Assessment of phenotype and genotype relationship in mitochondrial diseases, retrospective evaluation

Introduction: Mitochondrial diseases constitute an important part of hereditary metabolic diseases, which progress with disruption in oxidative phosphorylation and ATP production as a result of mitochondrial respiratory chain dysfunction. Diagnosis is very difficult due to its clinical and genetic heterogeneity. Mutations in mitochondrial DNA or nuclear DNA can result in mitochondrial dysfunction via total lack of a specific electron transport chain complex or through transcription and translation defect. Clinical, laboratory, radiological findings and histopathological or enzymatic evaluation of tissue samples such as muscle, liver, and fibroblasts via molecular methods are used for diagnosis. Aim: In our study demographic, clinical, biochemical and radiological features of mitochondrial diseases together with histopathological and enzymatic evaluation findings were evaluated retrospectively, aiming to assess the phenotype and genotype relationship in patients with mitochondrial respiratory chain disorder diagnosed using molecular analysis methods. Method and Findings: In our study, 240 patients who were followed with the diagnosis of mitochondrial diseases diagnosis between January 1990 and December 2020 at the Department of Pediatric Nutrition and Metabolism in Istanbul University Istanbul Medical Faculty were evaluated using the hospital automation system records and patient files. Twenty-seven patients were excluded from the study due to lack of adequate information or change in diagnosis. For 213 patients who are included; average age at presentation was 4.5 ± 6.8 years (range: 0 – 44 years), average follow-up period was 5.5 ±5.9 years (range: 0 – 33 years), and average current age was 16.6 ± 11.3 years (range: 1.3 – 60.7 years). In the study group, 45% of the patients were girls, 54.5% were boys, and the male / female ratio was 1.2. The most common age for onset of first clinical signs was in the 1-12 months period. Consanguineous marriages were present in patient history for 55.8%. Mortality rate was 14.4% with average age of death being 2.5 ± 2.8 years (range: 0.04 to 7.7 years). Multisystem involvement was present in 91.5% of the patients, and the most common involvement was skeletal muscles (88.6%) and central nervous system (80.5%). Cardiac involvement was present in 17.4% of the patients, and 91% of this involvement was manifested as cardiomyopathy. It was shown that 17.6% of the patients had ocular involvement, and 38% of this group had optic atrophy. As for the laboratory findings, 72.2% patients had elevated lactate levels, 51.1% had elevated alanine levels and 39.4% had metabolic acidosis. The most common cranial MR imaging finding was increase in basal ganglia signal (present in 50.3%) followed by atrophy in %11.4. Histopathological evaluation with muscle biopsy performed for 164 patients, showing disease-compatible changes in 68.3%, lipid accumulation myopathy in 46.3%, mitochondrial myopathy in 20.7%, and "red ragged fibers" in 1.2%. Respiratory chain enzyme activity was evaluated in 61 patients among which decrease in complex activities seen in 55.7%, isolated complex I and isolated complex IV deficiencies constituting the most. Molecular analysis perfomed in 104 patients, of which 29.8% had disease-related genetic changes. Among these patients; 8 had mtDNA and 23 had nDNA changes. In 47 (22%) of 213 patients defined mitochondrial syndromes as Leigh, LHON, MELAS, Kearns Sayre, Pearson syndrome, MINGIE were present. Among these, Leigh syndrome was most frequently seen with 53.1% (n = 25). Variants that are rare in the population and thought to be associated with the disease were included in the study. It was observed that the phenotype characteristics of the patients were compatible with the genetic data in the literature. Conclusion: Although the correct clinical evaluation of the patients and the evaluation of the genotype correlation are guiding in the diagnosis, it should be kept in mind that mitochondrial diseases are a heterogeneous group and different clinical presentations are possible for identical genetic mutations. Keywords: Mitochondrial diseases, phenotype, genotype, molecular analysis