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1.
Genet Med ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31316167

RESUMO

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

2.
Acta Neuropathol ; 138(3): 477-495, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31218456

RESUMO

Nemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We also establish the role of microtubule organisation in determining nuclear morphology, a phenomenon which is likely to contribute to nuclear alterations in this disease. Our results overlap with findings in diseases caused directly by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to explain some of the hallmarks of NM, including contractile filament disarray, altered mechanical properties and broad transcriptional alterations.

3.
J Muscle Res Cell Motil ; 40(2): 111-126, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31228046

RESUMO

Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.

4.
Semin Pediatr Neurol ; 29: 12-22, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31060721

RESUMO

The congenital myopathies form a large clinically and genetically heterogeneous group of disorders. Currently mutations in at least 27 different genes have been reported to cause a congenital myopathy, but the number is expected to increase due to the accelerated use of next-generation sequencing methods. There is substantial overlap between the causative genes and the clinical and histopathologic features of the congenital myopathies. The mode of inheritance can be autosomal recessive, autosomal dominant or X-linked. Both dominant and recessive mutations in the same gene can cause a similar disease phenotype, and the same clinical phenotype can also be caused by mutations in different genes. Clear genotype-phenotype correlations are few and far between.

5.
Semin Pediatr Neurol ; 29: 23-29, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31060722

RESUMO

Reports on pregnancy and delivery issues in women with congenital myopathies are scarce. In this review, we summarize the medical literature along with updates of our own data. Included are patients with nemaline myopathy (n = 11), central core disease (n = 6), multi-minicore disease (n = 2), cytoplasmic body myopathy (n = 1), and congenital fiber-type disproportion (n = 1). Apart from 1 patient with nemaline myopathy, who had used a wheelchair from the age of 18years, all other women were able to walk when becoming pregnant. In comparison with the general population, there were no increased pregnancy or delivery complications, apart from the fact that 38% elective Cesarean sections took place. Neonatal outcome was favorable. In cases where a possible influence of gestation on muscle function was assessed, a deterioration during or after pregnancy was not observed. Patients who wish to have children should be advised by a multidisciplinary team according to the specific diagnosis, severity, and distribution of muscle weakness.

6.
Neuromuscul Disord ; 29(2): 97-107, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30679003

RESUMO

We report the first family with a dominantly inherited mutation of the nebulin gene (NEB). This ∼100 kb in-frame deletion encompasses NEB exons 14-89, causing distal nemaline/cap myopathy in a three-generation family. It is the largest deletion characterized in NEB hitherto. The mutated allele was shown to be expressed at the mRNA level and furthermore, for the first time, a deletion was shown to cause the production of a smaller mutant nebulin protein. Thus, we suggest that this novel mutant nebulin protein has a dominant-negative effect, explaining the first documented dominant inheritance of nebulin-caused myopathy. The index patient, a young man, was more severely affected than his mother and grandmother. His first symptom was foot drop at the age of three, followed by distal muscle atrophy, slight hypomimia, high-arched palate, and weakness of the neck and elbow flexors, hands, tibialis anterior and toe extensors. Muscle biopsies showed myopathic features with type 1 fibre predominance in the index patient and nemaline bodies and cap-like structures in biopsies from his mother and grandmother. The muscle biopsy findings constitute a further example of nemaline bodies and cap-like structures being part of the same spectrum of pathological changes.

7.
Sci Rep ; 8(1): 15728, 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30356055

RESUMO

Nebulin is a very large protein required for assembly of the contractile machinery in muscle. Mutations in the nebulin gene NEB are a common cause of nemaline myopathy. Nebulin mRNA is alternatively-spliced so that each mRNA contains either exon 143 or exon 144. We have produced monoclonal antibodies specific for the regions of nebulin encoded by these two exons, enabling analysis of expression of isoforms at the protein level for the first time. All antibodies recognized a protein of the expected size (600-900 kD) and stained cross-striations of sarcomeres in muscle sections. Expression of exon 143 is developmentally-regulated since newly-formed myotubes in cell culture expressed nebulin with exon 144 only; this was confirmed at the mRNA level by qPCR. In fetal muscle, nebulin with exon 143 was expressed in some myotubes by 12-weeks of gestation and strongly-expressed in most myotubes by 17-weeks. In mature human muscle, the exon 144 antibody stained all fibres, but the exon 143 antibody staining varied from very strong in some fibres to almost-undetectable in other fibres. The results show that nebulin containing exon 144 is the default isoform early in myogenesis, while regulated expression of nebulin containing exon 143 occurs at later stages of muscle development.

8.
Muscle Nerve ; 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30265400

RESUMO

INTRODUCTION: Nebulin is a giant actin-binding protein in the thin filament of the skeletal muscle sarcomere. Studies of nebulin interactions are limited by the size, complexity, and poor solubility of the protein. We divided the nebulin super-repeat region into a super-repeat panel, and studied nebulin/actin interactions. METHODS: Actin binding was studied using a co-sedimentation assay with filamentous actin and 26 different nebulin super-repeats. RESULTS: The panel revealed notable differences in actin binding between the super-repeats. Both ends of the super-repeat region bound actin significantly more strongly, whereas the central part of the protein bound actin weakly. Thus, the binding between nebulin and actin formed a location-dependent pattern of strong vs. weak binding. DISCUSSION: The nebulin super-repeat panel allowed us to study the actin binding of each super-repeat individually. The panel will be a powerful tool in elucidating nebulin function in health and disease. Muscle Nerve, 2018.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30194038

RESUMO

We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2. The patients' phenotype includes developmental and epileptic encephalopathy with hypsarrhythmia, facial dysmorphism, severe intellectual disability, skeletal abnormalities, congenital cardiac disease and cortical visual impairment. Developmental and epileptic encephalopathy with hypsarrhythmia is present in most patients with SLC35A2 variants, and is drug-resistant in the majority of cases. Adrenocorticotropic hormone therapy may achieve partial or complete remission of seizures, but the effect is usually temporary. Isoelectric focusing of transferrins may be normal after infancy, therefore a congenital disorder of glycosylation should still be considered as a diagnosis in the presence of a suggestive phenotype. We also provide evidence that cortical visual impairment is part of the phenotypic spectrum.

10.
Skelet Muscle ; 8(1): 23, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-30060766

RESUMO

BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.


Assuntos
Variação Genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Distroglicanas/metabolismo , Feminino , Predisposição Genética para Doença , Glicosilação , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Mutação , Fenótipo , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
11.
Am J Med Genet A ; 176(8): 1748-1752, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30055040

RESUMO

Derangements in voltage-gated potassium channel function are responsible for a range of paroxysmal neurologic disorders. Pathogenic variants in the KCNA1 gene, which encodes the voltage-gated potassium channel Kv1.1, are responsible for Episodic Ataxia Type 1 (EA1). Patients with EA1 have an increased incidence of epilepsy, but KCNA1 variants have not been described in epileptic encephalopathy. Here, we describe four patients with infantile-onset epilepsy and cognitive impairment who harbor de novo KCNA1 variants located within the Kv-specific Pro-Val-Pro (PVP) motif which is essential for channel gating. The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early-onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved.

12.
J Neuromuscul Dis ; 5(3): 307-314, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30040739

RESUMO

BACKGROUND: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons 82-89, 90-97, 98-105). In the light of this knowledge, we have designed and validated an extended CGH array, which includes a selection of 187 genes known to cause neuromuscular disorders (NMDs). OBJECTIVE: Our aim was to develop a reliable method for CNV detection in genes related to neuromuscular disorders for routine mutation detection and analysis, as a much-needed complement to sequencing methods. METHODS: We have developed a novel custom-made 4×180 k CGH array for the diagnostics of NMDs. It includes the same tiled ultra-high density coverage of the 12 known or putative NM genes as our 8×60 k NM-CGH-array but also comprises a selection of 175 additional genes associated with NMDs, including titin (TTN), at a high to very high coverage. The genes were divided into three coverage groups according to known and potential pathogenicity in neuromuscular disorders. RESULTS: The array detected known and putative CNVs in all three gene coverage groups, including the repetitive regions of NEB and TTN. CONCLUSIONS: The targeted neuromuscular disorder 4×180 k array-CGH (NMD-CGH-array v1.0) design allows CNV detection for a broader spectrum of neuromuscular disorders at a high resolution.


Assuntos
Variações do Número de Cópias de DNA/genética , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/genética , Adulto , Conectina/genética , DNA/genética , Feminino , Genômica/métodos , Humanos , Masculino , Análise em Microsséries , Proteínas Musculares/genética , Mutação/genética , Miopatias da Nemalina/genética , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes
13.
Neuromuscul Disord ; 28(7): 614-618, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29910097

RESUMO

We describe two Finnish siblings in whom an incidentally detected elevated creatine kinase activity eventually led to a diagnosis of limb-girdle muscular dystrophy-dystroglycanopathy (Type C12; MDDGC12). When diagnosed at age 10 and 13 years, they were mildly affected with a slow or non-progressive disease course. The main symptoms comprised infrequent hip cramps triggered by flexion, neck cramps triggered by yawning, transient growing pains, calf hypertrophy and mild proximal muscle weakness. Their cognitive and motor developments were unremarkable and they were physically active. Whole-exome sequencing revealed compound heterozygous mutations, both of which were novel, in the protein O-mannosyl kinase (POMK) gene in both siblings; a missense mutation, p.Pro322Leu (c.965C > T), and a nonsense mutation, p.Arg46Ter (c.136C > T). The results were confirmed by Sanger sequencing, showing that the parents were heterozygous carriers of one mutation each. This report adds to the literature by providing phenotype and genotype data on this ultra-rare POMK-related dystroglycanopathy.

14.
J Community Genet ; 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29949066

RESUMO

Difficult ethical issues arise for patients and professionals in medical genetics, and often relate to the patient's family or their social context. Tackling these issues requires sensitivity to nuances of communication and a commitment to clarity and consistency. It also benefits from an awareness of different approaches to ethical theory. Many of the ethical problems encountered in genetics relate to tensions between the wishes or interests of different people, sometimes even people who do not (yet) exist or exist as embryos, either in an established pregnancy or in vitro. Concern for the long-term welfare of a child or young person, or possible future children, or for other members of the family, may lead to tensions felt by the patient (client) in genetic counselling. Differences in perspective may also arise between the patient and professional when the latter recommends disclosure of information to relatives and the patient finds that too difficult, or when the professional considers the genetic testing of a child, sought by parents, to be inappropriate. The expectations of a patient's community may also lead to the differences in perspective between patient and counsellor. Recent developments of genetic technology permit genome-wide investigations. These have generated additional and more complex data that amplify and exacerbate some pre-existing ethical problems, including those presented by incidental (additional sought and secondary) findings and the recognition of variants currently of uncertain significance, so that reports of genomic investigations may often be provisional rather than definitive. Experience is being gained with these problems but substantial challenges are likely to persist in the long term.

15.
Eur J Med Genet ; 61(10): 612-615, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29660408

RESUMO

Frontometaphyseal dysplasia 2 (FMD2) is a skeletal dysplasia with supraorbital hyperostosis combined with undermodeling of the bones, joint contractures and some extraskeletal features. It is caused by heterozygous mutations in MAP3K7, encoding the Mitogen-Activated Protein 3-Kinase 7. MAP3K7 is activated by TGF-ß and plays an important role in osteogenesis. Less than 20 patients with FMD2 and MAP3K7 mutations have been described thus far. The majority of the patients harbor a recurrent missense mutation, NM_003188.3: c.1454C > T [NP_003179.1: p.(Pro485Leu)], which leads to a more severe phenotype than mutations in other domains. Here we describe an additional patient with FMD2 caused by the recurrent c.1454C > T MAP3K7 mutation, identified as a de novo variant by whole-genome sequencing. The 17-year-old boy has the characteristic skeletal and facial features of FMD2. However, some novel features were also observed, including growth retardation and spina bifida occulta. In line with other patients harboring the same mutation he also showed keloid scars and had no intellectual disability. This report expands the clinical spectrum of FMD2 caused by the recurrent c.1454C > T [p.(Pro485Leu)] mutation in MAP3K7.

16.
Neuromuscul Disord ; 28(4): 323-326, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29433794

RESUMO

We present here a Finnish nemaline myopathy family with a dominant mutation in the skeletal muscle α-actin gene, p.(Glu85Lys), segregating in three generations. The index patient, a 5-year-old boy, had the typical form of nemaline myopathy with congenital muscle weakness and motor milestones delayed but reached, while his mother never had sought medical attention for her very mild muscle weakness, and his maternal grandmother had been misdiagnosed as having myotonic dystrophy. This illustrates the clinical variability in nemaline myopathy.

17.
Ann Neurol ; 79(6): 959-69, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27074222

RESUMO

OBJECTIVE: Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. METHODS: We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. RESULTS: Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap. INTERPRETATION: These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. Ann Neurol 2016;79:959-969.


Assuntos
Citoesqueleto/genética , Proteínas Musculares/genética , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Sarcômeros/genética , Actinas/genética , Animais , Estudos de Casos e Controles , Citoesqueleto/fisiologia , Humanos , Camundongos Knockout , Contração Muscular/genética , Contração Muscular/fisiologia , Proteínas Musculares/metabolismo , Proteínas Musculares/fisiologia , Músculo Esquelético/metabolismo , Mutação , Sarcômeros/fisiologia
18.
Eur J Hum Genet ; 24(4): 574-80, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26197980

RESUMO

Recently, new large variants have been identified in the nebulin gene (NEB) causing nemaline myopathy (NM). NM constitutes a heterogeneous group of disorders among the congenital myopathies, and disease-causing variants in NEB are a main cause of the recessively inherited form of NM. NEB consists of 183 exons and it includes homologous sequences such as a 32-kb triplicate region (TRI), where eight exons are repeated three times (exons 82-89, 90-97, 98-105). In human, the normal copy number of NEB TRI is six (three copies in each allele). Recently, we described a custom NM-CGH microarray designed to detect copy number variations (CNVs) in the known NM genes. The array has now been updated to include all the currently known 10 NM genes. The NM-CGH array is superior in detecting CNVs, especially of the NEB TRI, that is not included in the exome capture kits. To date, we have studied 266 samples from 196 NM families using the NM-CGH microarray, and identified a novel recurrent NEB TRI variation in 13% (26/196) of the families and in 10% of the controls (6/60). An analysis of the breakpoints revealed adjacent repeat elements, which are known to predispose for rearrangements such as CNVs. The control CNV samples deviate only one copy from the normal six copies, whereas the NM samples include CNVs of up to four additional copies. Based on this study, NEB seems to tolerate deviations of one TRI copy, whereas addition of two or more copies might be pathogenic.


Assuntos
Variações do Número de Cópias de DNA , Proteínas Musculares/genética , Miopatias da Nemalina/genética , Estudos de Casos e Controles , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , Humanos
19.
Eur J Med Genet ; 58(10): 556-61, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26403434

RESUMO

BACKGROUND: Congenital myopathies (CM) are a group of rare inherited muscle disorders characterized by particular histopathological alterations on muscle biopsy. Core-rod myopathy is a CM presenting with cores and rods as distinctive muscle morphological features. METHODS/RESULTS: We describe 3 young patients presenting congenital core-rod myopathy with bilateral foot-drop associated with autosomal recessive nebulin gene (NEB) mutations detected by exome sequencing. CONCLUSIONS: This report illustrates that core-rod congenital myopathy with foot-drop is frequently associated with NEB gene mutations and should be considered in the differential diagnosis of early onset distal myopathies.


Assuntos
Transtornos Neurológicos da Marcha/genética , Proteínas Musculares/genética , Miopatias Congênitas Estruturais/diagnóstico , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Criança , Exoma , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Miopatias Congênitas Estruturais/genética , Adulto Jovem
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