Medical Management Considerations
Resources for Families
Advisory Committee
Publication Information

Learning Points

  • Restate that pathogenic mtDNA mutations are found in at least one in 8,000 individuals.
  • Recognize that the mutations in mtDNA that cause delayed-onset progressive diseases may present with the same clinical problems as normal aging, such as hearing loss, poor vision, or exercise intolerance and that these mutations have also been linked to neurodegenerative disorders.
  • Confirm that diagnosis and treatment of mitochondrial disorders is complex, and can vary from person to person.
  • Recognize there is no effective treatment for most mitochondrial disorders.
  • Consider a potential mitochondrial diagnosis if neurologic, cardiac, gastrointestinal, endocrine, renal, and hematologic manifestations are seen in combination.
  • List the two most common disorders linked with Mitochondrial DNA mutations; e.g.,
    • MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes)
    • MERRF (myoclonic epilepsy with ragged red fibers)
  • Refer suspected cases of pathogenic mtDNA to a genetic or metabolic specialist.
  • Access additional online information on pathogenic mtDNA disorders.

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Description and Cause

Mitochondrial disorders are associated with a wide spectrum of diseases. They are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations of nuclear or mitochondrial DNA (mtDNA), but we mainly know about mutations found in the mtDNA (various pathogenic defects found, with more than 50 different point mutations). Duplications of the mtDNA may not necessarily be pathogenic, but can lead to the formation of pathogenic deletions when passed from an affected woman to her offspring.

Common disorders featured in this document include: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia and retinitis pigmentosa), LHON (Leber hereditary optic neuropathy), CPEO (chronic progressive external ophthalmoplegia), KSS (Kearns-Sayre syndrome), Pearson marrow-pancreas syndrome and Leigh syndrome.

Mutations in mtDNA that cause delayed-onset progressive diseases may present with the same clinical problems as normal aging, such as hearing loss, poor vision, or exercise intolerance. They have also been linked to neurodegenerative disorders such as Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. This suggests mitochondrial function in postmitotic tissues may decline with age, possibly as a result of the age-related accumulation of somatic mtDNA mutations.


  • Pathogenic mtDNA mutations are found in at least one in 8000 individuals.
  • Risk of recurrence is 25% for nuclear mutations, and variable up to 100% for mtDNA mutations depending on percentage of mutant mitochondra.

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Characteristic Features

  • Linked by a common etiology or pathogenesis – abnormal function of the mitochondria or deficient mitochondrial energy metabolism.
  • Clinical heterogeneity is characteristic of those with mtDNA mutations, ranging from single-organ involvement to severe multi-system disease.
  • Other factors: maternal inheritance (for mtDNA mutations) and autosomal recessive or dominant inheritance (for nuclear mutations).


The evaluation of a child with a mitochondrial disorder will usually require the coordinated efforts of the pediatrician, neurologist, and metabolic specialist.

Different mutations in the mtDNA can cause similar clinical syndromes, and the same mutation may also cause different diseases. Diagnosis and treatment of mitochondrial disorders are complex, and can vary from person to person. In addition, the extent of clinical symptoms (threshold of expression) depends on percentage of mutant mitochondria (mutational burden), tissue-specific energy requirements, and the patient’s age.

One should consider a potential mitochondrial diagnosis if the following symptoms are seen in combination:

  • Neurologic manifestations – seizures, strokes (especially in young persons), dementia, ataxia, peripheral neuropathy, myopathy, optic neuropathy, retinopathy, and sensorineural hearing loss.
  • Cardiac manifestations – cardiomyopathy and conduction defects.
  • Endocrine manifestations – diabetes mellitus, hypoparathyroidism, and growth hormone deficiency.
  • Gastrointestinal manifestations – colonic pseudo-obstruction, hepatopathy, and weight loss.
  • Renal manifestations – glomerulopathy (focul segmental glomerulosclerosis) and tubolopathy that resembles Fanconi syndrome
  • Hematologic manifestations – Bone marrow dysfunction with prominent sideroblastic anemia.

Other evaluation measures include:

  • Evidence of maternal inheritance pattern in the family history. Detailed cardiac and neurologic evaluation, including a dilated fundoscopic exam and formal audiologic examination.
  • Referral to a genetic or metabolic specialist is advised earlier rather than later in this process.
  • Electrocardiogram and echocardiogram.
  • Holter monitoring study or exercise tolerance test may be considered
  • Electromyography with nerve conduction studies (EMG/NCV) can help establish and characterize a myopathy or peripheral neuropathy.
  • Also consider: electroencephalogram (EEG), computed tomography (CT), magnetic resonance imaging (MRI) tests or magnetic resonance spectroscopy (MRS) of the brain.
  • The muscle tissue should be examined for the following: ragged red fibers (RRF) apparent under the light microscope with Gomori trichrome stain when excessive accumulation of mitochondria is present; abnormal cytochrome c oxidase (COX) staining pattern by immunohistochemistry; unusual number or structure of mitochondria by electron microscopy. Note: normal morphology does not rule out a biochemical or molecular defect.
  • If muscle biopsy is performed, then consider the following: ragged red fibers (RRF) apparent when abnormal mitochondria are stained with Gomori trichrome stain (note: RRFs are not pathognomic); abnormal cytochrome c oxidase (COX) staining in muscle tissue of some patients; assessment of respiratory chain enzymes.
  • Biochemical analysis of respiratory chain enzymes can be done in fibroblasts but the best results are obtained from fresh muscle biopsies. Note: the pattern of abnormal electron transport (complex I – complex V) does not predict for any specific mutation, but may point towards a nuclear gene versus a mtDNA defect.
  • Molecular analysis of mtDNA is clinically available as a panel of common mutations or by sequencing of the entire mtDNA molecule. Note: testing for nuclear genes (e.g., those responsible for MNGIE or mtDNA depletion syndromes) has recently moved from the research setting to clinical use.
  • Laboratory tests may include the following: serum lactate to pyruvate ratio, carnitine, acylcarnitine profile and amino acids; urine organic acids and acylglycine profile; blood glucose, urea nitrogen, creatinine and liver enzymes; complete blood count (CBC) and microscopic evaluation of a blood smear; cerebrospinal fluid lactate. Note: elevations of lactate are commonly seen in normal children who have difficulty with venipuncture procedures; arterial specimens may be more accurate, and finding an elevated alanine level helps to confirm that baseline (pre-venipuncture) lactate was abnormal; the lactate to pyruvate ratio is useful assuming the specimens are obtained simultaneously and measured by the same lab, but only meaningful if the lactate is elevated.


There is no effective treatment for most mitochondrial disorders, and results from studies are largely anecdotal. Prevention may be aided by early diagnosis and treatment of diabetes, eye abnormalities, and cardiac disease. Patients should also be monitored vigilantly over many years. Other forms of intervention may include surgery, cardiac pacing, and percutaneous gastrostomy. The following have been attempted; but again are based only upon anecdotal reports and efficacy cannot be guaranteed:

  • Carefully supervised physical conditioning (exercise) in conjunction with sodium dichloroacetate administration can markedly enhance both functional performance and biochemical measures of aerobic metabolism.
  • Antioxidants might help neutralize free radicals that accompany impaired oxidative phosphorylation. These include high doses of vitamins C, E, and coenzyme Q10.
  • Agents that enhance mitochondrial function include coenzyme Q10 (also called CoQ or ubiquinone) and idebenone. Many patients also take lipoic acid, thiamine, riboflavin, biotin, and other B-vitamins.
  • Carnitine supplementation is also prescribed frequently.
  • Dichloroacetate may indirectly enhance oxidative phosphorylation and decrease lactate levels

Common Disorders linked with Mitochondrial DNA mutations

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes)

MELAS is the most common mitochondrial disorder. It is caused by mutations in mtDNA that code for a transfer RNA molecule, leading to reduced mitochondrial protein synthesis and ultimately resulting in multisystem neuromuscular disease. MELAS is transmitted through maternal inheritance. Missense mutation AąG of bp3243 in tRNALeu (UUR) is present in 80% of patients.


  • It is frequently misdiagnosed due to a lack of standardized criteria, which poses difficulties in evaluating diagnostic methodologies. However, it has a clinical presentation similar to Herpes Simplex Encephalitis (HSE). Check for heteroplasmic mtDNA mutations in blood.
  • A common EEG feature is background slowing especially over the occipital regions. Photoparoxysmal EEG responses and periodic lateralized epileptiform discharges can be seen.


  • Usually presents in childhood or adolescence, and strokes begin invariably before age 40.
  • Includes progressive hearing loss and non-insulin-dependent diabetes. Seizures, cortical blindness, dementia, and ataxia are also frequent
  • Other symptoms or associated complications: migraines, cardiomyopathy,- renal failure from glomerulosclerosis, and need for gastrostomy feeding.

MERRF (myoclonic epilepsy with ragged red fibers)

MERRF is the second most common pathogenic tRNA mutation. MERRF is also transmitted through maternal inheritance. Missense mutations AąG in bp8344 or TąC in bp8356 or tRNA(Lys) are usually found in muscle rather than blood.


  • Evidence of symptoms in maternal relatives, revealing partial clinical syndromes such as multiple lipomas and cardiovascular disease.
  • Clinical presentations will be highly variable. Check for heteroplasmic mtDNA mutations. In families harboring the bp-8344 mutation causing MERRF, at least 85% mutant mtDNA are required in young adults for symptoms to appear.
  • Typical RRF on the muscle biopsy examination.


  • Usually presents in late adolescence.
  • Common features are myopathy – including ptosis, ataxia, spasticity, and sensorineural hearing loss. Myoclonus may occur in association with generalized seizures.
  • Other associated complications: optic atrophy, peripheral neuropathy, diabetes, cardiomyopathy, kidney and endocrine abnormalities.

NARP (neuropathy, ataxia, retinitis pigmentosa)

NARP is usually caused by a point mutation at bp8993 of the mtDNA, which codes for subunit 6 of ATP synthase, in over 50% of cases. There is better genotype-phenotype correlation for this mutation than for any other mtDNA disorder. The classical symptoms of NARP appear when the threshold of mutant mtDNA molecules exceeds 50-75%, and they evolve into Leigh syndrome (see below) when mutant load is over 90%. NARP is transmitted through maternal inheritance. Missense mutations TąG or less often TąC can be found in blood, urinary sediment, or hair follicles as well as muscle.


  • EMG/NCV studies will demonstrate peripheral neuropathy underlying the muscle weakness.
  • Brain imaging may or may not demonstrate cerebral and cerebellar atrophy.
  • Fundoscopic examination and/or ERG will demonstrate retinal abnormalities.
  • Lactic acidosis is hard to detect because a deficiency of ATP synthase or complex V, at the very end of the respiratory chain, does not block the transport of electrons to molecular oxygen. Mild or intermittently elevations can be found in CSF or in blood if the latter is obtained postprandially.
  • Biochemical testing of muscle tissue may be completely normal unless complex V is included in the analysis.
  • Check for heteroplasmic mtDNA mutations.


  • Usually presents during childhood, but can have a stable course for many years, sometimes with episodic deterioration associated with routine viral illnesses.
  • Other associated problems: migraines, seizures, learning disabilities, dementia, short stature, hearing loss, cardiac conduction defects and sudden death.

LHON (Leber hereditary optic neuropathy)

LHON is the most common cause of blindness in otherwise healthy young men. Its causes are multiple different missense mutations in mtDNA. LHON is transmitted through maternal inheritance. Specific environmental factors such as alcohol and tobacco use can increase the likelihood of LHON becoming symptomatic.


  • Cardiac defects are common, including abnormal QT interval, demonstrating acute sensitivity of the heart to mitochondrial defects. Check for homoplasmic mtDNA mutations in blood, but many of these are not included in “common mutation” panels.


  • Affects males 3-4 times more than females.
  • Mid-life acute or subacute blindness resulting from death of the retinal ganglion cells. Leads to central scotomas. Vision loss presents at an average age of 23, but ranges from 8 to 60 years.
  • Associated complications: occasionally seen with multiple sclerosis, dystonia, neurologic symptoms, or movement disorder.

CPEO (chronic progressive external ophthalmoplegia)

CPEO is linked to either large deletions in mtDNA or various point mutations in tRNA molecules, including the bp3243 mutation more commonly associated with MELAS. CPEO is transmitted through maternal inheritance.


  • 1/3 of patients carry the common deletion (5.0 kb), but this is not easily detected in blood.
  • This milder form of ocular myopathy usually presents after age 20.


  • Progressive disease, usually occurring during the second or third decades.
  • Ophthalmoplegia (paralysis of eye muscles) and ptosis (droopy eyelids).
  • Can affect many systems including cardiac conduction defects and heart block, encephalopathy, renal failure, and diabetes mellitus.

KSS (Kearns-Sayre syndrome)

KSS is a subtype of CPEO, and the most severe form of ocular myopathy. Its causes are rearrangements in mtDNA (deletions and duplications). Maternal inheritance is less common than with point mutations, and many cases are sporadic.


  • Atypical pigmentary retinopathy, ataxia, elevated cerebrospinal fluid protein, and heart block.
  • Changes in muscle biopsy (RRF with the modified Gomori trichrome stain).
  • Predominance of positive fibers with the succinate dehydrogenase (SDH) stain.
  • Failure of both RRF and SDH positive fibers to stain with the immunohistochemical reaction for cytochrome c oxidase (COX).
  • Decreased activities of respiratory chain complexes containing mtDNA-encoded subunits in muscle extracts.
  • Approximately 90% of patients with KSS have a large-scale (1.3-10 kb) mtDNA deletion that is usually present in muscle tissue but not blood.


  • Progressive disease, usually presenting before age 20 with pigmentary retinopathy and a cardiac conduction defect, ataxia, or raised CSF protein.
  • Additional features: short stature, progressive ophthalmoplegia, cardiomyopathy, limb weakness, ataxia, retinitis pigmentosa, deafness, diabetes (hypoparathyroidism, growth hormone deficiency), endocrine dysfunction, dysphagia, and behavioral disorders.
  • Prognosis much worse than isolated CPEO – few patients survive beyond age 30.

Pearson marrow-pancreas syndrome

Pearson marrow-pancreas syndrome is essentially the infantile form of KSS, in which the clinical effects are seen predominantly in bone marrow stem cells and exocrine pancreatic cells. This severe mtDNA rearrangement syndrome is caused by the same molecular abnormalities seen in KSS.


  • Bone marrow examination reveals ringed sideroblasts (normoblasts with excessive deposits of iron in mitochondria).
  • Malabsorption due to exocrine pancreatic insufficiency


  • Presents at during infancy or early childhood.
  • Frequently lethal and associated with pancytopenia (loss of all blood cells)
  • The few who survive will develop KSS (Kearns-Sayre Syndrome)

Leigh syndrome

Leigh syndrome is the most severe clinical presentation associated with mitochondrial defects. Its causes are various biochemical defects including pyruvate dehydrogenase deficiency or other enzymes involved in energy metabolism, such as those in the Krebs cycle or the respiratory chain. A deficiency of cytochrome c oxidase (COX) usually results from mutations in nuclear-coded assembly genes such as SURF1 and LRPPRC rather than the COX subunits themselves. Inheritance can be maternal, AR, or XLR. About 18% of Leigh syndrome cases are the result of mtDNA mutations, and this condition can be thought of as the severe or infantile form of NARP.


  • Characteristic changes in magnetic resonance imaging – bilateral, usually symmetrical, signal changes in the upper brainstem and thalamus.
  • Approximately 10-20% have the classic NARP mutations (TąG or TąC in bp8993). Another 10-20% have mutations in other mitochondrial genes.


  • Usually presents between birth and 2 years with hypotonia, seizures, developmental delay or regression, and lactic acidosis. Pyramidal signs, retinitis pigmentosa, ataxia, and CPEO may develop later.
  • Leigh syndrome is also associated with spasticity, optic atrophy, nystagmus, ophthalmoplegia, and respiratory defects – typically with bilateral degeneration of the basal ganglia. It can occasionally manifest as hypertrophic cardiomyopathy and asymmetric septal hypertrophy.
  • Patients typically die within a few months or years.

Atypical Presentations of Mitochondrial Disease

Below is a link to a table of some atypical features that raise the possibility of mitochondrial disease. Although the actual prevalence is unknown and possibly low, it is among these atypical cases that mitochondrial disease is more common.

Click here for Exceptional Parent article, Mitochondrial and Metabolic Disorders – a primary care physician’s guide.

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Peer-reviewed Journal Articles/Academies

Batshaw, ML (2002). Children with Disabilities. Fifth Edition. Baltimore: Brookes Publishing.

Chinnery, PF and Turnbull DM. (1999). Mitochondrial DNA and disease. The Lancet. 354 (Suppl. 1): 17-21.

Chinnery, PF, et al. (2000). The Epidemiology of Pathogenic Mitochondrial DNA Mutations. Annals of Neurology. 48(2): 188-193.

Chinnery, PF (2003). Mitochondrial Disorders Overview. GeneTests. Obtained online Nov. 22, 2005.

Chinnery, PF, et al (2004). Risk of developing a mitochondria DNA deletion disorder. The Lancet. 364(9434): 592-596.

Dimauro S, Mirano, M (2003). Mitochondrial DNA Deletion Syndromes. GeneTests. Obtained online Nov. 22, 2005.

Hesterlee, S. (1999). Mitochondrial myopathy: an energy crisis in the cells. Quest. 6(4). Obtained online Oct. 17, 2005.

Hesterlee, S. (1999). Mitochondrial disease in perspective of symptoms, diagnosis and hope for the future. Quest. 6(5). Obtained online Oct. 17, 2005.

Kelley, RI. (1996). Metabolic Diseases. Developmental Disabilities in Infancy and Childhood: Second Edition, Volume I. AJ Capute and PJ Accardo, eds. Baltimore: Paul H. Brookes Publishing. 125-126.

Leonard JV and Shapira, AHV. (2000) Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. The Lancet. 355(9200): 299-304.

Menendez, M, Garcia, A, and Bazquez-Menes, B. (2004). Diagnostic considerations on Melas syndrome. The Internet Journal of Neurology. 2:2. Obtained online Oct 24, 2005.

Naviaux R (2003). Overview: The Spectrum of Mitochondrial Disease. Obtained online May 4, 2006.

Simon, DK and Johns DR. (1999). Mitochondrial Disorders: Clinical and Genetic Features. Annual Review of Medicine. 50: 111-127.

Thorburn, DR and Rahman S. (2003). Mitochondria DNA-Associated Leigh Syndrome and NARP. GeneTests. Obtained online Nov. 22, 2005 at

Wallace, DC. (2000). Mitochondrial defects in cardiomyopathy and neuromuscular disease. American Heart Journal. 139(2): S70-S85.

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United Mitochondrial Disease Foundation

Muscular Dystrophy Association

National Organization for Rare Disorders


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Richard J. Brouette, M.D., F.A.A.F.P., D.A.B.F.P.
Theodore A. Kastner, M.D., M.S.
Patrick J. Maher, M.D.
Terrance D. Wardinsky, M.D.
Samuel P. Yang, M.D.

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This document does not provide advice regarding medical diagnosis or treatment for any individual case, and any opinions or statements contained in this document are not intended to serve as a standard of medical care. Physicians are encouraged to view the considerations presented in this document in light of evolving scientific information. This document is not intended for use by the layperson. Reproduction of this document may be done with proper credit given to California Department of Developmental Services.