RESUMO
Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.
Assuntos
Doenças Musculares , Distrofia Muscular do Cíngulo dos Membros , Chile , Perfil Genético , Humanos , Debilidade Muscular/genética , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genéticaRESUMO
Objective: To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants. Design: Observational study. Methods: Probands' phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports. Results: Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): -2.8 (0.9) and -3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: -4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference -3.0 (range: -4.7 to -1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process. Conclusions: Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.
Assuntos
Nanismo , Resistência à Insulina , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Nanismo/genética , Feminino , Humanos , Resistência à Insulina/genética , Masculino , Cãibra MuscularRESUMO
Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.
Assuntos
Proteínas de Ligação ao Cálcio , Defeitos Congênitos da Glicosilação , Glicoproteínas de Membrana , Receptores Citoplasmáticos e Nucleares , Receptores de Peptídeos , Proteínas de Ligação ao Cálcio/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/patologia , Tecido Conjuntivo/patologia , Glicosilação , Humanos , Masculino , Glicoproteínas de Membrana/genética , Fenótipo , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Peptídeos/genéticaRESUMO
INTRODUCCIÓN La sobrecarga del cuidador ha sido ampliamente descrita en gerontología, pocos estudios la abordan en niños con enfermedades neuromusculares. El cuidado de pacientes con atrofia muscular espinal (AME), requiere atención continua de un tercero, pudiendo afectar la salud del cuidador y la calidad de atención y bienestar del paciente. El objetivo del estudio fue determinar el nivel de sobrecarga de los cuidadores de pacientes AME, identificando factores protectores y de riesgo asociados MÉTODOS Estudio observacional analítico transversal en padres de pacientes con AME, de un hospital privado de Santiago de Chile. Se analizaron datos demográficos clínicos y encuesta Zarit autoreportada por los padres de los pacientes con AME, realizada entre septiembre de 2017 y febrero de 2018. Se usó estadística descriptiva y regresión logística uni y multivariada para identificar factores asociados a sobrecarga RESULTADOS De los 50 padres encuestados, 14 (28%) eran de pacientes non-sitters, con sobrecarga intensa, mediana de puntaje 59 (37-76), 29 (58%) de pacientes sitters sobrecarga ligera, mediana 48 (32-79) y 7(14%) de pacientes walkers, ausencia de sobrecarga mediana 38 (23-54). Se identificaron como factores protectores de sobrecarga los años de enfermedad OR 0,9 (0,8-0,95) P=0,037 y la mayor edad de los pacientes OR 0,9(08,0,98) p=0,018. Factores de riesgo el uso de silla de ruedas OR 7,2(1,2-4,3) p=0,029 y la vía de alimentación artificial OR 9,2(1-78,8) p=0,040 CONCLUSIÓN Los padres de pacientes con AME tienen un significativo nivel de sobrecarga y existen factores que la aumentan y disminuyen. El equipo multidisciplinario debe integrar la medición periódica del nivel de sobrecarga, para intervenir oportunamente y procurar el cuidado integral de la familia.
Caregiver burden has been widely described in gerontology, few studies address it in children with neuromuscular diseases. The care of patients with spinal muscular atrophy (SMA) requires permanent care from a third person, which may affect the caregiver health, quality of care and well-being of the patient. The aim of the study was to determine the burden of SMA patient's caregivers, identifying associated protective and risk factors METHODS Descriptive cross-sectional analytical study in SMA patient's parents, from a private hospital in Santiago de Chile., demographic Clinical and self-reported Zarit survey data, parents self reported, conducted between September 2017 and February 2018, were analyzed. Descriptive statistics and uni and multivariate logistic regression were used to identify factors associated with overloading RESULTS Parents of non-sitter patients showed a median of 59 (37-76), corresponding to intense burden and those of sitters, a light burden, with a median score of 48 (32-79) Walkers patient's parents, presented a median score of 38 (23-54) that corresponds to an absence of burden. The years of illness and the higher age of the patients were identified as protective factors of overload. As risk factors of burden, the use of a wheelchair and artificial airway. Of the 50 parents surveyed, 14 (28%) were non-sitter patients, with intense overload, median 59(37-76), 29(58%) sitters patients, light overload, median 48 (32-79) and 7(14%) walker patients, absence of overload, median 38 (23-54). Protective factors of overload were years of disease OR 0,9(0,8-0,95) p=0.037 and the patients major age OR 0.9(0.8-0.98) p=0.018. Risk factors were the use of wheelchair OR 7,2(1,2-4,3) p=0.029 and artificial feeding support OR 9,2(1-78.8) p=0.040 CONCLUSION SMA patient's parents have a significant level of overload and there are factors that increase and decrease it. The multidisciplinary team must integrate the periodic measurement of the burden level, to make on time interventions and to ensure the integral care in the family.
Assuntos
Humanos , Masculino , Feminino , Criança , Adulto , Atrofia Muscular Espinal/terapia , Carga de Trabalho/estatística & dados numéricos , Cuidadores , Pais , Modelos Logísticos , Estudos Transversais , Análise Multivariada , Inquéritos e Questionários , Fatores de Risco , Fatores de ProteçãoRESUMO
INTRODUCCIÓN: La calidad de vida (CV) es un aspecto fundamental del tratamiento en pacientes con Atrofia Muscular Espinal (AME). Existe escasa información a nivel local e internacional. OBJETIVO: Caracterizar la CV en una muestra de niños y adolescentes chilenos con AME. SUJETOS Y MÉTODO: Estudio observacional, transversal. Se aplicó un cuestionario y el módulo neuromuscular 3.0 de la encuesta PedsQLtm, a padres de niños con AME de 2-18 años. Ésta consta de 3 ámbitos: Enfermedad, Comunicación y Familia. Se consideró el puntaje >60 como CV buena, 30-60 regular y <30, deficiente. Se utilizó el programa MINITAB-17®, considerando significativo p ≤ 0,05. RESULTADOS: Se reclutaron 38 pacientes, con edad mediana 8 años (2-18), 52,7% hombres, y 17 (44,7%) AME I. Todos con confirmación genética. El puntaje total fue 51,92 ± 17, correspondiendo 31% a CV buena, 55% regular y 14% baja. En AME I fue 46,5 ± 15,2 y en AME II-III, 56,3 ± 17,4 (p = 0,071). Para el ámbito de Enfermedad fue 53,83 ± 18,1, de Familia 48,6 ± 23,14 y Comunicación 33,3 (RIC: 0,0-83,33). En este último, tuvieron mayor puntaje los pacientes con AME II o III, los mayores de 6 años, los con menor apoyo ventilatorio y los residentes en regiones. Sin embargo, en el análisis multivariado solamente el tipo de AME fue significativo, explicando 40,9% de la variación del puntaje del área de comunicación. Conclusiones: En esta muestra de pacientes con AME, la calidad de vida fue regular a buena en la mayoría. El área más baja fue la de Comunicación, con mayor puntaje en aquellos con mayor capacidad motora funcional.
INTRODUCTION: Quality of life (QoL) is a key aspect in the treatment of patients with Spinal Muscular Atrophy (SMA). International information regarding QoL in SMA is scarce, and is not available in our country. OBJECTIVE: To characterize QoL in a sample of Chilean children and adolescents with SMA. SUBJECTS AND METHOD: Observational, cross-sectional study. A general questionnaire and the PedsQLTM 3.0 Neuromuscular Module Inventory were applied to parents of children with SMA aged 2 to 18 years. It has three areas: Disease, Communication, and Family. A score >60 was considered as good QoL, 30-60 as regular, and <30 as low. MINITAB-17® software was used, considering significant a p <0.05 value. RESULTS: We recruited 38 patients, with median age 8 years (2-18), 52.63% were male, and 17 (44.7%) with SMA I. All had genetic confirmation. The total score of QoL was 51.92 ± 17, representing 31% good, 55% regular, and 14% low. Regarding SMA I, it was 46.5 ± 15.2 and SMA II-III, 56.3 ± 17.4 (p = 0.071). Concerning the area of Disease, it was 53.83 ± 18.1, Family 48.6 ± 23.14, and Communication 33.3 (IQR: 0.0; 83.33). In this last area, children with SMA II-III, older than 6 years., with non-invasive ventilatory support, or living out of the metropolitan area had hig her scores, however, in multivariate analysis, only SMA type was significant, which explained 40,9% of the variation in the communication area score. CONCLUSIONS: In this sample of SMA pediatric patients, the QoL was regular or good in most of them. The lowest area was communication, with a higher score in those children with higher motor function.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Qualidade de Vida/psicologia , Atrofias Musculares Espinais da Infância/fisiopatologia , Atrofias Musculares Espinais da Infância/psicologia , Atrofias Musculares Espinais da Infância/terapia , Indicadores Básicos de Saúde , Estudos Transversais , Comunicação , Relações Familiares , Destreza MotoraRESUMO
Immune-mediated necrotizing myopathy with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase is a subgroup of idiopathic inflammatory myopathies mainly described in adults and requiring long term immunomodulatory therapy for remission. Pediatric patients have been reported as small series or sporadic cases. We report an eight-year-old girl with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, presenting with subacute proximal limb weakness, high creatine kinase and a muscle biopsy displaying necrotizing pattern, initially diagnosed as limb-girdle muscular dystrophy, but subsequently negative genetic testing. A noteworthy spontaneous improvement in her weakness suggested the possibility of an acquired autoimmune myopathy, confirmed by positive testing of anti-HMGCR antibodies titers. After four years of follow-up, she maintains normal strength with high levels of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody. This patient shows that spontaneous fluctuations and spontaneous long-lasting symptomatic remission can occur in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy. Some patients could present a wane and wax clinical course, an important aspect when assessing response to therapy.
Assuntos
Doenças Autoimunes , Hidroximetilglutaril-CoA Redutases/imunologia , Miosite , Autoanticorpos , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Criança , Feminino , Humanos , Miosite/sangue , Miosite/imunologia , Miosite/patologia , Miosite/fisiopatologia , Remissão EspontâneaRESUMO
INTRODUCTION: Quality of life (QoL) is a key aspect in the treatment of patients with Spinal Muscular Atrophy (SMA). International information regarding QoL in SMA is scarce, and is not available in our country. OBJECTIVE: To characterize QoL in a sample of Chilean children and adolescents with SMA. SUBJECTS AND METHOD: Observational, cross-sectional study. A general questionnaire and the PedsQLTM 3.0 Neuromuscular Module Inventory were applied to parents of children with SMA aged 2 to 18 years. It has three areas: Disease, Communication, and Family. A score > 60 was considered as good QoL, 30-60 as regular, and < 30 as low. MINITAB-17« software was used, considering signifi cant a p < 0.05 value. RESULTS: We recruited 38 patients, with median age 8 years (2-18), 52.63% were male, and 17 (44.7%) with SMA I. All had genetic confirmation. The total score of QoL was 51.92 ± 17, representing 31% good, 55% regular, and 14% low. Regarding SMA I, it was 46.5 ± 15.2 and SMA II-III, 56.3 ± 17.4 (p = 0.071). Concerning the area of Disease, it was 53.83 ± 18.1, Family 48.6 ± 23.14, and Communication 33.3 (IQR: 0.0; 83.33). In this last area, children with SMA II-III, older than 6 years., with non-invasive ventilatory support, or living out of the metropolitan area had hig her scores, however, in multivariate analysis, only SMA type was significant, which explained 40,9% of the variation in the communication area score. CONCLUSIONS: In this sample of SMA pediatric patients, the QoL was regular or good in most of them. The lowest area was communication, with a higher score in those children with higher motor function.
Assuntos
Indicadores Básicos de Saúde , Qualidade de Vida , Atrofias Musculares Espinais da Infância , Adolescente , Criança , Pré-Escolar , Comunicação , Estudos Transversais , Relações Familiares , Feminino , Humanos , Masculino , Destreza Motora , Qualidade de Vida/psicologia , Atrofias Musculares Espinais da Infância/fisiopatologia , Atrofias Musculares Espinais da Infância/psicologia , Atrofias Musculares Espinais da Infância/terapiaRESUMO
METHODS: Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. RESULTS: We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. CONCLUSION: Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.
Assuntos
Doenças Neurodegenerativas/diagnóstico , Atrofias Musculares Espinais da Infância/diagnóstico , Adolescente , Adulto , Biópsia , Criança , Chile/epidemiologia , Estudos de Coortes , Eletromiografia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Neurodegenerativas/mortalidade , Doenças Neurodegenerativas/terapia , Fenótipo , Prevalência , Características de Residência , Respiração Artificial , Escoliose/cirurgia , Fatores Socioeconômicos , Atrofias Musculares Espinais da Infância/mortalidade , Atrofias Musculares Espinais da Infância/terapia , Adulto JovemRESUMO
Spinal muscular atrophy (SMA) type 0 is the most severe form of SMA, associated with the SMN1 gene and manifesting at birth. Most patients die in the first weeks of life. In this work, we present 3 patients with SMA type 0 who survived >1 year and presented diffuse and progressive brain abnormalities on magnetic resonance imaging, which are not usually seen in patients with SMA. Thus, severe brain involvement may likely be the full end manifestation of an already extreme SMA phenotype caused by substantial reduction of the SMN protein in the brain. ANN NEUROL 2019;86:458-462.