an appropriate tool to study the role of glycogen accumulation in progression of the pathology.


Subject(s)
Glucan 1,4-alpha-Glucosidase/metabolism , Glycogen Storage Disease Type II/metabolism , Glycogen/metabolism , Muscle, Skeletal/metabolism , Adolescent , Adult , Carbon Isotopes/pharmacokinetics , Child , Creatine/metabolism , Evaluation Studies as Topic , Female , Glucan 1,4-alpha-Glucosidase/genetics , Glycogen/analysis , Glycogen Storage Disease Type II/pathology , Humans , Magnetic Resonance Spectroscopy/methods , Male , Middle Aged , Molecular Biology/methods , Phenotype , Reproducibility of Results , alpha-Glucosidases
13.
Brain ; 126(Pt 11): 2341-9, 2003 Nov.
Article in English | MEDLINE | ID: mdl-12937085

ABSTRACT

We studied seven patients (fetuses/infants) from six unrelated families affected by central core disease (CCD) and presenting with a fetal akinesia syndrome. Two fetuses died before birth (at 31 and 32 weeks) and five infants presented severe symptoms at birth (multiple arthrogryposis, congenital dislocation of the hips, severe hypotonia and hypotrophy, skeletal and feet deformities, kyphoscoliosis, etc.). Histochemical and ultrastructural studies of muscle biopsies confirmed the diagnosis of CCD showing unique large eccentric cores. Molecular genetic investigations led to the identification of mutations in the ryanodine receptor (RYR1) gene in three families, two with autosomal recessive (AR) and one with autosomal dominant (AD) inheritance. RYR1 gene mutations were located in the C-terminal domain in two families (AR and AD) and in the N-terminal domain of the third one (AR). This is the first report of mutations in the RYR1 gene involved in a severe form of CCD presenting as a fetal akinesia syndrome with AD and AR inheritances.


Subject(s)
Fetal Diseases/genetics , Movement Disorders/genetics , Myopathy, Central Core/genetics , Ryanodine Receptor Calcium Release Channel/genetics , Abnormalities, Multiple/genetics , Female , Fetal Movement/genetics , Genes, Dominant , Genes, Recessive , Humans , Infant, Newborn , Male , Muscle, Skeletal/pathology , Myopathy, Central Core/pathology , Pedigree , Syndrome
14.
Neuromuscul Disord ; 13(3): 236-44, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12609505

ABSTRACT

Congenital myasthenic syndromes with endplate acetylcholinesterase deficiency are very rare autosomal recessive diseases, characterized by onset of the disease in childhood, general weakness increased by exertion, ophthalmoplegia and refractoriness to anticholinesterase drugs. To date, all reported cases are due to mutations within the gene encoding ColQ, a specific collagen that anchors acetylcholinesterase in the basal lamina at the neuromuscular junction. We identified two new cases of congenital myasthenic syndromes with endplate acetylcholinesterase deficiency. The two patients showed different phenotypes. The first patient had mild symptoms in childhood, which worsened at 46 years with severe respiratory insufficiency. The second patient had severe symptoms from birth but improved during adolescence. In both cases, the absence of acetylcholinesterase was demonstrated by morphological and biochemical analyses, and heteroallelic mutations in the COLQ gene were found. Both patients presented a novel splicing mutation (IVS1-1G-->A) affecting the exon encoding the proline-rich attachment domain (PRAD), which interacts with acetylcholinesterase. This splicing mutation was associated with two different mutations, both of which cause truncation of the collagen domain (a known 788insC mutation belonging to one patient and a novel R236X to the other) and may impair its trimeric organization. The close similarity of the mutations of these two patients with different phenotypes suggests that other factors may modify the severity of this disease.


Subject(s)
Acetylcholinesterase/deficiency , Acetylcholinesterase/genetics , Collagen/genetics , Motor Endplate/enzymology , Muscle Proteins , Mutation , Myasthenic Syndromes, Congenital/genetics , Acetylcholinesterase/metabolism , Adult , Alanine/genetics , Animals , Bungarotoxins , DNA Mutational Analysis/methods , Exons , Female , Gene Expression , Glycine/genetics , Humans , In Vitro Techniques , Microscopy, Confocal/methods , Microscopy, Electron/methods , Middle Aged , Motor Endplate/genetics , Motor Endplate/ultrastructure , Muscle, Skeletal/enzymology , Muscle, Skeletal/ultrastructure , Myasthenic Syndromes, Congenital/etiology , Myasthenic Syndromes, Congenital/metabolism , Myasthenic Syndromes, Congenital/ultrastructure , Oocytes , Polymerase Chain Reaction/methods , Polymorphism, Single-Stranded Conformational , RNA, Messenger/biosynthesis , Rats , Xenopus
15.
Clin Endocrinol (Oxf) ; 57(5): 691-7, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12390346

ABSTRACT

Hodgkin's disease appearing as, or associated with, fibrous thyroiditis has only been described rarely. We report the observation of a patient presenting with a goitre, fibrosis of the thyroid and adjacent structures, and hypothyroidism. The histological examination was compatible with fibrosclerotic thyroiditis. This diagnosis was reviewed 6 months later when the biopsy of a supraclavicular nodule that had subsequently appeared led to the diagnosis of a nodular-sclerosis type of Hodgkin's disease. The plasmatic levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) were very high compared to the levels in healthy subjects (12 and 40 IU/l vs. 0.05 and 2.0 IU/l, respectively). These cytokine levels decreased when the initial illness was treated, and their normalization was associated with the disappearance of the cervical and thyroidal fibroses. A parallel in vitro study of these cytokines and of TNF-alpha receptors and IL-13 was performed. The results suggest a possible cause-and-effect relationship between IL-6 and IL-13 produced locally by the tumoral tissue and the development of cervical fibrosis.


Subject(s)
Cytokines/immunology , Goiter/immunology , Hodgkin Disease/diagnosis , Hodgkin Disease/immunology , Hypothyroidism/immunology , Adult , Fibrosis , Goiter/diagnostic imaging , Goiter/pathology , Humans , Hypothyroidism/diagnostic imaging , Hypothyroidism/pathology , Interleukin-6/immunology , Thyroid Gland/diagnostic imaging , Thyroid Gland/pathology , Tomography, X-Ray Computed , Tumor Necrosis Factor-alpha/immunology
16.
Am J Hum Genet ; 71(4): 739-49, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12192640

ABSTRACT

Multiminicore disease (MmD) is an autosomal recessive congenital myopathy characterized by the presence of multiple, short core lesions (known as "minicores") in most muscle fibers. MmD is a clinically heterogeneous condition, in which four subgroups have been distinguished. Homozygous RYR1 mutations have been recently identified in the moderate form of MmD with hand involvement. The genes responsible for the three other forms (including the most prevalent phenotype, termed the "classical" phenotype) remained, so far, unknown. To further characterize the genetic basis of MmD, we analyzed a series of 62 patients through a combined positional/candidate-gene approach. On the basis of clinical and morphological data, we suspected a relationship between classical MmD and the selenoprotein N gene (SEPN1), which is located on chromosome 1p36 (RSMD1 locus) and is responsible for the congenital muscular dystrophy with rigid spine syndrome (RSMD). A genomewide screening, followed by the analysis of 1p36 microsatellite markers in 27 informative families with MmD, demonstrated linkage to RSMD1 in eight families. All showed an axial myopathy with scoliosis and respiratory failure, consistent with the most severe end of the classical MmD spectrum; spinal rigidity was evident in some, but not all, patients. We excluded linkage to RSMD1 in 19 families with MmD, including 9 with classical MmD. Screening of SEPN1 in the 8 families that showed linkage and in 14 patients with classical sporadic disease disclosed 9 mutations affecting 17 patients (12 families); 6 were novel mutations, and 3 had been described in patients with RSMD. Analysis of three deltoid biopsy specimens from patients with typical RSMD revealed a wide myopathological variability, ranging from a dystrophic to a congenital myopathy pattern. A variable proportion of minicores was found in all the samples. The present study represents the first identification of a gene responsible for classical MmD, demonstrates its genetic heterogeneity, and reassesses the nosological boundaries between MmD and RSMD.


Subject(s)
Chromosomes, Human, Pair 1 , Muscle Proteins/genetics , Muscular Diseases/genetics , Muscular Dystrophies/genetics , Spinal Diseases/genetics , Adolescent , Adult , Age of Onset , Child , Chromosome Mapping , Female , Humans , Male , Molecular Sequence Data , Mutation , Phenotype , Selenoproteins
17.
Ann Neurol ; 51(6): 750-9, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12112081

ABSTRACT

Multi-minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short-length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi-minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome-wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi-minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency ("classical" phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi-minicore disease.


Subject(s)
Genes, Recessive/genetics , Mutation , Myopathy, Central Core/genetics , Myopathy, Central Core/physiopathology , Ryanodine Receptor Calcium Release Channel/genetics , Adolescent , Adult , Algeria , Amino Acid Sequence , Animals , Biopsy , Child , Child, Preschool , Chromosomes, Human, Pair 19/genetics , Female , Genetic Linkage , Germany , Humans , Male , Molecular Sequence Data , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Myopathy, Central Core/diagnosis , Pedigree , Phenotype , Ryanodine Receptor Calcium Release Channel/metabolism , Sequence Alignment , Turkey
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