Although the mitochondria host several metabolic pathways including the tricarboxylic acid cycle, urea cycle, β-fatty acid oxidation, their primary function involves generation of adenosine triphosphate via aerobic respiration. Mitochondrial disorders are genetically and phenotypically a heterogeneous group with an estimated incidence of one in 4,000. Genetically, one of the 13 protein subunits of the respiratory chain complexes I, III, IV and V, one of the 22 tRNAs or the two rRNAs (mitochondrial encoded mitochondriopathy) ore one of the approximately 1,000 nuclear encoded proteins, which are important to mitochondrial structure and function, are impaired.
Mitochondrial encoded mitochondriopathies are inherited maternally, while nuclear encoded types are inherited with classical Mendelian inheritance (X-linked rescessive, autosomal recessive or autosomal dominant). The most severe inherited mitochondrial disorders, many of them lethal, become clinically apparent during infancy. Later appearance in early adulthood has been described. In mitochondrial DNA encoded disorders, the normal and mutant mitochondrial DNA coexist. "Heteroplasmy" refers to the random differences in the ratio of mutant to normal mitochondrial DNA present in the target tissue during embryogenesis, which explains partially the marked variability in clinical manifestations.
Usually mitochondriopathies are multi-systemic diseases, although single organ manifestations or specific symptoms may prevail. Organs with high energy turnover like the central nervous system, muscle, heart, liver and kidney are typically affected. Impaired renal bioenergetics produce tubular acidosis, and skeletal muscle abnormalities, which present largely as dystonia. Dysphagia, pseudo-obstruction and constipation suggest gastrointestinal involvement. Vision and hearing may be reduced. Endocrine organ involvement resulting in diabetes mellitus, hypoparathyroidism, hypothyroidism and gonadal failure has also been described. Seizures and ataxia are associated with myoclonic epilepsy with ragged-red fibers (MERRF), and encephalopathy is a symptom of Leigh syndrome. Necrotizing lesions within the brain, particularly in the midbrain and the brainstem, are typical pathological signs of Leigh syndrome. Clinically this syndrome, which typically begins within the first year of life, is characterized by dysphagia, epileptic seizures, muscle hypotonia, dystonia, ataxia, ophthalmoparesis, cardiomyopathy and finally respiratory failure. Dementia and stroke-like symptoms are major features of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Furthermore, the peripheral nervous system is affected, causing axonal sensory neuropathy. Cardiac involvement includes hypertrophic cardiomyopathy (seen in MELAS and Leigh syndrome) or heart block, dilated cardiomyopathy and pre-excitation syndrome.
Initial symptoms of adult-onset forms are typically progressive postural muscle weakness/exercise intolerance, sensory-neural hearing loss, ptosis, ophthalmoparesis, failing colour or night vision, and worsening ataxia. Hepatic insufficiency and renal involvement are common components of Toni-Debre-Fanconi syndrome (primarily in children).