RESUMO
Abstract Introduction: Anti-nucleosome and anti-C1q antibodies demonstrated an association with the development of glomerulonephritis in systemic lupus erythematosus (SLE). Some investigators have proposed that monitoring anti- C1q and anti-nucleosome antibodies might be valuable for making predictions about lupus nephritis (LN) and assessment of disease activity as a non-invasive biological marker of renal disease. Objectives: The current study was proposed to investigate the presence of anti-C1q and anti-nucleosome antibodies in the sera of Egyptian patients with SLE and their association with LN. Methods: Eighty patients with SLE were included. Patients were classified into, a LN group including 40 cases with active LN (based on the results of renal biopsy and renal SLEDAI≥4) and a non renal SLE group including 40 patients (with no clinical or laboratory evidence of renal involvement that were attributed in the past or present to SLE). They were subjected to full medical history taking, clinical examination, routine laboratory investigations, measurement of antinuclear antibody (ANA), anti-ds DNA, anti-C1q & anti-nucleosome antibodies. Results: Anti-C1q antibody showed a statistically significant association with the presence of vasculitis and nephritis while anti-nucleosome antibody didn't show a significant association with the presence of any clinical features. Double positivity of anti-nucleosome and anti-C1q antibodies showed a statistically significant association with the presence of vasculitis and photosensitivity, high ECLAM score, elevated ESR, low serum albumin and low C3 levels. Conclusion: Serum anti-C1q antibody has a significant association with LN while double positive antibodies have a significant association with vasculitis and low C3 levels in Egyptian patients with SLE.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumologia/métodos , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Teste em Amostras de Sangue Seco/normas , Transtornos de Início Tardio/diagnóstico , Pneumopatias/complicações , Biópsia , Doença de Depósito de Glicogênio Tipo II/sangue , Doença de Depósito de Glicogênio Tipo II/enzimologia , Diagnóstico Precoce , alfa-Glucosidases/metabolismo , Transtornos de Início Tardio/sangue , Transtornos de Início Tardio/enzimologia , Itália , Pneumopatias/sangue , Músculos/cirurgia , Músculos/enzimologiaRESUMO
Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.
Assuntos
Doença de Depósito de Glicogênio Tipo II/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/sangue , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , alfa-Glucosidases/sangue , Adulto , Biópsia , Feminino , Doença de Depósito de Glicogênio Tipo II/sangue , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Masculino , Distrofia Muscular do Cíngulo dos Membros/patologia , PrevalênciaRESUMO
ABSTRACT Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.
RESUMO A doença de Pompe é uma doença hereditária causada pela deficiência da enzima alfa-glicosidase ácida (GAA). Estudo observacional foi realizado, em um único centro, para determinar a prevalência da doença de Pompe de início tardio (LOPD) em uma população brasileira de alto risco, usando teste em gota seca (DBS) como ferramenta principal de triagem para detectar a deficiência da GAA. DBS foi coletado para avaliar a atividade da GAA em 24 pacientes com fraqueza muscular de cinturas "não explicada" sem miopatia vacuolar na biópsia muscular. As amostras com atividade enzimática reduzida foram também submetidas a análise de mutações no gene GAA. Dos 24 pacientes com DBS, baixa atividade da enzima GAA (NaG/AaGIA: 40.42; %INH: 87.22%) foi encontrada em um paciente (4.2%). Nessa paciente, a análise genética confirmou duas mutações em heterozigose composta no gene GAA (c.-32-13T > G/p.Arg854Ter). Nossos resultados confirmam que LOPD deve ser investigada quando a manifestação clínica é uma fraqueza muscular de cinturas "não explicada", mesmo na ausência de miopatia vacuolar na biópsia muscular.
Assuntos
Humanos , Masculino , Feminino , Adulto , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/sangue , alfa-Glucosidases/sangue , Biópsia , Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/sangue , Prevalência , Distrofia Muscular do Cíngulo dos Membros/patologiaRESUMO
BACKGROUND: Lysosomal storage diseases (LSD) are a group of genetic conditions which could present a vast spectrum of abnormalities that may include skeletal abnormalities, organ dysfunction, neuronal involvement, and tissue accumulation of complex molecules, among other manifestations. Definitive diagnosis of LSD is generally obtained by specific enzyme assays performed in leukocytes, fibroblasts, or more recently, dried-blood filter paper (DBFP) samples. METHODS: We recently introduced dried-leukocytes filter paper (DLFP) as an alternative source of enzyme to assay heparan sulfamidase and galactocerebrosidase activities, which could not be measured in DBFP samples using fluorometric methods. We present a new fluorometric methods on DLFP samples, for evaluation of α-glucosidase (GAA), ß-glucosidase (GBA), and N-acetylgalactosamine-6-sulfatase (GALNS) activities, key enzyme assays for the identification of patients with Pompe disease (PD), Gaucher disease (GD), and Morquio A disease (MD), respectively. RESULTS: We show a clear discrimination between confirmed PD, GD, and MD patients and healthy controls. CONCLUSIONS: We conclude that the assays of GAA, GBA, and GALNS on DLFP are reliable and useful methods for the identification of PD, GD, and MD diseases, respectively. As sample preparation is feasible in standard biochemical laboratories and transportation is very simple, it could enable patients living in remote areas to be investigated, diagnosed and eventually treated with the specific therapies available for these diseases.
Assuntos
Ensaios Enzimáticos/métodos , Doença de Gaucher/diagnóstico , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Leucócitos/enzimologia , Mucopolissacaridose IV/diagnóstico , Fitas Reagentes/análise , Estudos de Casos e Controles , Condroitina Sulfatases/metabolismo , Dessecação , Ensaios Enzimáticos/instrumentação , Doença de Gaucher/sangue , Doença de Depósito de Glicogênio Tipo II/sangue , Humanos , Leucócitos/patologia , Mucopolissacaridose IV/sangue , Papel , alfa-Glucosidases/metabolismo , beta-Glucosidase/metabolismoRESUMO
INTRODUCTION. Glycogen storage disease type II, or Pompe disease, is a lysosomal disease with an autosomal recessive pattern of inheritance. Late-onset Pompe disease is a progressive metabolic myopathy caused by decreased activity of the enzyme acid alpha-glucosidase (GAA), which gives rise to reduced degradation and later accumulation of glycogen in the lysosomes and cell cytoplasm. CASE REPORT. A 16-year-old Venezuelan male, diagnosed with late-onset glycogen storage disease type II, or Pompe disease, based on the patient's clinical picture and the biochemical findings. The patient presented unmistakable signs of muscular atrophy in the upper and lower limbs, as well as positive Gowers' sign. Levels of creatinkinase in serum were high. His functional respiratory capacity was diminished. The quantification of the enzymatic activity of acid alpha-glucosidase on filter paper did not show any significant decrease in activity. A molecular genetic analysis revealed the existence of two homozygotic mutations in the gene GAA, c.547-67C>G and c.547-39T>G, both on exon 2 of chromosome 17. According to the human genome database and the review that was undertaken, the changes detected in this patient represent new mutations in the acid alpha-glucosidase gene, GAA. This claim is in agreement with the clinical features and biochemical changes found in the patient. CONCLUSION. A molecular genetic study is mandatory in patients suspected of having this disease.
TITLE: Dos nuevas mutaciones en el gen que codifica la alfa-glucosidasa acida en un adolescente con enfermedad de Pompe de inicio tardio.Introduccion. La glucogenosis tipo II o enfermedad de Pompe es una enfermedad lisosomal con un patron de herencia autosomico recesivo. La enfermedad de Pompe de inicio tardio es una miopatia metabolica progresiva causada por una disminucion de la actividad de la enzima alfa-glucosidasa acida (GAA), lo que origina una disminucion de la degradacion y posterior acumulo del glucogeno dentro de los lisosomas y el citoplasma celular. Caso clinico. Adolescente venezolano, de 16 años, diagnosticado de glucogenosis tipo II o enfermedad de Pompe, de comienzo tardio, basado en la clinica del paciente y los hallazgos bioquimicos. La atrofia muscular de los miembros superiores e inferiores era evidente y presentaba maniobra de Gowers positiva. Los niveles sericos de creatincinasa eran elevados. Su capacidad funcional respiratoria estaba disminuida. La cuantificacion de la actividad enzimatica de la GAA en papel de filtro no mostraba una disminucion significativa de la actividad. El analisis genetico molecular revelo la existencia de dos mutaciones en condicion homocigotica en el gen GAA, c.547-67C>G y c.547-39T>G, ambas en el exon 2 del cromosoma 17. De acuerdo con la base de datos del genoma humano y la revision emprendida, los cambios detectados en este paciente representan nuevas mutaciones en el gen GAA. Esta afirmacion esta en concordancia con la clinica y cambios bioquimicos encontrados en el paciente. Conclusion. Es obligatorio el estudio genetico molecular en un paciente en el que se sospecha la enfermedad.
Assuntos
Glucana 1,4-alfa-Glucosidase/genética , Doença de Depósito de Glicogênio Tipo II/genética , Mutação de Sentido Incorreto , Mutação Puntual , Adolescente , Idade de Início , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores , Cromossomos Humanos Par 17/genética , Creatina Quinase/sangue , Éxons/genética , Doença de Depósito de Glicogênio Tipo II/sangue , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/patologia , Homozigoto , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Músculo Esquelético/patologia , Fenótipo , Análise de Sequência de DNA , VenezuelaRESUMO
OBJECTIVE: To assess the performance of a tandem mass spectrometry (MS/MS) technology in a newborn screening laboratory to simultaneously measure α-galactosidase, acid-α-glucosidase, and α-L-iduronidase for the detection of infants at risk to develop Fabry, Pompe, or mucopolysaccharidosis (MPS)-I diseases. STUDY DESIGN: Enzyme activity was assayed from a 3.2-mm punch from 100,000+ anonymous newborn blood spots. Punches with low enzyme activity were further evaluated by nucleotide sequence analysis of the responsible gene. Confirmation of affected infants was dependent on identification of mutations compatible with diminished enzyme activity. RESULTS: The technology for simultaneously measuring multiple enzyme activities by MS/MS was successful. The confirmation of diagnosis for Fabry, Pompe, or MPS-I, by DNA sequencing estimated the prevalence of Fabry disease at 1/7800 males (95% CI 1/17,800-1/3600); Pompe disease at 1/27,800 newborns (95% CI 1/90,000-1/10,200); and MPS-I at 1/35,500 newborns (95% CI 1/143,000-1/11,100). These estimates of prevalence are 2 to 4 times greater than the prevalence estimated by clinical diagnosis. The combined prevalence for the 3 disorders was 1/7500 newborns (95% CI 1/13,500-1/4500). CONCLUSIONS: MS/MS for the simultaneous assay of multiple lysosomal enzymes can be successfully introduced into a routine newborn screening laboratory. The technology has a positive predictive value equal to, or better, than methods currently used for the detection of nonlysosomal disorders. Using newborn blood spots, the combined prevalence of Fabry, Pompe, and MPS-I is estimated at 1/7500 newborns based on low-enzyme activity and confirmation by mutation analysis.
Assuntos
Doença de Fabry/sangue , Doença de Depósito de Glicogênio Tipo II/sangue , Mucopolissacaridose I/sangue , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem , Doença de Fabry/diagnóstico , Feminino , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Humanos , Recém-Nascido , Masculino , Mucopolissacaridose I/diagnóstico , Fatores de RiscoRESUMO
OBJECTIVE: To compare the effects of enzyme replacement therapy (ERT) on cardiac performance in symptomatic and symptom-free infants with Pompe disease. STUDY DESIGN: Patients diagnosed between 1983 and 2008 were identified. Before the initiation of ERT, systolic dysfunction appeared only in patients > or = 5 months; thus we used this cut-point in age to divide clinically symptomatic patients into early and late treatment groups (Clin-E and Clin-L). Newborn screening (NBS) identified symptom-free patients. RESULTS: Among a total of 40 patients, 14 received ERT: 5 in the Clin-L, 4 in the Clin-E, and 5 in the NBS groups. All patients showed cardiomegaly, hypertrophic myocardium, and elevated B-type natriuretic peptide (measured in the Clin-E and NBS groups). ERT improved the survival and outcomes. Regressed myocardial hypertrophy and lowered B-type natriuretic peptide level occurred after 1 to 6 months of ERT. Nonetheless, there were 2 deaths and 2 survivors requiring ventilator support in the Clin-L group. Despite the regressed QRS voltage and shortened QT dispersion, life-threatening arrhythmias were still observed in 3, but none in the NBS group. CONCLUSION: ERT may restore the cardiac function in both symptomatic and symptom-free patients, but the beneficial effect may be unpredictable if given after the age of 5 months.
Assuntos
Cardiomegalia/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , alfa-Glucosidases/uso terapêutico , Cardiomegalia/etiologia , Eletrocardiografia , Doença de Depósito de Glicogênio Tipo II/sangue , Doença de Depósito de Glicogênio Tipo II/complicações , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Lactente , Peptídeo Natriurético Encefálico/sangue , Estudos Prospectivos , Taquicardia/etiologiaRESUMO
BACKGROUND: Glycogen storage disease II is characterized by a deficiency of the lysosomal enzyme acid alpha-glucosidase. Currently, glycogen storage disease II is diagnosed by demonstrating the virtual absence or a marked reduction of acid alpha-glucosidase activity in muscle biopsies, cultured fibroblasts, or purified lymphocytes. Early diagnosis and treatment of glycogen storage disease II are considered to be critical for maximum efficacy of the enzyme replacement therapies that are in development. However, these existing diagnostic methods are not suited for newborn screening. We developed an assay useful for newborn screening for glycogen storage disease II. METHODS: A series of three enzyme assays to measure the alpha-glucosidase activities in dried blood spots on filter paper was developed. The measurement of acid alpha-glucosidase activity with minimal interference by other alpha-glucosidases was accomplished using maltose as an inhibitor. The method was used on samples from glycogen storage disease II patients, obligate heterozygotes, and healthy controls. RESULTS: Glycogen storage disease II patients were distinguished from carriers and healthy controls using the series of enzyme assays. CONCLUSIONS: We developed a simple and noninvasive screening method for glycogen storage disease II. The method could be incorporated into newborn screening.