Chapter 8 - Mitochondrial disorders

Abstract

Mitochondrial disorders represent a heterogeneous group of diseases caused by a dysfunction of oxidative phosphorylation in the mitochondria, the double membrane-bound organelles that generate energy in eukaryotic cells. This group collectively may involve any mode of inheritance, may present from the neonatal period to adulthood, and can clinically affect nearly every organ system. Symptoms are variable and evolve over time and may include developmental delay, myopathy, encephalopathy, seizures, ataxia, sensorineural hearing loss, ophthalmoplegia, retinopathy, diabetes mellitus, liver failure, cardiomyopathy, exercise intolerance, and gastric dysmotility. Given the variability of clinical presentations, establishing the diagnosis of a mitochondrial disorder is frequently challenging. Diagnostic delay or misdiagnosis is common. Mutations in 37 mitochondrial genes or over 100 nuclear genes can result in overlapping phenotypes. The reverse is also true with the same genetic mutation causing different clinical presentations. Not uncommonly, extensive laboratory evaluation is required including lactate and pyruvate levels, plasma amino acid profiles, urine organic acid profiles, plasma acylcarnitine profiles, and specific enzymatic analysis of skin and muscle. Neuroimaging is often needed. Recent developments in whole-exome sequencing have revolutionized diagnosis and expanded the molecular spectrum with discovery of new conditions. Although some symptomatic improvement may be achieved by the use of specialized vitamin and cofactor therapies as well as supportive illness management, there is no cure for these conditions and some can be fatal. Improvements in quality of life and survival can be achieved with multidisciplinary clinical management.