Publications by authors named "Juan J Vílchez"

33 Publications

A study of the phenotypic variability and disease progression in Laing myopathy through the evaluation of muscle imaging.

Eur J Neurol 2020 Nov 5. Epub 2020 Nov 5.

Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain.

Background: Laing myopathy is characterized by broad clinical and pathological variability. They are limited in number and protocol of study. We aimed to delineate muscle imaging profiles and validate imaging analysis as an outcome measure.

Methods: This was a cross-sectional and longitudinal cohort study. Data from clinical, functional and semi-quantitative muscle imaging (60 magnetic resonance imaging [MRI] and six computed tomography scans) were studied. Hierarchical analysis, graphic heatmap representation and correlation between imaging and clinical data using Bayesian statistics were carried out.

Results: The study cohort comprised 42 patients from 13 families harbouring five MYH7 mutations. The cohort had a wide range of ages, age at onset, disease duration, and myopathy extension and Gardner-Medwin and Walton (GMW) functional scores. Intramuscular fat was evident in all but two asymptomatic/pauci-symptomatic patients. Anterior leg compartment muscles were the only affected muscles in 12% of the patients. Widespread extension to the thigh, hip, paravertebral and calf muscles and, less frequently, the scapulohumeral muscles was commonly observed, depicting distinct patterns and rates of progression. Foot muscles were involved in 40% of patients, evolving in parallel to other regions with absence of a disto-proximal gradient. Whole cumulative imaging score, ranging from 0 to 2.9 out of 4, was associated with disease duration and with myopathy extension and GMW scales. Follow-up MRI studies in 24 patients showed significant score progression at a variable rate.

Conclusions: We confirmed that the anterior leg compartment is systematically affected in Laing myopathy and may represent the only manifestation of this disorder. However, widespread muscle involvement in preferential but variable and not distance-dependent patterns was frequently observed. Imaging score analysis is useful to categorize patients and to follow disease progression over time.
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http://dx.doi.org/10.1111/ene.14630DOI Listing
November 2020

Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy.

J Comp Eff Res 2020 10 27;9(14):973-984. Epub 2020 Aug 27.

NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London & UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital Trust, London, WC1N 1EH, UK.

Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300-<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2-34.1) m, p = 0.0473; ≥300-<400 m (n = 143), +43.9 (18.2-69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4-49.0) m, p = 0.0109. These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300-<400 m (the ambulatory transition phase), thereby informing future trial design.
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http://dx.doi.org/10.2217/cer-2020-0095DOI Listing
October 2020

Genotype-phenotype correlations in recessive titinopathies.

Genet Med 2020 Dec 11;22(12):2029-2040. Epub 2020 Aug 11.

Folkhälsan Research Center, Helsinki, Finland.

Purpose: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort.

Methods: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families).

Results: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364).

Conclusion: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
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http://dx.doi.org/10.1038/s41436-020-0914-2DOI Listing
December 2020

Persistent asymptomatic or mild symptomatic hyperCKemia due to mutations in ANO5: the mildest end of the anoctaminopathies spectrum.

J Neurol 2020 Sep 4;267(9):2546-2555. Epub 2020 May 4.

Department of Neurology, Hospital Universitario 12 de Octubre, Avda. de Córdoba, s/n, 28041, Madrid, Spain.

Background: The ANO5 gene encodes for anoctamin-5, a chloride channel involved in muscle cell membrane repair. Recessive mutations in ANO5 are associated with muscular diseases termed anoctaminopathies, which are characterized by proximal or distal weakness, or isolated hyperCKemia. We present the largest series of patients with asymptomatic/paucisymptomatic anoctaminopathy reported so far, highlighting their clinical and radiological characteristics.

Methods: Twenty subjects were recruited retrospectively from the Neuromuscular Disorders Units database of two national reference centers. All had a confirmed genetic diagnosis (mean age of diagnosis was 48 years) established between 2015 and 2019. Clinical and complementary data were evaluated through clinical records.

Results: None of the patients complained about weakness or showed abnormal muscular balance. Among paucisymptomatic patients, the main complaints or findings were generalized myalgia, exercise intolerance and calf hypertrophy, occasionally associated with calf pain. All patients showed persistent hyperCKemia, ranging from mild-moderate to severe. Muscle biopsy revealed inflammatory changes in three cases. Muscle magnetic resonance imaging revealed typical signs (preferential involvement of adductor and gastrocnemius muscles) in all but one patient. In two cases, abnormal findings were detectable only in STIR sequences (not in T1). Three patients showed radiological progression despite remaining asymptomatic. Twelve different mutations in ANO5 were detected, of which seven are novel.

Conclusions: Recessive mutations in ANO5 are a frequent cause of undiagnosed asymptomatic/paucisymptomatic hyperCKemia. Patients with an apparent indolent phenotype may show muscle involvement in complementary tests (muscle biopsy and imaging), which may progress over time. Awareness of anoctaminopathy as the cause of nonspecific muscular complaints or of isolated hyperCKemia is essential to correctly diagnose affected patients.
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http://dx.doi.org/10.1007/s00415-020-09872-7DOI Listing
September 2020

Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia.

J Med Genet 2020 09 11;57(9):643-646. Epub 2020 Mar 11.

Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.

Background: Mitochondrial progressive external ophthalmoplegia (PEO) encompasses a broad spectrum of clinical and genetic disorders. We describe the phenotypic subtypes of PEO and its correlation with molecular defects and propose a diagnostic algorithm.

Methods: Retrospective analysis of the clinical, pathological and genetic features of 89 cases.

Results: Three main phenotypes were found: 'pure PEO' (42%), consisting of isolated palpebral ptosis with ophthalmoparesis; Kearns-Sayre syndrome (10%); and 'PEO plus', which associates extraocular symptoms, distinguishing the following subtypes: : myopathic (33%), bulbar (12%) and others (3%). Muscle biopsy was the most accurate test, showing mitochondrial changes in 95%. Genetic diagnosis was achieved in 96% of the patients. Single large-scale mitochondrial DNA (mtDNA) deletion was the most frequent finding (63%), followed by multiple mtDNA deletions (26%) due to mutations in (n=8), (n=7), (n=6) or (n=2) genes, and point mtDNA mutations (7%). Three new likely pathogenic mutations were identified in the and genes.

Conclusions: Phenotype-genotype correlations cannot be brought in mitochondrial PEO. Muscle biopsy should be the first step in the diagnostic flow of PEO when mitochondrial aetiology is suspected since it also enables the study of mtDNA rearrangements. If no mtDNA deletions are identified, whole mtDNA sequencing should be performed.
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http://dx.doi.org/10.1136/jmedgenet-2019-106649DOI Listing
September 2020

A Roma founder mutation causes a novel phenotype of centronuclear myopathy with rigid spine.

Neurology 2018 07 27;91(4):e339-e348. Epub 2018 Jun 27.

From the Unidad de Enfermedades Neuromusculares, Department of Neurology (M.C.-S., C.P.), Instituto de Biomedicina de Sevilla (IBiS) (M.C.-S., F.M., C.P.), and Department of Pathology, Neuropathology Unit (E.R.), Hospital Universitario Virgen del Rocío, Sevilla, Spain; Laboratoire Diagnostic Génétique (V.B.), Faculté de Médecine-CHRU, Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (V.B., R.Á., J.L.), Illkirch, France; Harry Perkins Institute of Medical Research and Centre for Medical Research (B.M., N.G.L., L.K.), University of Western Australia, Nedlands; Department of Pathology (Neuropathology) (A.H.-L.), Hospital Universitario 12 de Octubre, Madrid Research Institute; Neuropathology Unit (M.O.), Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona; Department of Neurology and IIS La Fe (N.M., J.J.V.), Hospital Universitari i Politècnic La Fe, Valencia; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) (N.M., J.D.-M., J.J.V.); Department of Neurology (E.K.), Consulta de Enfermedades Neuromusculares y Unidad de ELA, Hospital General Universitario Santa Lucía, Cartagena, Murcia; Department of Neurology (A.C.), Hospital Virgen de las Nieves, Granada; Department of Neurology (P.Q.), Hospital Torrecárdenas, Almería; Unidad de Enfermedades Neuromusculares (J.D.-M.), Department of Neurology, Universidad Autónoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Department of Diagnostic Genomics (M.D.), PathWest Laboratory Medicine WA, Perth, Australia; Department of Neurology (C.D.), Hospital 12 de Octubre, Madrid, Spain; Unité de Morphologie Neuromusculaire (N.B.R.), Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris; Université Sorbonne (N.B.R.), UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France; Department of Medicine (J.J.V.), Universitat de Valencia; Department of Experimental and Health Sciences (D.C.), Institute of Evolutionary Biology (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain; Centre National de la Recherche Scientifique (J.L.), UMR7104, Illkirch; and Institut National de la Santé et de la Recherche Médicale (J.L.), U964, Illkirch, France.

Objective: To describe a large series of patients, in which a novel founder mutation in the Roma population of southern Spain has been identified.

Methods: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for mutations. Clinical, histologic, radiologic, and genetic features were analyzed.

Results: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma.

Conclusion: We have identified a founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.
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http://dx.doi.org/10.1212/WNL.0000000000005862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070382PMC
July 2018

ANKK1 is found in myogenic precursors and muscle fibers subtypes with glycolytic metabolism.

PLoS One 2018 14;13(5):e0197254. Epub 2018 May 14.

Centro de Investigación Príncipe Felipe, Valencia, Spain.

Ankyrin repeat and kinase domain containing 1 (ANKK1) gene has been widely related to neuropsychiatry disorders. The localization of ANKK1 in neural progenitors and its correlation with the cell cycle has suggested its participation in development. However, ANKK1 functions still need to be identified. Here, we have further characterized the ANKK1 localization in vivo and in vitro, by using immunolabeling, quantitative real-time PCR and Western blot in the myogenic lineage. Histologic investigations in mice and humans revealed that ANKK1 is expressed in precursors of embryonic and adult muscles. In mice embryos, ANKK1 was found in migrating myotubes where it shows a polarized cytoplasmic distribution, while proliferative myoblasts and satellite cells show different isoforms in their nuclei and cytoplasm. In vitro studies of ANKK1 protein isoforms along the myogenic progression showed the decline of nuclear ANKK1-kinase until its total exclusion in myotubes. In adult mice, ANKK1 was expressed exclusively in the Fast-Twitch muscles fibers subtype. The induction of glycolytic metabolism in C2C12 cells with high glucose concentration or treatment with berberine caused a significant increase in the ANKK1 mRNA. Similarly, C2C12 cells under hypoxic conditions caused the increase of nuclear ANKK1. These results altogether show a relationship between ANKK1 gene regulation and the metabolism of muscles during development and in adulthood. Finally, we found ANKK1 expression in regenerative fibers of muscles from dystrophic patients. Future studies in ANKK1 biology and the pathological response of muscles will reveal whether this protein is a novel muscle disease biomarker.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951577PMC
December 2018

Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet 2017 09 17;390(10101):1489-1498. Epub 2017 Jul 17.

Department of Pediatric Neurology, Catholic University, Rome, Italy.

Background: Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD.

Methods: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487.

Findings: Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment.

Interpretation: Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint.

Funding: PTC Therapeutics.
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http://dx.doi.org/10.1016/S0140-6736(17)31611-2DOI Listing
September 2017

Audiological Findings in Charcot-Marie-Tooth Disease Type 4C.

J Int Adv Otol 2017 Apr;13(1):93-99

Department of Neurology, Hospital Francisco de Borja, Av Medicina 6, Gandia, Spain.

Objective: Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary demyelinating early onset neuropathy with prominent unsteadiness and occasional cranial nerve involvement. Vestibulopathy caused by the dysfunction of cranial nerve VIII has been demonstrated in a high percentage of these patients, but the presence and degree of auditory neuropathy are unknown. The aim of the study was to characterize the hearing abnormalities of a series of patients with CMT4C and to determine the presence and severity of auditory neuropathy (AN) in these patients.

Materials And Methods: Ten patients with genetically confirmed CMT4C underwent comprehensive clinical and audiological testing. The results were compared among patients in different age groups and also to the results of vestibular testing that had already been performed.

Results: Only 3 patients had hearing problems, but 9 had hearing abnormalities on ancillary testing that were compatible with different degrees of auditory nerve dysfunction. In the mildest cases, only the abnormality of the stapedial reflex and distortion of wave I in auditory brainstem responses could be detected. In the more severe cases, tonal audiometry revealed asymmetric hearing loss. These findings were more severe in older patients, even after correcting for age-related hypoacusia. In these patients, vestibular dysfunction could also be detected and seemed to be more profound and symmetric than hearing loss.

Conclusion: This report confirms and defines the presence of different degrees of auditory neuropathy in all patients with CMT4C, being detectable, usually unilaterally, during infancy, and worsening with disease progression.
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http://dx.doi.org/10.5152/iao.2017.3379DOI Listing
April 2017

Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis.

Neurology 2017 Mar 1;88(13):1235-1242. Epub 2017 Mar 1.

From the Laboratorio de Neurología (E.T.-V., T.S., J.J.V., L.B.), Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, CIBERER, Valencia; Servicio de Anatomía Patológica (N.M.), Servicio de Neurofisiología Clínica (M.J.C.), and Servicio de Neurología (T.S., J.J.V., L.B.), Hospital Universitario y Politécnico La Fe, Valencia; Laboratorio de Neurobiología Comparada (A.C.-S., V.H.-P., J.M.G.-V.), Instituto Cavanilles, Universidad de Valencia, CIBERNED; Servicio de Neurología (G.M.), Hospital Central de Asturias, Oviedo, Spain; French Reference Center on Paraneoplastic Neurological Syndrome (B.J., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Bron, and Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310, Université de Lyon-Université Claude Bernard Lyon 1, France; Laboratori de Neurologia (J.D., F.G.), Institut d´Investigacions Biomèdiques August Pi I Sunyer, CIBERER, Barcelona, Spain; and Department of Neurology (J.D.), University of Pennsylvania, Philadelphia, and Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.

Objective: To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications.

Methods: Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers).

Results: Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma ( < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome ( = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus.

Conclusions: Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis.

Classification Of Evidence: This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%).
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http://dx.doi.org/10.1212/WNL.0000000000003778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373776PMC
March 2017

Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy.

Mol Neurobiol 2017 11 29;54(9):7212-7223. Epub 2016 Oct 29.

Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman Institute, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.

Tibial muscular dystrophy (TMD) is the first described human titinopathy. It is a mild adult-onset slowly progressive myopathy causing weakness and atrophy in the anterior lower leg muscles. TMD is caused by mutations in the last two exons, Mex5 and Mex6, of the titin gene (TTN). The first reported TMD mutations were dominant, but the Finnish founder mutation FINmaj, an 11-bp insertion/deletion in Mex6, in homozygosity caused a completely different severe early-onset limb-girdle muscular dystrophy 2J (LGMD2J). Later, we reported that not all TMD mutations cause LGMD when homozygous or compound heterozygous with truncating mutation, but some of them rather cause a more severe TMD-like distal disease. We have now performed targeted next-generation sequencing of myopathy-related genes on seven families from Albania, Bosnia, Iran, Tunisia, Belgium, and Spain with juvenile or early adult onset recessive distal myopathy. Novel mutations in TTN Mex5, Mex6 and A-band exon 340 were identified in homozygosity or compound heterozygosity with a frameshift or nonsense mutation in TTN I- or A-band region. Family members having only one of these TTN mutations were healthy. Our results add yet another entity to the list of distal myopathies: juvenile or early adult onset recessive distal titinopathy.
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http://dx.doi.org/10.1007/s12035-016-0242-3DOI Listing
November 2017

Primary lateral sclerosis and hereditary spastic paraplegia in sporadic patients. An important distinction in descriptive studies.

Ann Neurol 2016 07 10;80(1):169-70. Epub 2016 May 10.

Neuromuscular Diseases and Ataxias Research Unit, La Fe Research Institute, University of Valencia, Valencia, Spain.

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http://dx.doi.org/10.1002/ana.24671DOI Listing
July 2016

Clinical and neuroimaging characterization of two C9orf72-positive siblings with amyotrophic lateral sclerosis and schizophrenia.

Amyotroph Lateral Scler Frontotemporal Degener 2016 27;17(3-4):297-300. Epub 2015 Nov 27.

a Neuromuscular Research Unit , Instituto de Investigación Sanitaria la Fe (IIS La Fe) , Valencia .

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http://dx.doi.org/10.3109/21678421.2015.1112407DOI Listing
January 2017

Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

Brain 2016 Jan 24;139(Pt 1):62-72. Epub 2015 Oct 24.

2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 4 Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe (CIPF), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.
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http://dx.doi.org/10.1093/brain/awv311DOI Listing
January 2016

Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model.

Dis Model Mech 2015 Jul;8(7):679-90

Translational Genomics Group, Department of Genetics, University of Valencia, Burjassot 46100, Spain INCLIVA Health Research Institute, Valencia 46010, Spain

Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis.
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http://dx.doi.org/10.1242/dmm.018127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486854PMC
July 2015

Novel mutations widen the phenotypic spectrum of slow skeletal/β-cardiac myosin (MYH7) distal myopathy.

Hum Mutat 2014 Jul 21;35(7):868-79. Epub 2014 May 21.

Neurogenetic Unit, Department of Neurology, Royal Perth Hospital, Western Australia, Australia; Diagnostic Genomics Laboratory, Pathwest, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia.

Laing early onset distal myopathy and myosin storage myopathy are caused by mutations of slow skeletal/β-cardiac myosin heavy chain encoded by the gene MYH7, as is a common form of familial hypertrophic/dilated cardiomyopathy. The mechanisms by which different phenotypes are produced by mutations in MYH7, even in the same region of the gene, are not known. To explore the clinical spectrum and pathobiology, we screened the MYH7 gene in 88 patients from 21 previously unpublished families presenting with distal or generalized skeletal muscle weakness, with or without cardiac involvement. Twelve novel mutations have been identified in thirteen families. In one of these families, the father of the proband was found to be a mosaic for the MYH7 mutation. In eight cases, de novo mutation appeared to have occurred, which was proven in four. The presenting complaint was footdrop, sometimes leading to delayed walking or tripping, in members of 17 families (81%), with other presentations including cardiomyopathy in infancy, generalized floppiness, and scoliosis. Cardiac involvement as well as skeletal muscle weakness was identified in nine of 21 families. Spinal involvement such as scoliosis or rigidity was identified in 12 (57%). This report widens the clinical and pathological phenotypes, and the genetics of MYH7 mutations leading to skeletal muscle diseases.
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http://dx.doi.org/10.1002/humu.22553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112555PMC
July 2014

Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.

Brain 2014 Mar 22;137(Pt 3):683-92. Epub 2014 Jan 22.

1 Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.

Many neurodegenerative disorders present with sensory loss. In the group of hereditary sensory and autonomic neuropathies loss of nociception is one of the disease hallmarks. To determine underlying factors of sensory neurodegeneration we performed whole-exome sequencing in affected individuals with the disorder. In a family with sensory neuropathy with loss of pain perception and destruction of the pedal skeleton we report a missense mutation in a highly conserved amino acid residue of atlastin GTPase 3 (ATL3), an endoplasmic reticulum-shaping GTPase. The same mutation (p.Tyr192Cys) was identified in a second family with similar clinical outcome by screening a large cohort of 115 patients with hereditary sensory and autonomic neuropathies. Both families show an autosomal dominant pattern of inheritance and the mutation segregates with complete penetrance. ATL3 is a paralogue of ATL1, a membrane curvature-generating molecule that is involved in spastic paraplegia and hereditary sensory neuropathy. ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network. Mutant ATL3 p.Tyr192Cys fails to localize to branch points, but instead disrupts the structure of the tubular endoplasmic reticulum, suggesting that the mutation exerts a dominant-negative effect. Identification of ATL3 as novel disease-associated gene exemplifies that long-term sensory neuronal maintenance critically depends on the structural organisation of the endoplasmic reticulum. It emphasizes that alterations in membrane shaping-proteins are one of the major emerging pathways in axonal degeneration and suggests that this group of molecules should be considered in neuroprotective strategies.
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http://dx.doi.org/10.1093/brain/awt357DOI Listing
March 2014

Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene.

Brain 2013 May 29;136(Pt 5):1508-17. Epub 2013 Mar 29.

Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, VHIR, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129 08035 Barcelona, Spain.

In 2001, we reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, we identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Our results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand our knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies.
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http://dx.doi.org/10.1093/brain/awt074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634201PMC
May 2013

Trunk muscle involvement in late-onset Pompe disease: study of thirty patients.

Neuromuscul Disord 2012 Oct;22 Suppl 2:S148-54

Neuromuscular Disorders Unit, Department of Neurology, Universitat Autónoma de Barcelona, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.

Late-onset Pompe disease is characterized by progressive weakness involving proximal limb and respiratory muscles. Recently, treatment with enzyme replacement therapy (ERT) has been introduced partially improving patients' prognosis, but a standard consensus on when to start ERT is still lacking. There is also a lack of biomarkers related to the clinical progression of the disease. Here we used muscle magnetic resonance imaging (MRI) or computed tomography (CT) to study the abdominal and paravertebral muscles of 30 late-onset Pompe patients at different stages of disease. We observed a selective pattern of muscle damage, with early involvement of the Multifidus muscle, followed by the Obliquus internus abdominis and Longissimus muscle. Some degree of trunk involvement on MRI occurred even in asymptomatic patients. Severity of muscle involvement in MRI correlated with patients' functional stage. We suggest that: (a) the combination of paravertebral and abdominal muscle involvement may serve as a useful tool in the diagnostic work-up of patients with a clinical suspicion of Pompe disease; (b) trunk abnormalities appear at very early stages of disease and even in asymptomatic patients, possibly "announcing" the onset of the disease and thus the need for a closer clinical follow-up.
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http://dx.doi.org/10.1016/j.nmd.2012.05.011DOI Listing
October 2012

Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations.

J Neurol 2012 May 6;259(5):838-50. Epub 2011 Oct 6.

Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).
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http://dx.doi.org/10.1007/s00415-011-6262-zDOI Listing
May 2012

A retrospective clinical study of the treatment of slow-channel congenital myasthenic syndrome.

J Neurol 2012 Mar 7;259(3):474-81. Epub 2011 Aug 7.

Institute of Genetic Medicine, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.

Slow-channel congenital myasthenic syndrome (CMS) is a rare subtype of CMS caused by dominant "gain of function" mutations in the acetylcholine receptor. Clinically, the cervical and forearm extensor muscles seem to be preferentially weaker; and conventional treatment with anticholinesterases fails to improve symptoms. In contrast, open channel blockers such as fluoxetine and quinidine have been shown to be of benefit. The objectives of our study were to provide further insight into the clinical features of slow-channel CMS and evaluate response to recommended therapy. We carried out a retrospective clinical follow up study of 15 slow-channel CMS patients referred to the Munich CMS Centre. Detailed clinical data were collected by clinicians involved in the care of each patient, with a particular focus on response and tolerability to recommended therapy. Patients varied widely as regard onset of symptoms, severity of disease and mutations involved. Patients received up to four different medications and some had none. Our results strengthen previous reported findings in terms of clinical phenotype variability and the poor response to pyridostigmine. Although treatment with fluoxetine was beneficial in most patients, a number of our patients suffered significant adverse effects that hindered optimum dose titration or led to treatment cessation. Slow-channel CMS is rare and exhibits distinct clinical and genetic characteristics. Our study suggests that fluoxetine, despite being effective in most patients, can be associated with significant side effects, thus reducing treatment effectiveness in clinical practice.
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http://dx.doi.org/10.1007/s00415-011-6204-9DOI Listing
March 2012

Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect.

Am J Hum Genet 2011 Feb;88(2):162-72

Institute of Cell Biology, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland.

Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromuscular transmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6-phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general.
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http://dx.doi.org/10.1016/j.ajhg.2011.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035713PMC
February 2011

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease.

J Peripher Nerv Syst 2010 Dec;15(4):334-44

Department of Neurology, University Hospital Universitari La Fe, Valencia, Spain.

Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.
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http://dx.doi.org/10.1111/j.1529-8027.2010.00286.xDOI Listing
December 2010

Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway.

Hum Mol Genet 2009 Dec 10;18(23):4603-14. Epub 2009 Sep 10.

Genetics and Molecular Medicine Unit, Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia 46010, Spain.

Mutations in SH3TC2 (KIAA1985) cause Charcot-Marie-Tooth disease (CMT) type 4C, a demyelinating inherited neuropathy characterized by early-onset and scoliosis. Here we demonstrate that the SH3TC2 protein is present in several components of the endocytic pathway including early endosomes, late endosomes and clathrin-coated vesicles close to the trans-Golgi network and in the plasma membrane. Myristoylation of SH3TC2 in glycine 2 is necessary but not sufficient for the proper location of the protein in the cell membranes. In addition to myristoylation, correct anchoring also needs the presence of SH3 and TPR domains. Mutations that cause a stop codon and produce premature truncations that remove most of the TPR domains are expressed as the wild-type protein. In contrast, missense mutations in or around the region of the first-TPR domain are absent from early endosomes, reduced in plasma membrane and late endosomes and are variably present in clathrin-coated vesicles. Our findings suggest that the endocytic and membrane trafficking pathway is involved in the pathogenesis of CMT4C disease. We postulate that missense mutations of SH3TC2 could impair communication between the Schwann cell and the axon causing an abnormal myelin formation.
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http://dx.doi.org/10.1093/hmg/ddp427DOI Listing
December 2009

Novel human pathological mutations. Gene symbol: DMD. Disease: muscular dystrophy, Duchenne.

Hum Genet 2009 Aug;126(2):338

Medical Genetics Unit, Sistemas Genomicos, Paterna (Valencia), Spain.

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August 2009

Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy.

Brain 2008 Nov 23;131(Pt 11):3051-61. Epub 2008 Sep 23.

Department of Neurology, University Hospital La Fe, Valencia, Spain.

Cranial nerve involvement in Charcot-Marie-Tooth disease (CMT) is rare, though there are a number of CMT syndromes in which vocal cord paralysis is a characteristic feature. CMT disease due to mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) has been reported to be associated with vocal cord and diaphragmatic palsy. In order to address the prevalence of these complications in patients with GDAP1 mutations we evaluated vocal cord and respiratory function in nine patients from eight unrelated families with this disorder. Hoarseness of the voice and inability to speak loudly were reported by eight patients and one had associated symptoms of respiratory insufficiency. Patients were investigated by means of peripheral and phrenic nerve conduction studies, flexible laryngoscopy, pulmonary function studies and polysomnography. Nerve conduction velocities and pathological studies were compatible with axonal CMT (CMT2). Flexible laryngoscopy showed left vocal cord palsy in four cases, bilateral cord palsies in four cases and was normal in one case. Restrictive respiratory dysfunction was seen in the eight patients with vocal cord paresis who were all chair-bound. These eight had confirmed phrenic nerve dysfunction on neurophysiology evaluation. The patient with normal vocal cord and pulmonary function had a less severe clinical course.This study shows that CMT patients with GDAP1 mutations develop severe disability due to weakness of limb muscles and that laryngeal and respiratory muscle involvement occurs late in the disease process when significant proximal upper limb weakness has developed. The early and predominant involvement of the left vocal cord innervated by the longer left recurrent laryngeal nerve suggests a length dependent pattern of nerve degeneration. In GDAP1 neuropathy, respiratory function should be thoroughly investigated because life expectancy can be compromised due to respiratory failure.
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http://dx.doi.org/10.1093/brain/awn228DOI Listing
November 2008

Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes.

Brain 2008 Mar 7;131(Pt 3):747-59. Epub 2008 Jan 7.

Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the 'classical' phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.
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http://dx.doi.org/10.1093/brain/awm325DOI Listing
March 2008

Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes.

Brain 2007 Jun 17;130(Pt 6):1497-506. Epub 2007 Apr 17.

Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

Dok ('downstream-of-kinase') family of cytoplasmic proteins play a role in signalling downstream of receptor and non-receptor phosphotyrosine kinases. Recently, a skeletal muscle receptor tyrosine kinase (MuSK)-interacting cytoplasmic protein termed Dok-7 has been identified. Subsequently, we and others identified mutations in DOK7 as a cause of congenital myasthenic syndromes (CMS), providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Here we present clinical and molecular genetic data of 14 patients from 12 independent kinships with 13 different mutations in the DOK7 gene. The clinical picture of CMS with DOK7 mutations is highly variable. The age of onset may vary between birth and the third decade. However, most of the patients display a characteristic 'limb-girdle' pattern of weakness with a waddling gait and ptosis, but without ophthalmoparesis. Respiratory problems were frequent. Patients did not benefit from long-term therapy with esterase inhibitors; some of the patients even worsened. DOK7 mutations have emerged as one of the major genetic defects in CMS. The clinical picture differs significantly from CMS caused by mutations in other genes, such as the acetylcholine receptor (AChR) subunit genes. None of the patients with DOK7 mutations had tubular aggregates in the muscle biopsy, implying that 'limb-girdle myasthenia (LGM) with tubular aggregates' previously described in literature may be a pathogenic entity distinct from CMS caused by DOK7 mutations.
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http://dx.doi.org/10.1093/brain/awm068DOI Listing
June 2007

Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population.

Arch Neurol 2005 Aug;62(8):1256-9

Servicio de Neurología, Hospital Universitari La Fe, Valencia, Spain.

Background: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy.

Objective: To present the results of clinical and molecular analysis of 8 patients with dysferlinopathy from 5 unrelated families.

Design: Clinical assessment was performed with a standardized protocol. A muscle biopsy specimen was obtained and studied by immunohistochemistry. Genetic analysis was performed using single-stranded conformation polymorphism and direct sequencing of genomic DNA.

Results: All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation. A C-to-T transition at nucleotide position 6086 changes an arginine into a stop codon, leading to premature termination of translation. This mutation was expressed as 3 different clinical phenotypes (limb-girdle muscular dystrophy type 2B, Miyoshi distal myopathy, and distal anterior dysferlinopathy), but only 1 phenotype was found in the same family.

Conclusions: The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity. This homogeneous population in Sueca, Spain, should be helpful in studying the modifying factors responsible for the phenotypic variability.
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http://dx.doi.org/10.1001/archneur.62.8.1256DOI Listing
August 2005