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2.
Neuromuscul Disord ; 29(4): 269-273, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30737080
3.
Dysphagia ; 33(6): 789-802, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29725764

RESUMO

Dysphagia is one of the primary symptoms experienced by individuals with Oculopharyngeal Muscular Dystrophy (OPMD). However, we lack understanding of the discrete changes in swallowing physiology that are seen in OPMD, and the resulting relationship to impairments of swallowing safety and efficiency. This study sought to describe the pathophysiology of dysphagia in a small sample of patients with OPMD using a videofluoroscopy examination (VFSS) involving 3 × 5 mL boluses of thin liquid barium (22% w/v). The aim of this study is to extend what is known about the pathophysiology of dysphagia in OPMD, by quantifying changes in swallow timing, kinematics, safety, and efficiency, measured from VFSS. This study is a secondary analysis of baseline VFSS collected from 11 adults (4 male), aged 48-62 (mean 57) enrolled in an industry-sponsored phase 2 therapeutic drug trial. Blinded raters scored the VFSS recordings for safety [Penetration-Aspiration Scale (PAS)], efficiency [Normalized Residue Ratio Scale (NRRS)], timing [Pharyngeal Transit Time (PTT), Swallow Reaction Time (SRT), Laryngeal Vestibule Closure Reaction Time (LVCrt), Upper Esophageal Sphincter Opening Duration (UESD)], and kinematics (hyoid movement, pharyngeal constriction, UES opening width). Impairment thresholds from existing literature were defined to characterize swallowing physiology and function. Further, Fisher's Exact tests and Pearson's correlations were used to conduct a preliminary exploration of associations between swallowing physiology (e.g., kinematics, timing) and function (i.e., safety, efficiency). Compared to published norms, we identified significant differences in the degree of maximum pharyngeal constriction, hyoid movement distance and speed, as well as degree and timeliness of airway closure. Unsafe swallowing (PAS ≥ 3) was seen in only 3/11 patients. By contrast, clinically significant residue (i.e., NRRS scores ≥ 0.09 vallecular; ≥ 0.2 pyriform) was seen in 7/11 patients. Fisher's Exact tests revealed associations between prolonged SRT, PTT, and unsafe swallowing. Weak associations were also identified between post-swallow residue and poor pharyngeal constriction during the swallow. Detailed analysis of swallowing physiology in this series of adults with OPMD aligns with impaired muscular function (e.g., reduced pharyngeal constriction, incomplete laryngeal vestibule closure) associated with the disease, and primary functional challenges with swallow efficiency. Further work is needed to explore a greater range of food and liquid textures, and to identify additional physiological mechanisms underlying swallowing impairment in OPMD.

4.
Neuromuscul Disord ; 28(2): 158-168, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29305133

RESUMO

GNE myopathy is a rare distal myopathy, caused by mutations in the GNE gene, affecting sialic acid synthesis. Clinical presentation varies from asymptomatic early stage patients to severely debilitating forms. This first report describes clinical presentations and severity of the disease, using data of 150 patients collected via the on-line, patient-reported registry component of the GNE Myopathy Disease Monitoring Program (GNEM-DMP). Disease progression was prospectively analysed, over a 2-year period, using the GNE myopathy functional activity scale (GNEM-FAS). The average annual rates of decline in function were estimated at -9.6% and -3.2% in ambulant and non-ambulant patients respectively. 4.3% of participants became non-ambulant within one year. The mean time from onset to required use of a wheelchair was 11.9 years. Mean delay of genetic diagnosis from symptom onset was 5.2 years. Mutation specific analysis demonstrated genotype-phenotype relationships; i.e. p.Ala662Val may be associated with a more severe phenotype, compared to p.Val727Met. Patients with compound heterozygous mutation in epimerase and kinase domain appeared to have a more severe phenotype compared to patients with both mutations located within one domain. Acknowledging the limitations of the study, these findings suggest that the severity of the GNE mutations affects disease severity. The GNEM-DMP is a useful data collection tool, prospectively measuring the progression of GNE myopathy, which could play an important role in translational and clinical research and further understanding of genotype-phenotype correlations.

5.
J Clin Neuromuscul Dis ; 19(1): 19-26, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28827485

RESUMO

OBJECTIVE: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. METHODS: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). RESULTS: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. CONCLUSIONS: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.


Assuntos
Força Muscular/genética , Debilidade Muscular/etiologia , Músculo Esquelético/fisiopatologia , Miosite de Corpos de Inclusão/congênito , Adolescente , Adulto , Idoso , Feminino , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Atividade Motora/genética , Miosite de Corpos de Inclusão/complicações , Miosite de Corpos de Inclusão/genética , Ácido N-Acetilneuramínico/genética , Adulto Jovem
6.
Neuromuscul Disord ; 27(2): 136-140, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28024842

RESUMO

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.


Assuntos
Acetilcolinesterase/genética , Colágeno/genética , Proteínas Musculares/genética , Síndromes Miastênicas Congênitas/etnologia , Síndromes Miastênicas Congênitas/genética , Receptores Nicotínicos/genética , Análise Mutacional de DNA , Humanos , Irã (Geográfico)/etnologia , Iraque/etnologia , Israel/etnologia , Linhagem
7.
J Neuromuscul Dis ; 3(1): 49-66, 2016 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-27854209

RESUMO

BACKGROUND: GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. OBJECTIVE: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. METHODS: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 g/day or 6 g/day versus placebo was conducted in GNEM subjects (n = 47). After the first 24 weeks, placebo subjects crossed over to 3 g/day or 6 g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. RESULTS: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 g/day compared with placebo at Week 24 (LS mean difference +2.33 kg, p = 0.040), and larger in a pre-specified subgroup able to walk ≥200 m at Screening (+3.10 kg, p = 0.040). After cross-over, a combined 6 g/day group showed significantly better UEC strength than a combined 3 g/day group (+3.46 kg, p = 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06 kg, p = 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 g/day group compared with a combined 3 g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. CONCLUSIONS: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.


Assuntos
Miopatias Distais/tratamento farmacológico , Ácido N-Acetilneuramínico/farmacologia , Avaliação de Resultados (Cuidados de Saúde) , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/administração & dosagem , Ácido N-Acetilneuramínico/efeitos adversos , Adulto Jovem
8.
JAMA Neurol ; 73(3): 337-44, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26751635

RESUMO

IMPORTANCE: Preclinical studies have shown that neurotrophic growth factors (NTFs) extend the survival of motor neurons in amyotrophic lateral sclerosis (ALS) and that the combined delivery of these neurotrophic factors has a strong synergistic effect. We have developed a culture-based method for inducing mesenchymal stem cells (MSCs) to secrete neurotrophic factors. These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases. OBJECTIVE: To determine the safety and possible clinical efficacy of autologous MSC-NTF cells transplantation in patients with ALS. DESIGN, SETTING, AND PARTICIPANTS: In these open-label proof-of-concept studies, patients with ALS were enrolled between June 2011 and October 2014 at the Hadassah Medical Center in Jerusalem, Israel. All patients were followed up for 3 months before transplantation and 6 months after transplantation. In the phase 1/2 part of the trial, 6 patients with early-stage ALS were injected intramuscularly (IM) and 6 patients with more advanced disease were transplanted intrathecally (IT). In the second stage, a phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous MSC-NTF cells. INTERVENTIONS: Patients were administered a single dose of MSC-NTF cells. MAIN OUTCOMES AND MEASURES: The primary end points of the studies were safety and tolerability of this cell therapy. Secondary end points included the effects of the treatment on various clinical parameters, such as the ALS Functional Rating Scale-Revised score and the respiratory function. RESULTS: Among the 12 patients in the phase 1/2 trial and the 14 patients in the phase 2a trial aged 20 and 75 years, the treatment was found to be safe and well tolerated over the study follow-up period. Most of the adverse effects were mild and transient, not including any treatment-related serious adverse event. The rate of progression of the forced vital capacity and of the ALS Functional Rating Scale-Revised score in the IT (or IT+IM)-treated patients was reduced (from -5.1% to -1.2%/month percentage predicted forced vital capacity, P < .04 and from -1.2 to 0.6 ALS Functional Rating Scale-Revised points/month, P = .052) during the 6 months following MSC-NTF cell transplantation vs the pretreatment period. Of these patients, 13 (87%) were defined as responders to either ALS Functional Rating Scale-Revised or forced vital capacity, having at least 25% improvement at 6 months after treatment in the slope of progression. CONCLUSIONS AND RELEVANCE: The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01051882 and NCT01777646.


Assuntos
Esclerose Amiotrófica Lateral/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Fatores de Crescimento Neural/metabolismo , Avaliação de Resultados (Cuidados de Saúde) , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pessoa de Meia-Idade , Transplante Autólogo , Adulto Jovem
9.
J Neurol ; 262(10): 2346-51, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26194201

RESUMO

Adult polyglucosan body disease (APBD) is a rare glycogenosis manifesting progressive spastic paraparesis, sensorimotor polyneuropathy and neurogenic bladder. Misdiagnosis of APBD may lead to unnecessary investigations and to potentially harmful therapeutic interventions. To examine the frequency of misdiagnosis of APBD, we retrospectively reviewed the clinical data of 30 patients diagnosed between 1991 and 2013. Diagnosis was based on the combination of typical clinical and imaging findings, reduced glycogen branching enzyme activity, and the presence of p.Y326S GBE1 mutation. Initial symptoms started in the 5th-6th decade with bladder dysfunction (47 %), gait problems (33 %) or both. Diagnosis of APBD was delayed by 6.8 (±4.8) years. Consistent signs at diagnosis were spasticity in the legs (93 %), decreased or absent ankle reflexes (100 %), bilateral extensor plantar response (100 %) and distal sensory deficit (80 %). Nerve conduction study showed invariable sensorimotor polyneuropathy, and MRI demonstrated cervical spinal cord atrophy (100 %) and leukoencephalopathy (97 %). All 30 patients were initially misdiagnosed. Common misdiagnoses included cerebral small vessel disease (27 %), multiple sclerosis (17 %), amyotrophic lateral sclerosis (17 %) and peripheral neuropathies (20 %). Consequently, 27 % received inappropriate therapy. In addition, lower urinary tract symptoms in 60 % of men were attributed solely to prostatic disorders but did not respond to medical treatment or prostatectomy. These findings suggest that despite limited clinical variability, APBD is invariably misdiagnosed and patients are often mistreated. Physicians' unfamiliarity with the typical clinical and imaging features of APBD appears as the main reason for misdiagnosis.


Assuntos
Diagnóstico Tardio , Erros de Diagnóstico , Doença de Depósito de Glicogênio/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Adulto , Idoso , Feminino , Doença de Depósito de Glicogênio/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/terapia , Estudos Retrospectivos
10.
Hum Mutat ; 36(9): 836-41, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26077327

RESUMO

Genetic analysis of clinical phenotypes in consanguineous families is complicated by coinheritance of large DNA regions carrying independent variants. Here, we characterized a family with early onset cone-rod dystrophy (CRD) and muscular dystrophy. Homozygosity mapping (HM) followed by whole exome sequencing revealed a nonsense mutation, p.R270*, in ALMS1 and two novel potentially disease-causing missense variants, p.R1581C and p.Y2070C, in DYSF. ALMS1 and DYSF are genetically and physically linked on chromosome 2 in a genomic region suggested by HM and associated with Alström syndrome, which includes CRD, and with limb girdle muscular dystrophy, respectively. Affected family members lack additional systemic manifestations of Alström syndrome but exhibit mild muscular dystrophy. RNA-seq data did not reveal any significant variations in ALMS1 transcripts in the human retina. Our study thus implicates ALMS1 as a nonsyndromic retinal disease gene and suggests a potential role of variants in interacting cilia genes in modifying clinical phenotypes.


Assuntos
Consanguinidade , Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Proteínas/genética , Retinite Pigmentosa/genética , Análise Mutacional de DNA , Disferlina , Feminino , Estudos de Associação Genética , Humanos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Linhagem , Fenótipo , Retina/patologia , Retinite Pigmentosa/diagnóstico
12.
J Neurol Neurosurg Psychiatry ; 86(4): 385-92, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25002140

RESUMO

GNE myopathy is an autosomal recessive muscle disease caused by biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities, UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities' muscles, with marked sparing of the quadriceps. Characteristic findings on biopsies of affected muscles include 'rimmed' (autophagic) vacuoles, aggregation of various proteins and fibre size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based on the longest transcript (GenBank: NM_001128227), which encodes a 31-amino acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Based upon the pathophysiology of the disease, recent clinical trials as well as early gene therapy trials have evaluated the use of sialic acid or N-acetylmannosamine (a precursor of sialic acid) in patients with GNE myopathy. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.


Assuntos
Miopatias Distais/genética , Complexos Multienzimáticos/genética , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Miopatias Distais/diagnóstico , Miopatias Distais/epidemiologia , Miopatias Distais/patologia , Miopatias Distais/terapia , Humanos , Camundongos
13.
J Neuromuscul Dis ; 2(s2): S73-S76, 2015 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-27858758

RESUMO

GNE myopathy (previous names: HIBM, DMRV, IBM2) is a unique distal myopathy with quadriceps sparing. This recessively inherited myopathy has been diagnosed in various regions of the world with more than 150 disease-causing mutations already identified. Several of those are proven or suspected to be founder mutations in certain regional clusters and are described in this review. The review also discusses some historical aspects that might be relevant to the mutational distribution.

14.
J Neurol Sci ; 345(1-2): 168-71, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25085761

RESUMO

BACKGROUND: The syndrome of isolated progressive upper-limb distal weakness and atrophy results from disease processes affecting lower motor neurons originating in the cervical anterior horn gray matter. Lower motor neuron dysfunction restricted to the C7-T1 myotomes in the absence of neuropathy, upper motor neuron signs, sphincter disturbances or abnormality on conventional MR imaging is suggestive of either Hirayama disease (HD), or the initial manifestation of a progressive motor neuron disease such as amyotrophic lateral sclerosis (ALS). In HD the supposed etiologic mechanism is a mechanical compression of the cervical spinal cord during neck flexion; therefore, dynamic MRI (dMRI) of the cervical cord might help differentiate between these possibilities. METHODS: This was a multi-center observational cohort study. Over a 4-year period between 8/2009 and 8/2013, 22 patients were identified as having a disease consistent with HD. We identified a subgroup of patients suspected of suffering from active progressive disease and prospectively followed them after performing dynamic MRI studies of the cervical spine. RESULTS: Twenty-two patients were identified as having a disease consistent with HD, of whom 8 were defined as having actively progressive disease. Seven of these 8 patients demonstrated clear dynamic compression of the cervical spine during neck flexion. The patient who did not demonstrate the typical MRI changes associated with HD went on to develop generalized ALS. CONCLUSIONS: dMRI has a practical role in patients presenting with progressive upper-limb distal weakness and atrophy, and the presence of characteristic changes typical of HD may suggest a more optimistic prognosis.


Assuntos
Medula Cervical/patologia , Imagem por Ressonância Magnética , Atrofias Musculares Espinais da Infância/diagnóstico , Adolescente , Adulto , Criança , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Hum Mutat ; 35(7): 868-79, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24664454

RESUMO

Laing early onset distal myopathy and myosin storage myopathy are caused by mutations of slow skeletal/ß-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.


Assuntos
Miosinas Cardíacas/genética , Miopatias Distais/diagnóstico , Miopatias Distais/genética , Mutação , Cadeias Pesadas de Miosina/genética , Fenótipo , Adolescente , Adulto , Idoso , Biópsia , Miosinas Cardíacas/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Cadeias Pesadas de Miosina/metabolismo , Adulto Jovem
17.
J Neurol Sci ; 339(1-2): 210-3, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24485911

RESUMO

Action myoclonus renal failure (AMRF) syndrome is a rare form of progressive myoclonus epilepsy with renal dysfunction related to mutations in the SCARB2 gene. This gene is involved in lysosomal mannose-6-phosphate-independent trafficking of ß-glucocerebrosidase (GC), an enzyme deficient in Gaucher disease. We report a family with myoclonic epilepsy, ataxia and skeletal muscle atrophy but without cognitive impairment or overt renal disease. A novel SCARB2 mutation was indicated by a striking discrepancy between lymphocyte and fibroblast GC activity in the proband evaluated for possible Gaucher disease. Our findings expand the genetic and phenotypic diversity of AMRF and suggest that low GC activity may present an important biochemical clue to the diagnosis of AMRF.


Assuntos
Glucosilceramidase/metabolismo , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Mutação/genética , Epilepsias Mioclônicas Progressivas/enzimologia , Epilepsias Mioclônicas Progressivas/genética , Receptores Depuradores/genética , Adolescente , Ativação Enzimática/fisiologia , Seguimentos , Humanos , Masculino , Epilepsias Mioclônicas Progressivas/diagnóstico , Linhagem
18.
Eur J Hum Genet ; 22(6): 801-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24193343

RESUMO

Myosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.


Assuntos
Predisposição Genética para Doença/genética , Doenças Musculares/genética , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Oftalmoplegia/genética , Adulto , Biópsia , Criança , Códon sem Sentido , Análise Mutacional de DNA , Saúde da Família , Feminino , Expressão Gênica , Genes Recessivos , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Musculares de Contração Rápida/patologia , Debilidade Muscular/patologia , Doenças Musculares/patologia , Oftalmoplegia/patologia , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Handb Clin Neurol ; 121: 1673-85, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24365440

RESUMO

Increased survival of critically ill patients has focused the attention on secondary complications of intensive care unit (ICU) stay, mainly ICU-acquired weakness (ICUAW). ICUAW is relatively common with significant impact on recovery. Prolonging mechanical ventilation and overall hospitalization time, increased mortality, and persistent disability are the main problems associated with ICUAW. The chapter deals mainly with the differential diagnosis of neuromuscular generalized weakness that develops in the ICU, but focal ICUAW is reviewed too. The approach to the diagnosis and the yield of various techniques (mainly electrophysiological and histological) is discussed. Possible therapeutic interventions of this condition that modify the course of this deleterious situation and lead to better rehabilitation are discussed. The current postulated mechanisms associated with ICUAW (mainly the more frequent critical illness neuropathy and myopathy) are reviewed.


Assuntos
Cuidados Críticos , Doenças Neuromusculares/etiologia , Humanos , Debilidade Muscular/etiologia , Debilidade Muscular/terapia , Doenças Neuromusculares/epidemiologia , Doenças Neuromusculares/terapia , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/terapia , Respiração Artificial/efeitos adversos
20.
Acta Myol ; 33(2): 107-10, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25709382

RESUMO

The trip is not over yet as definite therapy for GNE myopathy is not yet available. Also the exact mechanisms by which GNE defects lead to isolated muscle disease in humans are not fully recognized. But in the Gaetano Conte lecture of 2013 I have tried to describe how much a progress was made in several research laboratories and clinical institutes in the investigation of this unique myopathy.


Assuntos
Miopatias Distais/terapia , Miopatias Distais/etiologia , Miopatias Distais/fisiopatologia , Humanos , Complexos Multienzimáticos/genética
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