Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Muscle Nerve ; 66(1): 63-70, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35474226

RESUMO

INTRODUCTION/AIMS: Becker muscular dystrophy (BMD) is an X-linked disease leading to muscle wasting and weakness. The decrease in lean body mass (LBM) in Duchenne muscular dystrophy, has shown correlation with loss of muscle function and bone density (BD). Myokines (including irisin) are hormones secreted by skeletal muscle that allow crosstalk between muscle and bone. The present study analyzed body composition and circulating myokine levels in a cohort of BMD patients; moreover, the association between dual energy X-ray absorptiometry (DXA) parameters, functional motor assessments, and myokine levels was investigated. METHODS: All patients underwent DXA, blood samples for myokine assays, and functional motor assessments. A group of healthy controls (HCs) was also included. RESULTS: Thirty BMD patients, median age at evaluation 36.0 y [26.0-41.0], were included. Twenty-nine patients underwent whole-body DXA. Median value of total body Z-score was -0.70. The prevalence of low skeletal muscle mass defined as appendicular skeletal muscle mass index (ASMMI) < 7.59 kg/m2 was 83%. Irisin levels were significantly lower in BMD compared to HCs (p = .03). All DXA parameters showed significant correlation with the functional motor assessments, in particular the h2 -standardized lean mass lower limb index (p = .0006); h2 -standardized total fat mass showed negative correlations with North Star Ambulatory Assessment and 6 min walk test (p = .03). DISCUSSION: DXA is a useful tool to evaluate body composition in BMD patients; the decrease in BD and LBM is associated with a reduction of motor function in BMD.


Assuntos
Distrofia Muscular de Duchenne , Absorciometria de Fóton , Composição Corporal/fisiologia , Densidade Óssea/fisiologia , Fibronectinas , Humanos , Músculo Esquelético , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/diagnóstico por imagem
2.
Am J Hum Genet ; 97(1): 186-93, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26094573

RESUMO

Chronic progressive external ophthalmoplegia (CPEO) is common in mitochondrial disorders and is frequently associated with multiple mtDNA deletions. The onset is typically in adulthood, and affected subjects can also present with general muscle weakness. The underlying genetic defects comprise autosomal-dominant or recessive mutations in several nuclear genes, most of which play a role in mtDNA replication. Next-generation sequencing led to the identification of compound-heterozygous RNASEH1 mutations in two singleton subjects and a homozygous mutation in four siblings. RNASEH1, encoding ribonuclease H1 (RNase H1), is an endonuclease that is present in both the nucleus and mitochondria and digests the RNA component of RNA-DNA hybrids. Unlike mitochondria, the nucleus harbors a second ribonuclease (RNase H2). All affected individuals first presented with CPEO and exercise intolerance in their twenties, and these were followed by muscle weakness, dysphagia, and spino-cerebellar signs with impaired gait coordination, dysmetria, and dysarthria. Ragged-red and cytochrome c oxidase (COX)-negative fibers, together with impaired activity of various mitochondrial respiratory chain complexes, were observed in muscle biopsies of affected subjects. Western blot analysis showed the virtual absence of RNase H1 in total lysate from mutant fibroblasts. By an in vitro assay, we demonstrated that altered RNase H1 has a reduced capability to remove the RNA from RNA-DNA hybrids, confirming their pathogenic role. Given that an increasing amount of evidence indicates the presence of RNA primers during mtDNA replication, this result might also explain the accumulation of mtDNA deletions and underscores the importance of RNase H1 for mtDNA maintenance.


Assuntos
Replicação do DNA/genética , DNA Mitocondrial/fisiologia , Encefalomiopatias Mitocondriais/genética , Oftalmoplegia Externa Progressiva Crônica/genética , RNA/metabolismo , Ribonuclease H/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Southern Blotting , Western Blotting , DNA Mitocondrial/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Encefalomiopatias Mitocondriais/patologia , Dados de Sequência Molecular , Mutação/genética , Oftalmoplegia Externa Progressiva Crônica/patologia , Linhagem
3.
Orphanet J Rare Dis ; 18(1): 196, 2023 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-37480080

RESUMO

BACKGROUND: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. RESULTS: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion-amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. CONCLUSIONS: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS.


Assuntos
Disseminação de Informação , Doenças Raras , Humanos , Projetos Piloto , Europa (Continente) , União Europeia
4.
Front Hum Neurosci ; 16: 925299, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967003

RESUMO

Falls are frequent in Myotonic Dystrophy type 1 (DM1), but the pathophysiology of the balance impairment needs further exploration in this disease. The current work aims to provide a richer understanding of DM1 imbalance. Standing balance in 16 patients and 40 controls was tested in two posturographic tests (EquiTest™). In the Sensory Organization Test (SOT), standstill balance was challenged by combining visual (eyes open vs. closed) and environmental conditions (fixed vs. sway-tuned platform and/or visual surround). In the "react" test, reflexes induced by sudden shifts in the support base were studied. Oscillations of the body centre of mass (COM) were measured. In the SOT, COM sway was larger in patients than controls in any condition, including firm support with eyes open (quiet standing). On sway-tuned support, COM oscillations when standing with closed eyes were larger in patients than controls even after taking into account the oscillations with eyes open. In the "react" paradigm, balance reflexes were delayed in patients. Results in both experimental paradigms (i.e., SOT and react test) are consistent with leg muscle weakness. This, however, is not a sufficient explanation. The SOT test highlighted that patients rely on vision more than controls to maintain static balance. Consistently enough, evidence is provided that an impairment of proprioceptive and vestibular systems contributes to falls in DM1. Rehabilitation programs targeted at reweighting sensory systems may be designed to improve safe mobility in DM1.

5.
Can Respir J ; 2022: 2321909, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35762008

RESUMO

Introduction: Respiratory insufficiency is one of the main causes of death in myotonic dystrophy type 1 (DM1). Although there is general consensus that these patients have a restrictive ventilatory pattern, hypoventilation, chronic hypercapnia, and sleep disturbances, the prevalence of respiratory disease and indication for the effects of noninvasive ventilation (NIV) need to be further explored. Objectives: To describe respiratory function and need for NIV at baseline and over time in a cohort of adult patients with DM1. Methods: A total of 151 adult patients with DM1 were subjected to arterial blood gas analysis, sitting and supine forced vital capacity (FVC), peak cough expiratory flow (PCEF), nocturnal oximetry, and maximal inspiratory pressure and expiratory pressure (MIP/PEP). Results: On first assessment, 84 of 151 had normal respiratory function (median age: 38 years, median BMI: 23.9, and median disease duration: 11 years); 67 received an indication to use NIV (median age: 49 years, median BMI: 25,8, and median disease duration: 14 years). After a median time of 3.85 years, 43 patients were lost to follow-up; 9 of 84 required NIV; only 17 of 67 with the new NIV prescription were adherent. Conclusions: We provide additional data on the natural history of respiratory function decline and treatment adherence in a relatively large cohort of well-characterized patients with DM1. A high proportion (28%) was lost to follow-up. A minority (11%) required NIV, and only 25% were treatment adherent, irrespective of specific demographics and respiratory features. Our results also confirm previous findings, showing that age, disease duration, and higher BMIs are predisposing factors for respiratory impairment.


Assuntos
Distrofia Miotônica , Ventilação não Invasiva , Insuficiência Respiratória , Adulto , Humanos , Hipercapnia/etiologia , Hipercapnia/terapia , Pessoa de Meia-Idade , Distrofia Miotônica/complicações , Distrofia Miotônica/terapia , Respiração , Insuficiência Respiratória/terapia
6.
J Clin Sleep Med ; 17(12): 2383-2391, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34170223

RESUMO

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 is mostly of central origin but it may coexist with sleep-related breathing disorders. However, there is no consensus on the sleep protocols to be used, assessments vary, and only a minority of patients are regularly tested or are on treatment for EDS. Our study presents data on self-reported and objective EDS in adult-onset myotonic dystrophy type 1. METHODS: Sixty-three patients with adult-onset DM1 were subjected to EDS-sleep assessments (polysomnography, Multiple Sleep Latency Test, Epworth Sleepiness Scale). Correlation coefficients were computed to assess the relationship between sleep and sleepiness test results, fatigue, and quality of life. RESULTS: 33% and 48% of patients had EDS based, respectively, on the Epworth Sleepiness Scale and the Multiple Sleep Latency Test, with a low concordance between these tests (k = 0.19). Thirteen patients (20%) displayed 2 or more sleep-onset rapid eye movement periods on Multiple Sleep Latency Test. Patients having EDS by Multiple Sleep Latency Test had a shorter disease duration (P < .05), higher total sleep time and sleep efficiency and lower wake after sleep onset on polysomnography. Patients with self-reported EDS reported significantly higher fatigue score compared with patients without EDS (P < .05). No other difference was found in demographic, clinical, and respiratory features. CONCLUSIONS: EDS test results are contradictory, making treatment options difficult. Combining quantitative tests and self-reported scales may facilitate physicians in planning EDS care with patients and families. CITATION: Sansone VA, Proserpio P, Mauro L, et al. Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1. J Clin Sleep Med. 2021;17(12):2383-2391.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Distrofia Miotônica , Adulto , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/epidemiologia , Humanos , Distrofia Miotônica/complicações , Polissonografia , Qualidade de Vida , Autorrelato
7.
Neuromuscul Disord ; 30(4): 301-309, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32305258

RESUMO

Symptoms of respiratory involvement are frequently present but overlooked by patients with Myotonic Dystrophy type 1 (DM1). A respiratory symptom checklist was designed to test whether a DM-specifically designed checklist to detect symptoms of respiratory involvement (The Respicheck Questionnaire) could help patients be more aware of their respiratory problems, if any, and help clinicians in identifying potential candidates for intervention. The Respicheck questionnaire was administered to 58 consecutive adult-onset patients with genetically determined DM1 who did not complain of respiratory involvement per history at enrollment. Based on respiratory function test results patients were divided into 3 groups: A, (n = 17) having no signs of respiratory involvement; B (n = 13), patients having borderline results on respiratory assessments and having no need for respiratory intervention; C, (n = 28) patients having respiratory impairment requiring intervention. Respiratory test results and Respicheck scores were analyzed. Respicheck total score and subscales correlated positively with global respiratory impairment. Respicheck appears to be able to discriminate between patients having a higher level of respiratory dysfunction from those having a lower risk of respiratory involvement. This might allow to better target efforts and resources in respiratory management in DM1.


Assuntos
Distrofia Miotônica/diagnóstico , Transtornos Respiratórios/diagnóstico , Índice de Gravidade de Doença , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/classificação , Distrofia Miotônica/complicações , Ventilação não Invasiva , Transtornos Respiratórios/classificação , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/terapia , Testes de Função Respiratória , Insuficiência Respiratória , Sensibilidade e Especificidade , Espirometria , Inquéritos e Questionários/normas
8.
Europace ; 11(9): 1243-4, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19556250

RESUMO

Cardiac involvement in myotonic dystrophy type 1 (DM1) is frequent with increased incidence of conduction disturbances and sudden cardiac death when compared with general population. We describe a 38-year-old man in whom the diagnosis of DM1 was made 8 years after occurrence of cardiac arrest owing to ventricular fibrillation and discuss management of DM1 patients at risk for sudden cardiac death.


Assuntos
Parada Cardíaca/complicações , Parada Cardíaca/prevenção & controle , Distrofia Miotônica/complicações , Distrofia Miotônica/terapia , Ressuscitação , Adolescente , Seguimentos , Humanos , Masculino , Recidiva , Resultado do Tratamento , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/etiologia
9.
Neuromuscul Disord ; 27(11): 1047-1053, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28890289

RESUMO

The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, self-reported outcome measure that assesses total disease burden and 17 areas of Myotonic Dystrophy type 1 (DM1) specific health. This study translated the MDHI into Italian and validated the instrument using a cohort of Italian DM1 patients. Italian DM1 patients were interviewed regarding the form and content of the instrument. Thirty-eight DM1 patients were subsequently recruited to test the reliability and concurrent validity of the instrument by serially completing the MDHI and a battery of clinical tests. Lastly, we determined the internal consistency of the Italian MDHI and each of its subscales. The internal consistency was excellent in the total Italian MDHI score and acceptable in all of its subscales; the test-retest reliability was high (intraclass correlation coefficient = 0.95); Italian MDHI total scores and subscales were associated with neuromuscular function, cognitive and social health, respiratory function, and quality of life. Overall, the Italian MDHI is valid and well suited to measure the multi-dimensional aspects of disease burden in Myotonic Dystrophy clinical trials.


Assuntos
Efeitos Psicossociais da Doença , Distrofia Miotônica/diagnóstico , Medidas de Resultados Relatados pelo Paciente , Cultura , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/psicologia , Qualidade de Vida , Reprodutibilidade dos Testes , Autorrelato , Índice de Gravidade de Doença , Tradução
10.
Mol Genet Metab Rep ; 10: 24-27, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28070494

RESUMO

To date, only few mutations in the mitochondrial DNA (mtDNA)-encoded ND2 subunit of Complex I have been reported, usually presenting a severe phenotype characterized by early onset encephalomyopathy and early death. In this report, we describe a new mutation in the MTND2 gene in a 21-year-old man with a mild myopathic phenotype characterized by exercise intolerance and increased plasma lactate at rest. Electromyography and brain NMR were normal, and no cardiac involvement was present. Muscle biopsy showed a massive presence of ragged red - COX-positive fibres, with enlarged mitochondria containing osmiophilic inclusions. Biochemical assays revealed a severe isolated complex I deficiency. We identified a novel, heteroplasmic mutation m.4831G > A in the MTND2 gene, causing the p.Gly121Asp substitution in the ND2 protein. The mutation was present in the 95% of mitochondrial genomes from patient's muscle tissue, at a lower level in cells from the urinary tract and at a lowest level in lymphocytes from patient's blood; the base substitution was absent in fibroblasts and in the tissues from proband's healthy mother and brother. The specific skeletal muscle tissue involvement can explain the childhood-onset and the relatively benign, exclusively myopathic course of the disease.

11.
EMBO Mol Med ; 7(7): 918-29, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25872942

RESUMO

We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole-exome sequencing, we found a homozygous nucleotide change in XRCC4 (c.673C>T), predicted to introduce a premature stop codon (p.R225*). XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non-homologous end joining of DNA double-strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the Xrcc4 KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult-onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients.


Assuntos
Encefalopatias/complicações , Encefalopatias/genética , Cardiomiopatias/complicações , Cardiomiopatias/genética , Códon sem Sentido , Proteínas de Ligação a DNA/genética , Proteínas Mutantes/genética , Adulto , Animais , Proteínas de Ligação a DNA/análise , Fibroblastos/química , Perfilação da Expressão Gênica , Estudos de Associação Genética , Homozigoto , Humanos , Camundongos , Camundongos Knockout
12.
Front Genet ; 5: 397, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25452764

RESUMO

Isolated complex III (cIII) deficiency is a rare biochemical finding in mitochondrial disorders, mainly associated with mutations in mitochondrial DNA MTCYB gene, encoding cytochrome b, or in assembly factor genes (BCS1L, TTC19, UQCC2, and LYRM7), whereas mutations in nuclear genes encoding cIII structural subunits are extremely infrequent. We report here a patient, a 9 year old female born from first cousin related parents, with normal development till 18 months when she showed unsteady gait with frequent falling down, cognitive, and speech worsening. Her course deteriorated progressively. Brain MRI showed cerebellar vermis hypoplasia and bilateral lentiform nucleus high signal lesions. Now she is bed ridden with tetraparesis and severely impaired cognitive and language functions. Biochemical analysis revealed isolated cIII deficiency in muscle, and impaired respiration in fibroblasts. We identified a novel homozygous rearrangement in TTC19 (c.213_229dup), resulting in frameshift with creation of a premature termination codon (p.Gln77Argfs*30). Western blot analysis demonstrated the absence of TTC19 protein in patient's fibroblasts, while Blue-Native Gel Electrophoresis analysis revealed the presence of cIII-specific assembly intermediates. Mutations in TTC19 have been rarely associated with mitochondrial disease to date, being described in about ten patients with heterogeneous clinical presentations, ranging from early onset encephalomyopathy to adult forms with cerebellar ataxia. Contrariwise, the biochemical defect was a common hallmark in TTC19 mutant patients, confirming the importance of TTC19 in cIII assembly/stability. Therefore, we suggest extending the TTC19 mutational screening to all patients with cIII deficiency, independently from their phenotypes.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA