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Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.
Assuntos
Doenças Desmielinizantes , Doenças Neurodegenerativas , Humanos , Criança , Irã (Geográfico) , Heterogeneidade Genética , Imageamento por Ressonância Magnética , Encéfalo , Oxirredutases do ÁlcoolRESUMO
UNLABELLED: Patients with CVID are at greater risk of developing lung complications than patients with XLA because of delayed diagnosis and possible immune dysregulation. Early diagnosis and appropriate treatment reduces the incidence of pulmonary infections in both groups of patients. However, CVID patients are prone to progressive lung disease despite optimal immunoglobulin therapy. BACKGROUND AND OBJECTIVE: Pulmonary disease is the most common complication in patients with common variable immunodeficiency (CVID) or X-linked agammaglobulinaemia (XLA). Pulmonary disease may progress despite immunoglobulin replacement therapy. In this study pulmonary complications were compared in patients with CVID or XLA. METHODS: Pulmonary complications were evaluated in 115 patients (76 with CVID and 39 with XLA) by reviewing hospital records of chest infections, pulmonary function tests and high-resolution CT scans. RESULTS: Thirty-two patients with XLA (82%) presented with 59 episodes of pneumonia before diagnosis, whereas 15 patients (38.4%) experienced pneumonia after immunoglobulin replacement therapy (1.67 vs 0.45 episodes per patient per year). Among the CVID patients, 196 episodes of pneumonia were documented in 59 patients (77.6%) before diagnosis, while 36 patients (47.3%) experienced pneumonia after therapy (1.11 vs 0.58 episodes of pneumonia per patient per year). Forty-seven (41%) patients (38 with CVID and 9 with XLA) developed chronic lung disease. The CVID patients developed more complications, including bronchiectasis and lymphoid interstitial pneumonitis, than the XLA patients. CONCLUSIONS: Patients with CVID had a greater likelihood of developing lung disease, possibly due to delayed diagnosis and immune dysregulation, as compared with XLA patients. Early diagnosis of patients with primary antibody deficiencies and adequate i.v. immunoglobulin replacement therapy substantially reduces the number of pulmonary infections. However, CVID patients are prone to progression of lung disease despite optimal immunoglobulin therapy because of the nature of the disease. This important issue should be addressed in further studies.
Assuntos
Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Pneumopatias/epidemiologia , Adolescente , Adulto , Agamaglobulinemia/terapia , Bronquiectasia/epidemiologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/terapia , Progressão da Doença , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Imunização Passiva , Doenças Pulmonares Intersticiais/epidemiologia , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Prevalência , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Alexander disease (AD) is a sporadic leukodystrophy that predominantly affects infants and children and usually results in death within ten years after onset. The infantile form comprises the most of affected individuals. It presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly and frontal bossing, seizures, pyramidal signs and ataxia. The diagnosis is based on magnetic resonance imaging (MRI) findings and confirmed by GFAP gene molecular testing. GFAP gene encodes glial fibrillary acidic protein, is the only gene in which mutation is currently known to cause AD which is inherited in autosomal dominant manner. CASE PRESENTATION: In this article we report the first two Iranian cases of infantile AD and their clinical, brain MRI and molecular findings. We report two novel mutations too in the GFAP gene that are associated with infantile form of AD. CONCLUSION: GFAP gene mutations are a reliable marker for infantile AD diagnosed according to clinical and MRI defined criteria. A genotype-phenotype correlation had been discerned for the two most frequently reported GFAP gene mutations in infantile type of AD (R79 and R239), with the phenotype of the R79 mutations appearing much less severe than that of the R239 mutations. Our findings confirm this theory.
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BACKGROUND: Classic Pelizaeus-Merzbacher disease is a rare x-linked disorder of proteolipid protein expression first described clinically in 1885. This disease is characterized by abnormal eye movements, very slow motor development and involuntary movements. The causative gene is PLP1. CASE PRESENTATION: A 1-year-old boy was referred to our clinic due to abnormal eye movements. He had horizontal and flickering eye oscillation, psychomotor retardation, hypotonia and head nodding. We found hypomyelination in brain MRI. CONCLUSION: The possibility of Pelizaeus-Merzbacher disease should be considered in boys with abnormal eye movements, psychomotor retardation and hypotonia.
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BACKGROUND: Primary antibody deficiencies are characterized by defective antibody production and recurrent infections. Patients usually present with recurrent respiratory tract infections with consequent chronic pulmonary damage and bronchiectasis, which could potentially influence cardiac function. Our aim was to assess noninvasively the cardiac complications due to pulmonary disease in patients with primary antibody deficiency. METHODS: A cross-sectional series of patients with primary antibody deficiency syndromes from our referral immunology center were recruited. Individuals undergoing high-resolution computed tomography (HRCT) and transthoracic echocardiography were reviewed. RESULTS: Thirty primary immunodeficient patients aged 5-55 years of age (21 males and 9 females) were enrolled in this study. Half of the patients (50%) were found to have bronchiectasis in HRCT imaging. In echocardiographic examination, 20 patients (67%) had at least one abnormality; among which pulmonary hypertension was the most common (33%). Patients with bronchiectasis had higher pulmonary artery pressures and HRCT bronchiectasis score was strongly correlated with pulmonary artery pressure (regression R = 0.59, P value = 0.001). CONCLUSION: Echocardiographic evaluation of right ventricular function and noninvasive estimation of pulmonary artery pressure could have an important diagnostic role in the follow-up and therapeutic management of patients with primary immune deficiency.