RESUMO
Nemaline myopathy is a rare congenital disease that generally occurs in childhood. We report a case of a 50-year-old man who presented with severe heart failure as the initial manifestation of nemaline myopathy. Soon after he developed acute restrictive respiratory failure due to the diaphragmatic paralysis. The diagnosis of "nemaline myopathy" was obtained on muscle biopsy performed one year later. After starting appropriate cardiological treatment and non-invasive ventilation, his cardiac and pulmonary functions improved substantially, remaining stable for over the 10 years since diagnosis. In the last two years the patient had a progressive deterioration of respiratory function, enabling him to attend daily activities. Few cases of respiratory failure in patients with adult-onset nemaline myopathy are reported, but the insidious onset in this case is even more unusual. This case highlights the wide spectrum of presenting features of adult-onset nemaline myopathy and the temporary efficacy of non invasive ventilation on respiratory function.
Assuntos
Cardiomiopatia Dilatada/complicações , Miopatias da Nemalina/complicações , Insuficiência Respiratória/etiologia , Paralisia Respiratória/etiologia , Idade de Início , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias da Nemalina/epidemiologiaRESUMO
Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23-38.6) in patients who could benefit of mechanical ventilation.This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age.
Assuntos
Distrofia Muscular de Duchenne/mortalidade , Adolescente , Adulto , Causas de Morte , Criança , Progressão da Doença , Feminino , Cardiopatias/complicações , Humanos , Estimativa de Kaplan-Meier , Masculino , Distrofia Muscular de Duchenne/complicações , Doenças Respiratórias/complicações , Estudos Retrospectivos , Adulto JovemRESUMO
Pompe disease is caused by glycogen accumulation due to a deficiency of the lysosomal acid alpha-glucosidase enzyme by which it is degraded. It is a rare disease, accounting for 1:40.000 births. It is inherited as an autosomal recessive trait so that a couple presents a recurrent risk of 25% to have a child affected, at each pregnancy. The diagnosis could be achieved by biochemical and/or molecular testing. Carrier detection and prenatal diagnosis are available when the molecular defect is known.
Assuntos
Aconselhamento Genético , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Criança , Pré-Escolar , Feminino , Triagem de Portadores Genéticos , Doença de Depósito de Glicogênio Tipo II/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Gravidez , Diagnóstico Pré-NatalRESUMO
The spinal muscular atrophies (SMAs) include a group of disorders characterized by progressive weakness of the lower motor neurons. Several types of SMAs have been described based on age onset of clinical features: Acute infantile (SMA type I), chronic infantile (SMA type II), chronic juvenile (SMA type III), and adult onset (SMA type IV) forms. The incidence is about 1:6,000 live births with a carrier frequency of 1:40 for the severe form and 1:80 for the juvenile form. The mortality and/or morbidity rates of SMAs are inversely correlated with the age at onset. SMAs are believed to only affect skeletal muscles; however, new data on SMA mice models suggest they may also impact the heart. Aim of the study was to retrospectively examine the cardiological records of 37 type molecularly confirmed II/III SMA patients, aged 6 to 65 years, in order to evaluate the onset and evolution of the cardiac involvement in these disorders. All patients had a standard ECG and a routine echocardiography. The parameters analysed were the following: Heart rate (HR), PQ interval, PQ segment, Cardiomyopathic Index (ratio QT/PQs), ventricular and supraventricular ectopic beats, pauses > or = 2,5 msec, ventricle diameters, wall and septum thickness, ejection fraction, fiber shortening. The results showed that HR and the other ECG parameters were within the normal limits except for the Cardiomyopathic Index that was higher than the normal values (2,6-4,2) in 2 patients. Left ventricular systolic function was within the normal limits in all patients. A dilation of the left ventricle without systolic dysfunction was observed in only 2 patients, aged respectively 65 and 63 years; however they were hypertensive and/or affected by coronary artery disease. Data here reported contribute to reassure patients and their clinicians that type II/III SMAs do not present heart dysfunction.
Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Atrofia Muscular Espinal/complicações , Adolescente , Adulto , Fatores Etários , Idoso , Cardiomiopatias/fisiopatologia , Criança , Eletrocardiografia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/diagnóstico por imagem , Atrofia Muscular Espinal/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia , Função Ventricular Esquerda/fisiologia , Adulto JovemRESUMO
Mutations in the lamin A/C gene (LMNA) have been associated with several phenotypes ranging from systemic to prevalent of muscle, heart, skin, nerve etc. More recently they have been associated with dilated cardiomyopathy (DCM) and severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). We report four novel mutations - 3 missense and 1 deletion - in 4 unrelated patients showing different phenotypes, ranging from the early onset congenital form of laminopathy to classical LGMD phenotype, to LGMD and heart involvement. All these newly identified variants were not found in 300 ethnicallymatched control subjects. The variant c.103-105del CTG was described post-mortem in a young patient with congenital muscular dystrophy who presented at the age of 9 a first degree A-V block and subsequently several episodes of supraventricular parossystic tachycardia. Two patients presented as onset symptom lower limbs muscle weakness, and developed heart conduction defects requiring pacemaker implantation at the age of 26 and 38 years, respectively. One of them who carried the mutation c.1339G>C died at the age of 40 by intractable heart failure; the second one carrying the mutation 265C>T died at the age of 30, for a trmboembolic event. A classical LGMD phenotype without heart involvement was observed in the patient with the mutation 1579C>T, who died at the age of 68 years for respiratory insufficiency.
Assuntos
Lamina Tipo A/genética , Distrofias Musculares/genética , Adulto , Idoso , Bloqueio Atrioventricular/genética , Biópsia , Síndrome de Brugada/genética , Doença do Sistema de Condução Cardíaco , Criança , Evolução Fatal , Deleção de Genes , Insuficiência Cardíaca/genética , Humanos , Mutação de Sentido Incorreto , Fenótipo , Insuficiência Respiratória/genética , Taquicardia Supraventricular/genéticaRESUMO
Becker muscular dystrophy (BMD) was first described in 1953 by Emile Becker as a benign variant of Duchenne muscular Dystrophy (DMD). Compared with DMD, BMD is clinically more heterogeneous, with initial presentation in the teenage years and loss of ambulation beyond the age of 16 and a wide spectrum of clinical presentations, ranging from only myalgias and muscle cramps to exercise intolerance and myoglobinuria, asymptomatic elevation of serum creatin-kinase, or mild limb-girdle weakness and quadriceps myopathy. About 50% of patients become symptomatic by the age of 10 and the most part by the age of 20 years. However few patients can be free of symptoms till their fifties and cases of late-onset Becker Muscular Dystrophy have also been described. In this report we describe the clinical features of patients with dystrophinopathy sharing a deletion of exons 45-55, occasionally or retrospectively diagnosed. These data are important for both the prognostic aspects of children presenting this dystrophin gene mutation, and for the genetic counseling in these families (reassuring them on the benign course of the disease), and last but not least to keep in mind a diagnosis of BMD in asymptomatic adults with mild hyperckemia.
Assuntos
Distrofina/genética , Éxons , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Deleção de Sequência , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , Pré-Escolar , Creatina Quinase/sangue , Creatina Quinase/metabolismo , Tolerância ao Exercício , Aconselhamento Genético , Humanos , Pessoa de Meia-Idade , Cãibra Muscular/diagnóstico , Cãibra Muscular/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Mialgia/diagnóstico , Mialgia/fisiopatologia , Mioglobinúria/diagnóstico , Mioglobinúria/fisiopatologia , Prognóstico , RNA Mensageiro/genética , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. RESULTS: Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). CONCLUSIONS: We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.
Assuntos
Cardiomiopatia Dilatada/etiologia , Genes Modificadores , Estudos de Associação Genética , Predisposição Genética para Doença , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/genética , Adolescente , Criança , Genótipo , Glucocorticoides/uso terapêutico , Humanos , Padrões de Herança , Estimativa de Kaplan-Meier , Proteínas de Ligação a TGF-beta Latente/genética , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/mortalidade , Osteopontina/genética , Prognóstico , Adulto JovemRESUMO
OBJECTIVE: To test the effect of the single nucleotide polymorphism -66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD). METHODS: This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the north star ambulatory assessment (NSAA) and the 6-minute walk test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups. RESULTS: Eighty patients were selected (age 4.1-19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values. CONCLUSIONS: These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.