Caracterização clínica, neurorradiológica e genética de pacientes com síndrome de Leigh

Abstract

Introduction: Leigh Syndrome (LS) is recognized as the most common mitochondrial disease in childhood. It presents a great heterogeneity of clinical manifestation and besides, from the genetic point of view, being that there are currently reports of mutations in more than 50 genes responsible for causing such disease. LS is caused by mutations in both nuclear DNA and mitochondrial DNA, and therefore different forms of inheritance may be involved: Mendelian (autosomal recessive or X-linked) and maternal. This study was carried out with the in order to characterize patients with Leigh Syndrome (LS) / Leigh-like Syndrome (LLS) clinically, neuroradiologically and genetically, in the Neuromuscular Disease Outpatient Clinic at HC-UFMG. Materials and methods: An observational, crosssectional study was performed on 18 patients with LS / LLS who accepted to take part in the project. All of them were submitted to clinical evaluation by the same neurologist, in which a protocol with relevant clinical data and neurological examination related to LS was filled. Complementary examinations such as analysis of arterial blood gas, lactate dosage, electroneuromyography (ENMG), results of cardiological evaluation (echocardiogram), results of ophthalmologic evaluation - among others - were obtained from medical records. The muscle biopsy laminas previously performed at the time of diagnosis were reevaluated by the supervisor of this project. Previously performed brain magnetic resonance imaging (MRI) were reevaluated by two pediatric neuroradiologists. The results of the biochemical study of the mitochondrial respiratory chain conducted by the Columbia University project coordinator in 2013, according to that institution's protocol, were used in this project. Finally, 5 of the most common point mutations in mitochondrial DNA (mtDNA) (3243A> G; 8344A> G; 8993T> G; 8993T> C; 1644T> G) were screened. Results: the mean age of the 18 patients evaluated was 16.8 years; the clinical course of the disease was chronic and low mortality rate, with only one documented death. We should say that increased serum lactate was found as well as lactic acidemia at a lower frequency than described in the literature. In the muscular biopsy, only 1 patient had ragged red fibers, and in histochemistry, 1 child had presented a total cytochrome C oxidase deficiency, which, together with their clinical findings, made it possible to target the underlying genetic defect, detecting mutations in composite heterozygotes in the SCO2 gene. The biochemical study of the respiratory chain (BSRC) was performed in 9 patients, it was normal in 6 patients, with complex I deficiency in one patient and complex IV in another patient. As a result, in 15 patients, MRI exams were affected in 100% of the cases (with predominant involvement of the putamen) and in the brainstem in 20% of the patients. The white substance was abnormal in 8 patients (53.3%), but in varying degrees, being more evident and diffuse in two cases, corresponding to 13.3%. None of the patients had the mtDNA mutations screened. Conclusion: In the present study, the data evaluated, in general, were in agreement with the literature. Among the clinical findings, a survival rate higher than that one described in the literature was observed, which may be a consequence of the genetic defects prevalent in the studied population vary from those found in other countries. Regarding the laboratory tests, it was pointed out that the serum lactate dosage was altered in a few patients, showing that this is not a very sensitive screening test. The reevaluated magnetic resonance imaging tests presented typical findings of LS, with predominant involvement in basal ganlia, more frequently in putamen. Resonance spectroscopy has been shown aiming to be a more sensitive method for the detection of lactate increase and therefore should be performed routinely in the investigation of patients suspected of LS or mitochondrial diseases. The histopathological study with histochemical and biochemical analysis of the mitochondrial respiratory chain (RC) was normal in most patients, in agreement with the findings described in the literature. In cases where BSRC was altered, the specific findings helped to conduct the genetic study. Regarding molecular findings, considering the fact that childhood mitochondrial encephalopathies, including LS / LLS, are most often caused by nuclear genes, the next-generation sequencing study using panels or the study of the entire exome is, currently considered a more effective vehicle used in the investigation of these patients. A family of this series was recently submitted to the study of exome, which revealed a new mutation in homozygosis in the SUCLA2 gene in two siblings. In another family, also through the exome study, a mutation in heterozygosis was found composed in a gene recently related to LS.