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1.
Neurol Genet ; 10(3): e200155, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38725677

RESUMEN

Background and Objectives: Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS). Methods: Nine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. Results: All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. Discussion: The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.

2.
Hum Mol Genet ; 32(21): 3029-3039, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37070754

RESUMEN

Recessive mutations in the DNAJB2 gene, encoding the J-domain co-chaperones DNAJB2a and DNAJB2b, have previously been reported as the genetic cause of progressive peripheral neuropathies, rarely involving pyramidal signs, parkinsonism and myopathy. We describe here a family with the first dominantly acting DNAJB2 mutation resulting in a late-onset neuromyopathy phenotype. The c.832 T > G p.(*278Glyext*83) mutation abolishes the stop codon of the DNAJB2a isoform resulting in a C-terminal extension of the protein, with no direct effect predicted on the DNAJB2b isoform of the protein. Analysis of the muscle biopsy showed reduction of both protein isoforms. In functional studies, the mutant protein mislocalized to the endoplasmic reticulum due to a transmembrane helix in the C-terminal extension. The mutant protein underwent rapid proteasomal degradation and also increased the turnover of co-expressed wild-type DNAJB2a, potentially explaining the reduced protein amount in the patient muscle tissue. In line with this dominant negative effect, both wild-type and mutant DNAJB2a were shown to form polydisperse oligomers.


Asunto(s)
Enfermedades Neuromusculares , Enfermedades del Sistema Nervioso Periférico , Humanos , Chaperonas Moleculares/genética , Mutación , Isoformas de Proteínas/genética , Proteínas Mutantes/genética , Proteínas del Choque Térmico HSP40/genética
3.
J Neuromuscul Dis ; 7(2): 153-166, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32039858

RESUMEN

BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.


Asunto(s)
Cardiomiopatías , Conectina/genética , Enfermedades Musculares , Guías de Práctica Clínica como Asunto/normas , Cardiomiopatías/clasificación , Cardiomiopatías/congénito , Cardiomiopatías/genética , Humanos , Enfermedades Musculares/clasificación , Enfermedades Musculares/congénito , Enfermedades Musculares/genética
4.
Neurol Genet ; 5(3): e337, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31192305

RESUMEN

OBJECTIVE: We report a second family with autosomal dominant transportinopathy presenting with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. METHODS: Patients had clinical examinations, muscle MRI, EMG, and muscle biopsy studies. The MYOcap gene panel was used to identify the gene defect in the family. Muscle biopsies were used for histopathologic and protein expression studies, and TNPO3 constructs were used to study the effect of the mutations in transfected cells. RESULTS: We identified a novel heterozygous mutation, c.2757delC, in the last part of the transportin-3 (TNPO3) gene in the affected family members. The mutation causes an almost identical frameshift affecting the stop codon and elongating the C-term protein product of the TNPO3 transcript, as was previously reported in the first large Spanish-Italian LGMD1F kindred. TNPO3 protein was increased in the patient muscle and accumulated in the subsarcolemmal and perinuclear areas. At least one of the cargo proteins, the splicing factor SRRM2 was normally located in the nucleus. Transiently transfected mutant TNPO3 constructs failed to localize to cytoplasmic annulate lamellae pore complexes in cells. CONCLUSIONS: We report the clinical, molecular genetic, and histopathologic features of the second transportinopathy family. The variability of the clinical phenotype together with histopathologic findings suggests that several molecular pathways may be involved in the disease pathomechanism, such as nucleocytoplasmic shuttling, protein aggregation, and defective protein turnover.

5.
J Neurol ; 266(3): 680-690, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30666435

RESUMEN

OBJECTIVE: Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied. METHODS: Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated. RESULTS: Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF. CONCLUSIONS: Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.


Asunto(s)
Conectina/genética , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/fisiopatología , Enfermedades Musculares/genética , Enfermedades Musculares/fisiopatología , Insuficiencia Respiratoria/genética , Insuficiencia Respiratoria/fisiopatología , Adulto , Edad de Inicio , Femenino , Enfermedades Genéticas Congénitas/diagnóstico por imagen , Enfermedades Genéticas Congénitas/patología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Enfermedades Musculares/diagnóstico por imagen , Enfermedades Musculares/patología , Mutación , Linaje , Insuficiencia Respiratoria/diagnóstico por imagen , Insuficiencia Respiratoria/patología , Adulto Joven
6.
J Neuromuscul Dis ; 6(1): 143-146, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30372688

RESUMEN

TRIM63 mutations have been described as a potential cause for cardiac and skeletal myopathy in only one family so far. We describe a new patient carrying the same homozygous TRIM63 nonsense mutation c.739 C>T p.Q247X, that was originally reported in two members of a Spanish family manifesting cardiac hypertrophy. One of these original patients also had an additional heterozygous mutation in TRIM54 and a much more severe phenotype also involving skeletal muscles, and a digenic inheritance was therefore suggested. Our case report confirms the role of TRIM63 as a new cardiac myopathy gene, although it is unclear whether the homozygous p.Q247X mutation alone is sufficient to cause an additional skeletal myopathy.


Asunto(s)
Cardiomegalia/genética , Codón sin Sentido , Proteínas Musculares/genética , Enfermedades Musculares/genética , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genética , Anciano , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Diagnóstico Diferencial , Femenino , Homocigoto , Humanos , Enfermedades Musculares/diagnóstico por imagen , Enfermedades Musculares/patología , Enfermedades Musculares/fisiopatología , Fenotipo
7.
J Clin Invest ; 128(3): 1164-1177, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29457785

RESUMEN

Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget's disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid-phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S-persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Miopatías Distales/genética , Demencia Frontotemporal/genética , Osteítis Deformante/genética , Proteína Sequestosoma-1/genética , Antígeno Intracelular 1 de las Células T/genética , Anciano , Animales , Autofagia , Línea Celular , Estudios de Cohortes , Femenino , Fibroblastos/metabolismo , Homeostasis , Humanos , Masculino , Ratones , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Mutación , Polimorfismo de Nucleótido Simple
9.
Neuromuscul Disord ; 27(7): 627-630, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28478914

RESUMEN

Mutations in GMPPB gene have been reported in patients with early-onset disease ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy (LGMD) with mental retardation. More recently mutations in GMPPB have been identified with congenital myasthenic syndromes as well as milder phenotypes. We report two unrelated cases with LGMD that underwent clinical, histopathological and genetic studies. In both cases, we found identical compound heterozygous GMPPB mutations c.79G>C p.D27H and c.859C>T p.R287W, leading to a glycosylation defect of alpha-dystroglycan. The onset of muscle weakness was 30-40 years and the progression rate mild to moderate. Case 2 became wheelchair-bound at the age of 60. No cognitive or behavioral symptoms were noted. These cases provide further evidence that GMPPB mutations can also cause late-onset recessive LGMD with milder phenotypes than previously reported, and thus should be considered in the differential diagnosis of patients with adult-onset muscular dystrophies.


Asunto(s)
Distrofia Muscular de Cinturas/genética , Mutación/genética , Nucleotidiltransferasas/genética , Adulto , Anciano , Análisis Mutacional de ADN , Distroglicanos/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Distrofia Muscular de Cinturas/patología
10.
Neurology ; 88(16): 1520-1527, 2017 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-28330959

RESUMEN

OBJECTIVE: To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation. METHODS: Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the SCN4A gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp. RESULTS: The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise- and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation. CONCLUSIONS: The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milder SCN4A mutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.


Asunto(s)
Mutación , Mialgia/genética , Mialgia/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.4/genética , Canal de Sodio Activado por Voltaje NAV1.4/metabolismo , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Familia , Femenino , Fibromialgia/genética , Fibromialgia/fisiopatología , Finlandia , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Distrofia Miotónica/genética , Distrofia Miotónica/fisiopatología , Técnicas de Placa-Clamp , Fenotipo , Población Blanca/genética , Adulto Joven
12.
Mol Neurobiol ; 54(9): 7212-7223, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-27796757

RESUMEN

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.


Asunto(s)
Conectina/genética , Miopatías Distales/diagnóstico por imagen , Miopatías Distales/genética , Marcación de Gen/métodos , Mutación/genética , Análisis de Secuencia de ADN/métodos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Linaje , Adulto Joven
13.
Clin Case Rep ; 4(12): 1151-1156, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27980752

RESUMEN

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare disorder outside Quebec causing childhood-onset cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs. A Finnish family with milder form of ARSACS was found to harbor three mutations, p.E1100K, p.N1489S, and p.M1359T, in SACS gene. The mutations segregated with the disease.

14.
J Neuromuscul Dis ; 3(2): 275-281, 2016 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-27854214

RESUMEN

Most myotilinopathy patients present with a dominant late onset distal phenotype and myofibrillar pathology, although the first MYOT mutation in a family reported to have LGMD phenotype. We report here a French family affected with a late onset proximal and distal muscle weakness and myofibrillar myopathy on muscle pathology, in which the siblings known to be clinically affected were homozygous for the c.179C>T (p.Ser60Phe) myotilin gene mutation. One subjectively asymptomatic member of the family was heterozygous for this mutation. This is the first report of a family with patients being homozygous for a known dominant MYOT mutation. Dominant negative mutations are generally considered not to cause a more severe disease in homozygosity, but our data clearly demonstrate the existence of dominant MYOT mutations with a possible dose effect causing a more severe disease phenotype in homozygosity in the spectrum of myofibrillar myopathies (MFM).


Asunto(s)
Conectina/genética , Homocigoto , Distrofias Musculares/genética , Miopatías Estructurales Congénitas/genética , Adulto , Anciano , Electromiografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Distrofias Musculares/diagnóstico por imagen , Distrofias Musculares/patología , Distrofias Musculares/fisiopatología , Mutación , Miopatías Estructurales Congénitas/diagnóstico por imagen , Miopatías Estructurales Congénitas/patología , Miopatías Estructurales Congénitas/fisiopatología , Linaje , Índice de Severidad de la Enfermedad , Hermanos
15.
Neurol Genet ; 2(6): e109, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27766310

RESUMEN

Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM #226670) is an autosomal recessive disorder characterized by neonatal blistering and later-onset muscle weakness.

16.
PLoS One ; 11(3): e0151376, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26999347

RESUMEN

The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary "myopathic" changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.


Asunto(s)
Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/patología , Músculo Esquelético/patología , Edad de Inicio , Biopsia , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Mitocondrias/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/ultraestructura
17.
Neurology ; 86(4): 391-8, 2016 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-26718575

RESUMEN

OBJECTIVE: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes. METHODS: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing. RESULTS: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A > G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. CONCLUSION: We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects.


Asunto(s)
Miopatías Distales/genética , Proteínas de Choque Térmico/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Miopatías Distales/patología , Exoma , Femenino , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Masculino , Persona de Mediana Edad , Chaperonas Moleculares , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Linaje , Fenotipo
18.
Duodecim ; 132(18): 1635-44, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-29188941

RESUMEN

Distal myopathies are a group of rare muscular dystrophies comprising more than 20 different genetic entities. The first distal myopathy in Finland, tibial muscular dystrophy, was identified more than 20 years ago. Muscle weakness predominantly affects the feet and hands, although variable weakness can be detected clinically and on muscle MRI in the proximal muscles in the later stages of the disease. Advanced molecular genetic techniques have enabled identification of several distinct distal myopathies in Finland. The clinical findings of different distal myopathies overlap, but there are also distinguishable differences that might help final genetic diagnostics.


Asunto(s)
Miopatías Distales/epidemiología , Miopatías Distales/genética , Finlandia/epidemiología , Humanos
19.
Am J Pathol ; 185(10): 2833-42, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26269091

RESUMEN

Despite the expression of the mutated gene in all muscles, selective muscles are involved in genetic muscular dystrophies. Different muscular dystrophies show characteristic patterns of fatty degenerative changes by muscle imaging, even to the extent that the patterns have been used for diagnostic purposes. However, the underlying molecular mechanisms explaining the selective involvement of muscles are not known. To test the hypothesis that different muscles may express variable amounts of different isoforms of muscle genes, we applied a custom-designed exon microarray containing probes for 57 muscle-specific genes to assay the transcriptional profiles in sets of human adult lower limb skeletal muscles. Quantitative real-time PCR and whole transcriptome sequencing were used to further analyze the results. Our results demonstrate significant variations in isoform and gene expression levels in anatomically different muscles. Comparison of the known patterns of selective involvement of certain muscles in two autosomal dominant titinopathies and one autosomal dominant myosinopathy, with the isoform and gene expression results, shows a correlation between the specific muscles involved and significant differences in the level of expression of the affected gene and exons in these same muscles compared with some other selected muscles. Our results suggest that differential expression levels of muscle genes and isoforms are one determinant in the selectivity of muscle involvement in muscular dystrophies.


Asunto(s)
Expresión Génica/genética , Distrofias Musculares/genética , Distrofias Musculares/patología , Anciano , Anciano de 80 o más Años , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa
20.
J Neurol Sci ; 355(1-2): 143-6, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-26059445

RESUMEN

There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%-77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage.


Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Electromiografía , Potenciales Evocados Motores/fisiología , Enfermedad de la Neurona Motora/patología , Músculo Esquelético/fisiopatología , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Enfermedad de la Neurona Motora/fisiopatología , Mutación/genética , Examen Neurológico , Estudios Retrospectivos
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