Special Report

Diseases of the Mitochondrial Genome

By Louis J. Elsas, II, MD

A great deal of mysticism shrouds the diagnosis of a mitochondrial disease because these heritable diseases are rare and have unique mechanisms of transmission as well as protean and ubiquitous signs and symptoms. This summary will review the features of mitochondrial diseases and classify mitochondrial syndromes by type of mitochondrial DNA (mtDNA) changes. Recommendations for diagnostic workups are included. Since no clearly defined interventions to treat affected patients are currently available, this topic must await future development. However, benefits of a DNA diagnosis to the family include awareness of diagnosis, ability to determine genetic risks in other family members, and ability to provide genetic counseling including reproductive options.

The mtDNA has two circular strands that are 16,569 base pairs in length located in the mitochondria. Each cell may have 10,000 mitochondria. The mitochondrial genome codes for subunits of multiprotein complexes that are involved in mitochondrial oxidation/phosphorylation reactions (OX/PHOS). These are crucial in cellular oxidative energy metabolism. Mutations in mtDNA may result in disordered energy metabolism, and if there are a sufficient number of tissue cells that contain large amounts of mutant mtDNA, as compared to normal mtDNA (heteroplasmy), tissue function could be impaired, and disease may result.

MtDNA, both normal and abnormal, is passed on to progeny from mothers by way of the cytoplasm of their fertilized ovum. There is no contribution from the father. Thus, all offspring of an affected mother may be affected to some degree, while none of the offspring of an affected father can be affected. The phenotypes of affected persons may vary markedly despite similar genotypes due primarily to the degree of heteroplasmy in individual cells and tissues.

During cell division, mtDNA is randomly distributed into newly formed mitochondria in the daughter cells. In conditions of mtDNA heteroplasmy, random proportions of normal and mutant mtDNAs are found in the daughter cells. Selective pressures may promote the proliferation of normal mtDNAs. In some mitochondrial myopathies or neuropathies, blood cells may not have the mitochondrial mutation because they were selected against while muscle or nerve cells have the mitochondrial mutation and impaired OX/PHOS, because they are not replicating cells.

Each tissue relies on ATP generation by oxidative phosphorylation to varying degrees. When the ATP generating capacity of OX/PHOS falls below the level required for normal cellular function, cellular dysfunction occurs, and disease manifestations become evident. The nervous system—particularly the optic nerve—is commonly affected early when OX/PHOS is impaired, followed by Type I (oxidative) skeletal muscle fibers, cardiac muscle, active transport by proximal renal tubule, endocrine organs, and liver.

Mitochondrial diseases

MtDNA Point Mutations: (Single nucleotide substitution in mtDNA). Leber’s Hereditary Optic Neuropathy (LHON) was the first human disease associated with abnormal mtDNA and almost always associated with one of three specific point mutations. LHON presents with acute or subacute painless loss of central visual acuity that usually occurs between age 12 and 30. The typical ophthalmoscopic features of acute LHON include telangiectatic microangiopathy and swelling of the nerve fiber layer around the optic disc. There may be a wide range of disease expression in affected individuals in the same pedigree.

MtDNA Deletions and Duplications: (Large changes in mtDNA). Kearns-Sayre Syndrome (KSS) is characterized by progressive ophthalmoplegia, pigmentary retinopathy, as well as variable cardiac conduction defects, ataxia, nystagmus, and muscular weakness. Mitochondrial dysfunction was originally suspected because of the finding of ragged red fiber in skeletal muscles, indicating mitochondrial proliferation. A variant of this syndrome can begin in infancy, childhood, or adolescence with Chronic Progressive External Ophthalmoplegia (CPEO). Deletions of mtDNA are found in most cases of KSS as well as CPEO without KSS.

Fahr’s disease includes cerebral calcifications and neurodegeneration. This disorder is caused by the smallest pathologic deletion known of the mitochondrial genome, a the single base in position 3271.

Pearson syndrome, a refractory sideroblastic anemia, vacuolated hematopoietic precursors, exocrine pancreatic dysfunction, and lactic acidosis, has been identified in more than 75 infants. Severe transfusion-dependent anemia and variable neutropenia and thrombocytopenia are present in early infancy. Exocrine pancreatic dysfunction may be evident or only demonstrated by provocative tests. Most patients die with severe lactic acidosis in infancy. A few patients have had hematological remissions but subsequently developed features of KSS in later life.

Myoclonic Epilepsy and Ragged Red Fiber disease is a syndrome of myoclonic epilepsy—cerebellar ataxia and ragged red muscle fibers beginning in late childhood to early adult life. Additional findings can include dementia, deafness, corticospinal tract degeneration, myopathy, lactic acidosis, and renal tubular dysfunction.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are characterized by "strokes in the young." The finding of lactic acidosis may suggest mitochondrial OX/PHOS impairment. Specific focal lesions may be seen with a brain MRI.

Leigh’s disease and syndromes are characterized by subacute, necrotizing encephalopathy that becomes manifest in early childhood by progressive ataxia, central respiratory dysfunction, cranial nerve involvement, pathognomonic lesions in the brain stem, basal ganglia, and cerebellum on T-2 weighted MRI. Retinitis pigmentosa is often an associated finding. Mutations of proteins in the ATPase of mitochondrial OX/PHOS are thought to cause these disorders. Southern blot analyses for mitochondrial deletions and duplications have also revealed associated mtDNA changes in a few patients with Leigh’s syndrome.


Diagnosis of these syndromes requires southern blot analysis of mtDNA from blood, muscle, or both for nucleotide deletions and duplications. These assays can be performed in many genetic referral centers. Muscle assays are necessary after infancy because there may be selection against hematopoietic cells with defective OX/PHOS, but heteroplasmy persist in the more stable muscle mtDNA. Elevated blood lactate and elevated lactate/pyruvate ratios in the blood suggest an abnormality of OX/PHOS.


There is only limited effective therapy for mitochondrial disorders. These include correction of metabolic abnormalities such as lactic acidosis, possible activation of enzyme activity by drugs or cofactors, and removal of reactive oxygen species.

When should you consider a mtDNA evaluation in a patient? When progressive neurological or neuroophthalmological disease occurs in childhood with or without myopathy. When, in such children, a family history suggests maternal inheritance. When biochemical studies include lactic acidemia, hyperalaminemia, or renal tubular malabsorption. Both blood and muscle samples for mtDNA analyses may provide a diagnosis. If myopathy is present, muscle tissue should also have immunohistochemical analysis. Biochemical studies of muscle mitochondrial OX/PHOS may be helpful, but, because the results of OX/PHOS studies have not been completely validated, their predictive value for these disorders is not certain.


1. Wallace DL, et al. Mitochondrial DNA mutation associated with Leber’s Hereditary Optic Neuropathy. Science 1988;242:1427-1430.

2. Shoffner JM, et al. Oxidative phosphorylation diseases. In: The Inherited Basis of Metabolic Diseases. Scriver CR, et al (eds). McGraw-Hill, Inc; 1995.

3. Kerr DS. Protean manifestations of mitochondrial diseases: A mini review. J Pediatr Hemat/Oncol 1997;14:279-286.