OVERVIEW: What every practitioner needs to know

Are you sure your patient has a Mitochondrial disease? What are the typical findings for this disease?

  • Multiorgan system involvement is the hallmark, although some mitochondrial disorders affect a single organ such as the eye in Leber hereditary optic neuropathy (LHON) (see below).

  • Mitochondrial disorders are clinically heterogeneous.

  • Result from dysfunction of the mitochondrial respiratory chain.

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  • Caused by mutations of either nuclear or mitochondrial DNA (nDNA or mtDNA).

  • Neurological involvement (central and/or peripheral nervous system) is the most common manifestation and can be present initially or later in the disease course, although other organ systems can be present early or later.

  • The specific findings depend upon the type of mitochondrial disorder, heteroplasmy and genetic background, although many of the phenotypes overlap.

  • Many individuals display a cluster of clinical features that define a discrete clinical syndrome or condition.

  • The most common mitochondrial disorders are listed below.


Leigh syndrome (LS)

  • Encephalopathy and/or regression

  • Seizures

  • Brainstem dysfunction

  • Ophthalmological findings including optic atrophy, motility disorders and retinal changes

The most common symptoms in LS:

Feeding and swallowing difficulties/dysphagia, vomiting

Failure to thrive

Motor symptoms: spasticity, hypotonia, dystonia

Peripheral neuropathy

Abnormal eye movements

Optic atrophy

Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)

Strict diagnostic criteria for NARP have not been established.

  • Neurogenic muscle weakness and late childhood or adult onset peripheral neuropathy

  • Ataxia

  • Retinitis pigmentosa

Other common symptoms:

Learning disorders


Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS)

  • Stroke-like episodes

  • Epilepsy

  • Progressive dementia

  • Migraine-type headaches

Other common symptoms:

Muscle weakness, easy fatigability


Gastrointestinal dysmotility

Sensorineural hearing loss

Diabetes mellitus

Myoclonic Epilepsy with Ragged-red Fibers (MERRF)

  • Myopathy with ragged red fiber myopathy (on muscle biopsy)

  • Hearing loss

  • Optic atrophy

  • Cognitive decline

  • Features may overlap with MELAS except NO STROKES

Other symptoms:


Cognitive decline

mtDNA Polymerase Gamma-1 (POLG-1) spectrum

The majority are autosomal recessive.

Childhood versions of POLG


  • Seizures

  • Encephalopathy

  • Hypotonia

  • Liver failure

  • Myocerebrohepatopathy Syndrome

Next most common:

Renal tubulopathy


Adult presentations of POLG

  • Autosomal dominant progressive external ophthalmoplegia

  • Autosomal recessive progressive external ophthalmoplegia

  • Autosomal recessive syndromes with and without mtDNA depletion

  • Mitochondrial recessive ataxia syndrome (MIRAS)

  • Ataxia neuropathy spectrum syndrome (ANS)

  • Myoclonus, epilepsy, myopathy, and sensory ataxia (MEMSA)

  • Sensory ataxic neuropathy with dysarthria and ophthalmoparesis in later life (SAND)

Leber Hereditary Optic Neuropathy (LHON)

  • Bilateral, painless, subacute visual failure

  • Develops during young adult life

  • Severely reduced visual acuity

Next most common:

Cardiac arrhythmias

Postural tremor

Peripheral neuropathy

Nonspecific myopathy

Movement disorder

A multiple sclerosis-like process may develop, predominantly in Caucasian females

Chronic progressive external ophthalmoplegia (CPEO) related mitochondrial disorders

  • Bilateral ptosis (Figure 1)

  • External ophthalmoplegia

  • Some forms with proximal myopathy

Figure 1.

Patient with mitochondrial disease showing ptosis (droopy eyelids).

Next most common:

May be associated with Parkinsonian features

Mitochondrial DNA (mtDNA) deletion syndromes

  • Three overlapping phenotypes that are usually simplex (i.e., a single occurrence in a family),

  • May evolve in a given individual over time.

  • Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (CPEO)

Kearns Sayre syndrome (KSS)

  • Progressive external ophthalmoplegia (PEO) onset before age 20 years

  • Pigmentary retinopathy

  • Cerebellar ataxia

Next most common:

CSF protein greater than 1 gram/L

Heart block

Recently, a number of patients with KSS have been found additionally to have cerebral folate deficiency

Other symptoms

  • Bilateral hearing loss or deafness

  • Myopathy

  • Dysphagia

  • Diabetes mellitus

  • Dementia

  • Hypoparathyroidism

Pearson syndrome

  • Childhood onset sideroblastic anemia

  • Pancytopenia

  • Exocrine pancreatic failure

Other symptoms:

May have cardiomyopathy and be fatal

Renal tubular acidosis

Pyruvate Dehydrogenase complex (PDH)

There are 3 primary clinical presentations for PDH

  • In the neonatal period, infants present with symptoms of lactic acidosis and cerebral dysgenesis.

  • Another set of patients develop Leigh’s encephalopathy in the first 5 years of life, with developmental delay, seizures, ataxia, episodic weakness, basal ganglia and brainstem dysfunction, and progressive neuropathy.

  • Less commonly, patients are initially much less severely affected, with intermittent episodes of ataxia and a slow progression over years to Leigh’s encephalopathy.

Most common symptoms:

Lactic acidosis – poor feeding, lethargy, tachypnea

Developmental and growth delays

Next most common:


Seizure disorder


Dysconjugate eye movements

Poor visual tracking

Episodic dystonia

Pyruvate carboxylase complex (PDC)

  • Failure to thrive

  • Developmental delay

  • Seizures

  • Metabolic acidosis

The three clinical presentations of PC deficiency:

Type A: infantile or North American form

Type B: severe neonatal or French form

Type C: intermittent/benign form

Barth syndrome

  • Heart failure due to noncompaction of the ventricles

  • Myopathy

  • Neutropenia

Next most common:

Skeletal muscle weakness

Growth retardation

Infections due to neutropenia

Mitochondrial neurogastrointestinal encephalopathy (MNGIE)

  • Severe gastrointestinal (GI) dysmotility

  • Cachexia with severe weight loss

  • Ptosis

  • External ophthalmoplegia

  • Sensorimotor neuropathy (usually mixed axonal and demyelinating) and nutritional deficiencies contribute

Next most common:

Hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis


Early-onset sensorineural hearing loss

Short stature

Autonomic nervous system dysfunction (usually orthostatic hypotension)

Bladder dysfunction

Cardiac: ventricular hypertrophy, bundle branch block

Increased CSF protein (typically 60 – >100 mg/dL; normal: 15 – 45 mg/dL)

Lactic acidemia


Overview of Mitochondrial Diseases

  • Mutations in nuclear and mitochondrial DNA impacting mitochondrial respiratory chain function result in disease manifestations.

  • The range of symptoms can be early death to less severe abnormalities of brain and other organs to those involving a single organ system or just muscle fatigue and exercise intolerance.

  • The definitive diagnosis of a mitochondrial disorder can be difficult to establish.

  • Diagnosis can be challenging because of the protean nature of clinical manifestations.

  • Identical phenotypes can result from different genotypes with gene mutations in a mitochondrial gene or a nuclear gene or from epigenetic effects.

  • Conversely, the same genotype can give rise to varying phenotypes.

  • The interplay between nuclear and mitochondrial genomes creates the wide variety of presentations of mitochondrial disease that makes diagnosis difficult.

  • There are novel genetic concepts in mitochondrial biology such as heteroplasmy, threshold, age dependency on oxidative phosphorylation, and somatic mutations that further complicate recognition and diagnosis.

Leigh syndrome

  • Leigh syndrome is characterized by bilateral, symmetric lesions involving the deep gray nuclei.

  • The most common findings involve the subcortical, midbrain, and pontine structures, especially the periaqueductal gray and floor of the fourth ventricle.

  • Most patients have somnolence, nystagmus, respiratory abnormalities and ataxia.


  • Characterized by peripheral neuropathy, ataxia and retinitis pigmentosa.

  • May be associated with basal ganglia signal abnormalities.

  • The Electroretinogram (ERG) may be abnormal, including small amplitude waveforms, or could be normal. There may be predominantly cone dysfunction in some pedigrees and mainly rod dysfunction in others.

  • The ocular manifestations of NARP are extremely variable and range from a mild salt and pepper retinopathy to bull’s eye maculopathy and classic retinitis pigmentosa with bone spicule formation.

  • Electromyography (EMG) and nerve conduction studies may demonstrate peripheral neuropathy (which may be a sensory or sensorimotor axonal polyneuropathy).


  • Presents with sudden onset of strokes, usually precipitated by focal or generalized seizures.

  • Usually has its onset in childhood, but can present at any age.

  • Children may be asymptomatic prior to this event or have varying degrees of underlying developmental disabilities.

    Although recovery from stroke-like episodes in MELAS is typically rapid and may be complete early in the disease course, once the first stroke-like episode occurs, a patient’s neurologic status continues to deteriorate.

    Recurrent strokes result in increasing disability, dementia, and early death.

    Stroke-like episodes present with variable neurologic symptoms including seizures, headaches, altered mental status, focal weakness, visual loss, sensory loss, dysarthria, and ataxia. More than one of these symptoms may occur together.

    The affected areas typically involve the cortex and subjacent white matter, with sparing of the deep white matter.

    Acute changes may enlarge, involve additional areas, or disappear completely during the acute to subacute phase of the stroke.

  • Strokes often start in the occipital lobes and seizures may present as visual auras or hallucinations with occipital headaches.

  • Over time, strokes can involve any part of the cortex and may be asymmetric.

  • Patients may present with occipital status epilepticus or epilepsia partialis continua (EPC) (Demarest, et al.)

    Migraine with nausea and vomiting is common and may precede stroke-like events.

  • Treatment guidelines have recently been established (Koenig, et al.).


  • MERRF is a mitochondrial disorder due to one of several mutations in the mtDNA, with the A>G8344 mutation seen most commonly.

  • Ataxia eventually develops.

  • Affected individuals may have short stature, and develop hearing loss, optic atrophy, myopathy, and cognitive decline.

  • Due to the prominence of myoclonus and eventual neurologic decline, MERRF is classified as one of the progressive myoclonic epilepsy (PME) syndromes.

  • Lactic acidosis and ragged red fibers on muscle biopsy histology are characteristic findings though they are not always present early in the disease course.

POLG -1 spectrum –

Alpers-Huttenlocher syndrome (AHS)

  • One of the most severe phenotypes.

  • Childhood-onset progressive encephalopathy with intractable epilepsy and hepatic failure.

Childhood myocerebrohepatopathy spectrum (MCHS)

  • Developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive.

  • Include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss.

Myoclonic epilepsy myopathy sensory ataxia (MEMSA)

  • Epilepsy, myopathy, and ataxia without ophthalmoplegia.

Ataxia neuropathy spectrum (ANS)

  • 90% ataxia and neuropathy as core features.

  • Two-thirds develop seizures.

  • One-half develop ophthalmoplegia.

Autosomal recessive progressive external ophthalmoplegia (arPEO)/
Autosomal dominant progressive external ophthalmoplegia (adPEO)

  • Generalized myopathy.

  • Variable degrees of:

    Sensorineural hearing loss

    Axonal neuropathy







  • Identical POLG mutations can give rise to distinct disease phenotypes, with wide variation in age of onset, electron transport chain activities, and either recessive or dominant inheritance patterns

  • in children, Alpers’ or Alpers’-like disease is common

  • Occipital epilepsy is common.


  • Visual blurring, affecting the central visual field in one eye,

  • Progression over the next 2-6 months to involve the other eye,

  • In 25% of cases it is bilateral at onset.

  • Patients can have other symptoms such as cardiac arrhythmias, Postural tremor, Peripheral neuropathy, Nonspecific myopathy, or Movement disorder.

  • A multiple sclerosis-like process may develop, predominantly in Caucasian females.


  • Tends to be of adult onset.

  • Associated with bilateral ptosis and external ophthalmoplegia.

  • Other forms may be associated with myopathy or parkinsonism.


  • Is one form of CPEO.

  • Affects the heart and endocrine organs.

  • Patients can have a secondary cerebral folate deficiency.


  • Characterized by sideroblastic anemia and exocrine pancreas dysfunction.

  • Fatal in infancy,

  • Ptosis, (ophthalmoplegia), oropharyngeal weakness.


  • Presents with lactic acidosis, elevated pyruvate, seizures and cerebral dysgenesis.

  • May present similar to LS.


Characterized by:

Failure to thrive.

Developmental delay.

Recurrent seizures.

Metabolic acidosis.

Type A (infantile form), most children die in infancy or early childhood.

Type B (severe neonatal) presents as spasticity and movement disorders and patients die within first 3 months of life.

Type C (milder) version where patient are normal or mildly abnormal neurological development episodic metabolic acidosis.

Barth syndrome.


  • Characterized by progressive gastrointestinal dysmotility and cachexia.

  • Manifests as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and diarrhea.

  • Ptosis/ophthalmoplegia or ophthalmoparesis.

  • Hearing loss.

  • Demyelinating peripheral neuropathy (tingling, numbness, and pain).

  • Symmetric and distal weakness.

Barth syndrome

  • X-linked recessive disease.

  • Caused by mutations in the tafazzin gene.

  • Patients have reduced concentration and altered composition of cardiolipin, a specific mitochondrial phospholipid.

  • Variable clinical findings involving skeletal muscle, heart, and immune system.

  • Should consider this disorder when faced with noncompaction of the ventricular.

  • A mild cognitive phenotype has been described.

  • Proximal limb weakness.

Age prevalence

  • In general, mitochondrial disorders can present at any age from infancy to older adults. However, certain clinical phenotypes may have an age prevalence as discussed below.

  • Until recently, common teaching was that nDNA disorders present in childhood and mtDNA disorders present in adults, but this is not always the case.

  • Earlier disease manifestations are usually nuclear in origin.

  • Pathological mutations in mtDNA are usually milder and expressed along a spectrum from childhood to late adulthood.

Leigh syndrome

  • Typically seen in infants and children and less common in adults.


  • Can present in childhood or early adulthood.


  • Typically has onset in childhood or young adulthood, but could present at any age, usually before age 40.


  • Symptoms typically begin in the adolescent or young adult years with myoclonic epilepsy.


  • Can present from infancy to adulthood.

  • Environmental factors like valproic acid and infection can unmask POLG disease, causing it to occur earlier in life than when not exposed to these factors.

  • Other drugs like nucleoside reverse transcriptase inhibitors can produce genotype-specific POLG pharmacogenetic disease.

  • Presentation in childhood can be Alpers’ or Alpers’-like syndrome, with devastating intractable epilepsy and psychomotor regression with or without liver involvement.

  • In adults the phenotype can include Parkinsonism to multiple sclerosis.

  • SANDO is a phenotype of adult type POLG1 mutations (Sensory ataxic neuropathy with dysarthria and ophthalmoparesis in late life).

  • Autosomal Dominant POLG1 Mutation has been reported in a family With Metabolic Strokes, Posterior Column Spinal Degeneration, and Multi-Endocrine Disease.


  • Typically presents in young adult males, although it is not sex-linked.

  • 95% of those who develop vision loss do so by 50 years of age.


  • Tends to be of later onset.


  • Childhood to adulthood.


  • Most frequent in childhood.


  • Most common in infancy and first few years of life.

  • Type A: infantile onset.

  • Type B: neonatal onset.

  • Type C: milder, later onset.

Barth syndrome

  • Variability in the age of onset, the expression of symptoms, and the rate of progression.


  • Onset is usually between the first and fifth decades.

  • 60% of individuals will have symptoms begin before age 20 years.

What other disease/condition shares some of these symptoms?

  • Other mitochondrial disorders can mimic LS, MELAS, and other inborn errors of metabolism may mimic mitochondrial disorders.

  • Methylmalonic acidemia: commonly affects basal ganglia, but preferentially globus pallidus.

  • Other inborn errors can mimic the encephalopathy and seizures seen in mitochondrial disorders; they will be diagnosed by specific patterns of abnormalities on plasma amino acids and /or

  • urine organic acids.

  • Mutations in the RANBP2 gene affecting a nuclear pore protein present a similar phenotype.

  • Isolated bilateral striatal necrosis due to glutaric aciduria may mimic as well as mutations in the SLC25A19 agene,

  • Other mimics include hypoxic ischemic encephalopathy, viral and bacterial infections of the infant.

  • The vascular territories of focal brain lesions and the prior medical history of patients with MELAS differ substantially from those of typical patients with stroke.

  • Mitochondrial disorders should be considered any time a progressive multi-system disorder is suspected and sometimes for isolated symptoms such as optical atrophy, sensori-neuro deafness, cardiomyopathy, pseudo-obstruction, neuropathy, myopathy, liver disease, early strokes, seizures.


  • Leber hereditary optic neuropathy may be missed in patients who develop the multiple sclerosis-like illness.

  • Other mtDNA complex I mutations cause optic atrophy in association with severe neurologic deficits including ataxia, dystonia, and encephalopathy. Patients have also been identified with mtDNA complex I mutations and clinical features of both LHON and MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).

  • Other causes of bilateral visual failure must be excluded.

  • Other causes of sporadic and inherited optic neuropathies should also be distinguished from LHON, including deafness-dystonia-optic neuropathy (DDON).

mt DNA deletion syndromes such as KSS and CPEO may overlap with the following other neurological conditions:

  • Myasthenia gravis (diplopia, weakness).

  • Oculopharyngeal muscular dystrophy (late onset, ptosis, CPEO, dysphagia).

  • Oculopharyngeal distal myopathy (late onset, distal limb weakness).

  • Myotonic dystrophy type 1.

  • Myopathy.

PDH mimics

  • Pyruvate carboxylase deficiency.

  • Other mitochondrial disorders resulting in lactic acidosis.

What caused this disease to develop at this time?

  • The severity of the mutation or degree of heteroplasmy may influence timing of disease manifestations in mitochondrial disorders.

  • Illness or other stressor may cause disease to manifest or acutely worsen the clinical presentation.

  • Several genetic etiologies are contributory for early onset diseases in LS for example, including mutations in nuclear genes such as SURF-1 and the COX assembly genes, mtDNA complex V (maternally inherited Leigh syndrome) or pyruvate dehydrogenase.

  • A convincing clinical history, physical examination, magnetic resonance imaging (MRI) pattern (see details below and Table 1), and family history may enable one to proceed with more definitive diagnosis. Lactate need not be elevated or may be elevated after certain conditions such as exercise, glucose loading, illness, or be elevated in the brain (CSF) only.

  • LHON typically presents in young adults.

  • 95% of those who develop vision loss do so by 50 years of age.

  • In PDH, mutations of one of the subunits of the pyruvate dehydrogenase complex lead to dysfunction of the citric acid (Krebs) cycle. The body is deprived of energy derived from carbohydrate metabolism, and lactic acid accumulates.

  • In PDH, the disease process may begin in utero with cerebral dysgenesis or may manifest later in infancy or childhood.

  • In Barth syndrome, tafazzin, a phospholipid acyltransferase, is involved in acyl-specific remodeling of cardiolipin, which promotes structural uniformity and molecular symmetry among the cardiolipin molecular species. Inhibition of this pathway subsequently leads to changes in mitochondrial architecture and function which may be exacerbated by stress/developmental demand.

Table 1.n

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Several disorders have a distinct clinical or MRI presentation, such that one may go directly to molecular genetic testing (i.e. KS, MELAS, KSS, LHON).

Biochemical laboratory testing

  • Lactate is usually elevated in blood, but this is not a universal factor and can be normal at baseline. It is more likely to be elevated in the post-prandial state. Testing multiple blood samples is more sensitive than testing a single random sample, since lactate determination may be affected by several artifacts of collection, including tight tourniquet, patient crying or breath holding, or failure to transport on ice.

  • Lactate elevation is more consistent in CSF samples than blood samples but will require CSF collection by lumbar puncture or access to 1H MRS, which can noninvasively measure CNS lactate.

  • Plasma amino acids may show elevated alanine concentration (formed from the transamination of pyruvate), reflecting persistent elevation of plasma lactate concentration, but not in all cases.

  • Low plasma citrulline concentration has been reported in individuals with the m.8993T>G mutation.

  • Urine organic acid analysis often detects lactic aciduria (if present, is about 4 uM) and is useful in excluding other organic acidurias.

  • Biochemical results can be normal even in patients who are later proven to have a mitochondrial disorder. This is the case in individuals with mtDNA mutations affecting complex V subunits.

  • Proton magnetic resonance spectroscopy (1H MRS) can also be useful in detecting regional elevations in brain lactate levels (see below).

  • In Barth syndrome, there are two distinct findings: elevated urinary excretion of 3-methylglutaconic acid and hypocholesterolemia.

  • MNGIE: Increase in plasma thymidine concentration greater than 3 µmol/L and increase in plasma deoxyuridine concentration greater than 5 µmol/L; thymidine phosphorylase enzyme activity in leukocytes less than 10% of the control mean. Of note, heterozygotes display about 30-35% residual thymidine phosphorylase activity.

Muscle biopsy

  • Used to be universally performed, now molecular genetic testing may obviate need for tissue diagnosis.

  • Divided into histology and EM examinations, respiratory analysis, and mtDNA analysis.

  • Usually, histologic examination shows only minimal if any changes, such as accumulation of intracytoplasmic neutral lipid droplets.

  • Ragged red fibers (a hallmark of adult-onset mitochondrial diseases) are rarely, if ever, seen in children less than age 5 years, so absence is not diagnostic.

  • Cytochrome c oxidase-negative fibers are occasionally found in individuals with Leigh syndrome caused by certain mtDNA and nuclear gene mutations.

  • Adults with POLG1 defects often have normal muscle morphology and biochemistry.

  • Children with POLG1 usually show combined deficiency of respiratory chain enzymes.

  • In MNGIE: there may be ragged red fibers on Gomori trichrome staining.

  • IN KSS may show ragged red fibers.

Respiratory chain enzyme studies

  • Biochemical analysis of tissue biopsies or cultured cells may disclose deficient activity of one or more of the respiratory chain enzyme complexes.

  • Isolated defects of complex I or complex IV are the most common enzyme abnormalities.

  • The finding of aberrant enzyme complex activity may help guide subsequent molecular genetic testing of mtDNA or nuclear genes.

  • Skeletal muscle is usually the tissue of choice for enzyme studies.

  • Skin fibroblasts can be used, but only about 50% of respiratory chain enzyme defects identified in skeletal muscle are also identified in skin fibroblasts,

  • Depending upon mutational load, may be normal.

  • There remains debate over use of fresh versus frozen tissue for diagnosis.

  • In KSS shows decrease of respiratory chain complexes containing mtDNA encoded subunit.

  • In MNGIE there may be defects in a single or multiple OXPHOS enzyme complexes, particularly complex IV (cytochrome oxidase).

Molecular diagnosis

The diagnosis of NARP and mtDNA-associated Leigh syndrome is established using clinical criteria and molecular genetic testing.

Mutations in the following mitochondrial genes are associated with Leigh/NARP:

  • mT-ATP6, mT-TL1, mT-TK, mT-TW, mT-TV, mT-ND1, mT-ND2, mT-ND3, mT-ND4, mT-ND5, mT-ND6 and mT-CO3 are associated with mtDNA-associated Leigh syndrome.

  • mT-ATP6 is the only gene associated with NARP.

  • Approximately 10-20% of individuals with Leigh syndrome have either the m.8993T>G or m.8993T>C MT-ATP6 mutation; approximately 10-20% have mutations in other mitochondrial genes.

  • Molecular genetic testing for these mtDNA mutations is offered on a clinical basis through several laboratories.

Leigh syndrome

  • MRI typically shows deep gray matter hyperintensity on T2 (see below),

  • If this is the case, biochemical testing may show lactic acidosis;

  • Definitive diagnosis will be made by finding a mutation in one of the genes associated with LS in either nuclear or mtDNA,

  • Common nuclear mutations include NDUFS1, NDUFS4, NDUFSA7, NDUFSA 8, NDUFSA V1, SDHA, SDHAF-1, NDUFS2, SURF1, LRPPPRC, SCO1, SCO2, COX10, COX15, BCS1L, ATPAF2, GFM1, MRPS16, PUS1, TUFM, TACO1, POLG1, POLG2, TK2, DGUOK.


  • m.8993T>G is most common.

  • m.8993T>C has also been described.

  • Most mtDNA mutations are heteroplasmic m.8993T>G.

  • m.8993T>C mutations do not appear to show any significant variation in mutation load among tissues.


  • 80% of patients have an adenine to guanine transition at the tRNA for leucine at position 3243 in the mtDNA.

  • Mutations in MT-TL1 or MT-ND5.

  • Mutations can usually be detected in mtDNA from leukocytes.

  • Heteroplasmy can result in varying tissue distribution of mutated mtDNA.

  • Mutation may be undetectable in leukocytes and may be detected only in other tissues (cultured skin fibroblasts, hair follicles, urinary sediment, and skeletal muscle).


  • (mtDNA) gene MT-TK encoding tRNALys is the gene most commonly associated with MERRF.

  • Over 80% have an A-to-G transition at nucleotide 8344 (m.8344A>G).


  • Identification of two disease-causing POLG mutations for all phenotypes except adPEO, for which identification of one disease-causing POLG mutation is diagnostic. POLG molecular genetic testing is available on a clinical basis.


  • Molecular genetic testing with targeted mutation analysis detect one of the 3 primary pathogenic mtDNA mutations (m.11778G>A, m.14484T>C, or m.3460G>A) in 95% of individuals.

mtDNA deletion syndromes

  • mtDNA deletions ranging in size from two to ten kilobases.

  • Approximately 90% of individuals with KSS have a large-scale (i.e., 1.1- to 10-kb) mtDNA deletion that is usually present in all tissues but usually undetectable in blood therefore requiring examination of muscle.

  • In Pearson syndrome, mtDNA deletions are usually more abundant in blood than in other tissues.

  • In CPEO, mtDNA deletions are confined to skeletal muscle.


  • Sequence analysis of two of the genes associated with PDH are commercially available.

  • PDHA1 (pyruvate dehydrogenase E1 deficiency).

  • DLAT (pyruvate dehydrogenase E2 deficiency).

  • Most pathogenic mutations involve the X-linked gene PDHA1, which encodes the E1 alpha subunit.


  • Molecular genetic testing of PC, the gene associated with PC deficiency, is available on a research basis only.


  • Maps to the distal portion of Xq28 [4,10] involving the G4.5 gene, multiple mutations have been reported in the gene.


  • Mutations in TMP, the gene encoding thymidine phosphorylase, detects mutations in approximately 100%.

Other studies

  • KSS: Electromyogram and nerve conduction studies. Consistent with a myopathy, but neuropathy may also coexist.

Would imaging studies be helpful? If so, which ones?


Characteristic neuroimaging features of Leigh syndrome include the following:

  • MRI scans of patients with SURF-1 mutations have lesions in the brain stem, subthalamic nuclei, and cerebellum with few patients having basal ganglia abnormalities (Farina et al., 2002).

  • Patients with Leigh syndrome from other etiologies have T2 hyperintensities in the putamen, caudate nuclei, globus pallidi, thalami, and brain stem, while some patients with diffuse supratentorial white matter changes (Farina et al., 2002; Valanne et al., 1998).

  • Symmetric involvement of deep gray structures in the absence of hypoxia, ischemia, or infection would be suggestive of mitochondrial defect.

  • In a small percentage of patients with Leigh syndrome, MRI may show diffuse supratentorial leukodystrophy of the deep lobar white matter.

  • For reviews of MRI in Leigh and other mitochondrial disorders see [Friedman, et al., 2010; Gropman 2013;).

Other findings:

  • Bilateral symmetric hypodensities in the basal ganglia on computed tomography (CT).

  • Bilateral symmetrical hyperintense signal abnormality in the brain stem and/or basal ganglia on T2-weighted MRI.

  • Specific lesions of mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum.

  • In NARP, cerebral and cerebellar atrophy may be noted on MRI.

  • MRI is helpful in allowing recognition of the most common features of mitochondrial disease (see Table 2).

  • LS has the description of that of subacute necrotizing encephalomylelopathy.

  • NARP may show cerebral and/or cerebellar atrophy.

  • Findings in LS are similar to that seen in Wernicke syndrome/thiamine deficiency except mamillary bodies are spared.

Table 2.n

Organ system involvement in POLG-1 related mitochondrial disorders

Imaging findings in MELAS:

  • On the MRI, the stroke-like lesions are often transient.

  • Lesions predominantly affect gray matter and not confined to vascular territories.

  • Diffuse white matter lesions involving periventricular white matter and centrum semiovale.

  • Chronic lesions display T2 and FLAIR signal hyperintensities with normal to increased apparent diffusion coefficient.

  • Acute stroke episodes show hyperintense T2 and FLAIR signal with reduction in apparent diffusion coefficient.

  • DWI sequences can differentiate acute from chronic.

  • MR angiography will be normal.

Imaging findings in MERRF:

  • Nothing specific.

Imaging findings in POLG 1:

  • Cortical and deep gray matter abnormalities.

  • Predilection for the posterior parts of the brain or thalamus.

Imaging findings in LHON:

  • MRI is often normal.

  • May show high signal within the optic nerves, likely indicating edema or gliosis during the atrophic phase.

Imaging in KSS:

  • T2/FLAIR hyperintense bilateral lesions in subcortical white matter, thalamus, basal ganglia and brainstem.

  • Subcortical cerebral white matter may be abnormal.

  • Basal ganglia involvement not common.

  • Involvement of the subcortical U fibers with sparing of the periventricular white matter differentiates it from most lysosomal and peroxisomal disorders where subcortical regions are only affected late in the disease.

Imaging in PDH:

  • Imaging studies may document cerebral dysgenesis in PDH.

  • Ventriculomegaly.

  • Cerebral atrophy.

  • Partial or complete absence of the corpus callosum.

  • Absence of the medullary pyramids, or dysmorphic or ectopic inferior olives.

  • Gliosis may be observed in the cortex, basal ganglia, brainstem, or cerebellum.

  • Diffuse hypomyelination.

Imaging in MNGIE:

  • Asymptomatic leukoencephalopathy.

  • Prominent leukoencephalopathy in almost all patients.

  • Corpus callosum is usually spared.

Confirming the diagnosis

Several paradigms have been developed to address the probability of having a mitochondrial disorder including the one from Baylor College of Medicine and the Walker and Bernier criteria:


http://www.bcm.edu/geneticlabs/index.cfm?pmid=15857 (algorithm)

If you are able to confirm that the patient has a mitochondrial disease, what treatment should be initiated?

  • There is no treatment for most mitochondrial disorders.

  • Supportive care is advocated.

  • Supportive management includes treatment of the following:

    Acidosis: Sodium bicarbonate or sodium citrate for acute exacerbations of acidosis.

    Seizures: Appropriate antiepileptic drugs tailored to the type of seizure under the supervision of a neurologist. Sodium valproate and barbiturates should be avoided because of their inhibitory effects on the mitochondrial respiratory chain, especially in patients suspected or confirmed to have POLG-1 (see below).

    Testing for POLG-1 is often advocated before even considering use of Valproate.

    Dystonia: multiple drugs including, baclofen, tetrabenezine, and gabapentin may be useful, alone or in various combinations.

    Botulinum toxin injection has also been used in individuals with spasticity or intractable dystonia.

    Cardiomyopathy: Therapy for congestive heart failure may be required and should be supervised by a cardiologist.

    All patients will benefit from regular assessment of daily caloric intake and adequacy of dietary structure including micronutrients.

    Feeding management is indicated as many patients will require G tubes to meet caloric needs.

    Some physicians will treat with a vitamin cocktail, but this is decided on an individual basis (see also below).

    MELAS : there is some evidence that arginine and/or citrulline may prevent further strokes by action on neuronal NOS influencing vascular tone.

    In 2006, Koga, et al. noted that patients with MELAS had significantly low levels of L-arginine during the acute phase of their stroke-like episodes and showed effectiveness of arginine in decreasing the severity of stroke-like symptoms, reducing the frequency of stroke-like episodes, enhancing circulatory dynamics, and reducing tissue injury although there have been no official clinical trials.

    Management of visual loss in LHON is supportive and includes visual aids and registration with social services if a patient meets criteria for legal blindness.

    Mitochondrial disorders with secondary cerebral folate deficiency may be treated with folinic acid.

    Some physicians will treat with a vitamin cocktail containing coenzyme Q10, carnitor, thiamine, riboflavin, lipoic acid, vitamin C, vitamin E, possibly creatinine, however there is not consensus on this or what elements to add to the cocktail.

    Dichloroacetate is toxic to peripheral nerves, particularly in MELAS; it may be helpful in Leigh syndrome and PDH.

    EPI 743.


    Magnesium has been used recently to treat the refractory seizures associated with POLG1.

  • Barth syndrome: One trial with pantothenic acid failed to reduce the number of infectious episodes and prevent dilated cardiomyopathy. Surveillance for infection and cardiomyopathy constitute treatment. Management of developmental issues with appropriate therapies is recommended.

  • There are studies underway using EPI-743, an antioxidant in Leigh syndrome and other mitochondrial disorders.


    Management of GI dysfunction and nausea and vomiting, early attention to swallowing difficulties.

    Celiac plexus block with bupivicaine for GI pain in MNGIE. Splanchnic nerve block has been used.

    Nutritional support including, when necessary, bolus feedings, gastrostomy tube placement, and total parenteral nutrition.

    Antibiotic therapy for intestinal bacterial overgrowth in MNGIE which can be a complication of dysmotility.

In pyruvate carboxylase: treatment strategies

  • Intravenous glucose-containing fluids, hydration, and correction of the metabolic acidosis.

  • Correction of biochemical abnormalities and supplementation with citrate, aspartic acid, and biotin may improve somatic findings but not neurologic.

  • Orthotopic liver transplantation may be indicated in some patients.

  • Anaplerotic therapies, such as triheptanoin show some promise, especially for the neurologic manifestations.

  • Prevention of clinical manifestations: high-carbohydrate and high-protein diet to counteract gluconeogenesis.

In all mitochondrial disorders: surveillance:

Follow the organ systems that may be affected –

  • Eye

  • Ear

  • Heart

  • Kidney

  • CNS

  • PNS

Vitamin therapy in mitochondrial disorders:

  • No universal consensus on its use or effectiveness.

  • Effectiveness may vary by patient and disease.

  • May include riboflavin, thiamine, and coenzyme Q10 (each at 50-100 mg/3x/day).

  • A high-fat diet, providing 50-60% of daily caloric intake from fat, may be prescribed to individuals with Leigh syndrome resulting from complex I deficiency, although currently there is no evidence supporting this therapeutic rationale in this particular disorder.

  • Biotin, creatine, succinate, and idebenone have also been used and may show partial efficacy in patients who have milder symptoms.

  • Several recent studies have investigated whether upregulation of mitochondrial biogenesis may provide an effective therapeutic approach for mitochondrial respiratory chain diseases using agonists such as bezafibrate or resveratrol which stimulate the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) path.

What are the adverse effects associated with each treatment option?

  • Arginine at high levels can cause peripheral nerve damage.

  • Dichloroacetate can lead to hepatic failure and peripheral neuropathy.

  • Sodium valproate and barbiturates, and anesthesia, worsen mitochondrial function and should be avoided because of their inhibitory effect on the mitochondrial respiratory chain.

  • Ketogenic diet may worsen pyruvate carboxylase.

What are the possible outcomes of Mitochondrial diseases?

  • The prognosis of LS is poor, especially in infancy-onset disease, as most children will die in the first years of life.

  • Mitochondrial disorders are generally progressive, although there may be decompensation with some recovery; however, the net effect is a decline over time.

  • Most children die of an intercurrent infection, which compromises their pulmonary function.

  • MELAS may stabilize, or present with recurrent strokes over time with resultant loss of previous motor and cognitive function, resulting in fixed motor deficits and dementia.

  • In LHON, symptomatic patients develop severe visual loss. Significant improvements in visual acuity are very rare.

  • Pyruvate carboxylase (types A and B) are associated with early death in infancy or childhood.

  • MNGIE disease is a progressive, degenerative disease with a poor prognosis.

What causes this disease and how frequent is it?

  • In 2008, the incidence of “at-risk” carriers of mitochondrial DNA mutations in the United Kingdom was estimated at 1:10,000 adults, the equivalent of 1:200 persons [DiMauro, 2010].

  • MELAS is the most common of the mitochondrial disorders with a prevalence as frequent as 1 in 6000 people.

  • Mitochondrial dysfunction is found in diseases as diverse as cancer, infertility, diabetes, heart diseases, blindness, deafness, kidney disease, liver disease, stroke, migraine, dwarfism, and resulting from numerous medication toxicities.

  • Mitochondrial dysfunction is also involved in normal aging and age-related neurodegenerative diseases such as Parkinson and Alzheimer dementia.

    About 20% of mitochondrial diseases are inherited maternally, as little or no mtDNA is transferred from sperm to the fertilized egg.

    Mitochondrial diseases can also occur sporadically or be inherited in an autosomal dominant or recessive manner.

    More than 200 mitochondrial DNA (mtDNA) point mutations or deletions have been associated with mitochondrial disease.

    Approximately 100 nuclear DNA (nDNA) mutations have also been described, mostly since 2006.

  • Disease can occur across the lifespan, since the regulation of many mitochondrial proteins is developmental and may also be impacted by environmental toxins.

  • Carrier proteins normally acting as chaperonins and mitochondrial fusion/fission abnormalities have also been described as the causes for mitochondrial diseases.

  • There can be tissue specific mtDNA changes that are hard to detect with only non-invasive blood or urine studies.

  • Clinical presentation of some mitochondrial disorders such as LHON (Leber’s Heritary Optic Neuropathy) and sensori-neuro deafness may be impacted by gene-gene interactions.

  • Primary LHON-causing mtDNA mutations have reduced penetrance – 50% of males and 90% of females with a known mutation do not develop blindness.

  • Gender (males are on average four times more likely to develop vision loss) and age (blindness is unlikely to develop if not present by 50 years of age) are important risk factors.

  • History, including family history with evidence of a maternal inheritance pattern characteristic of mitochondrial disease.

How do these pathogens/genes/exposures cause the disease?

  • The genes involved in mitochondrial disorders play a role in the function of the mitochondrial respiratory chain.

  • Most patients with mitochondrial disorders have molecular defects affecting the mitochondrial OXPHOS system, which is made up of 87 protein subunits forming five multiprotein complexes (Complexes I–V) embedded in the inner mitochondrial membrane.

  • Among the 87 proteins, 13 are encoded by the mitochondrial genome and the remainder are encoded by the nuclear genome.

  • To form the OXPHOS complexes, a number of nuclear-encoded assembly factors are required.

  • Certain mutations of the pyruvate dehyrogenase complex influence the timing of presentation of disease features.

  • Patients with a PDH mutation are more susceptible to malnutrition as well as infection and other periods of increased energy demands.

Other clinical manifestations that might help with diagnosis and management

  • In addition to findings suggestive of lactic acidosis, particular features on physical exam may support the diagnosis of PDH. There is a characteristic dysmorphology that includes trigonocephaly, hypertelorism, a thin upper lip, bilateral epicanthal folds, upward slanting eyes, high palate, and pectus excavatum.

  • Neurologic exam may demonstrate microcephaly, hypotonia, ataxia, progressive encephalopathy, poor visual tracking, dysconjugate eye movements, diminished papillary responses, choreoathetosis, or dystonia.

What complications might you expect from the disease or treatment of the disease?

  • Most mitochondrial disorders worsen over time.

  • Sodium valproate and barbiturates, anesthesia, and dichloroacetate (DCA) may worsen symptoms.

  • Ketogenic diet may worsen pyruvate carboxylase deficiency.

  • Some mitochondrial disorders may be worsened by carnitine.

Are additional laboratory studies available; even some that are not widely available?

  • Whole exon sequencing and next generation sequencing panels of nuclear genes may aid in the diagnosis of nuclear mutations and novel mutations, but are not widely available.

  • Some laboratory panels are making use of this technology to increase the number of gene defects that can be detected.

How can mitochondrial disorders be prevented?

  • Since this is a genetically determined disorder, there is no prevention.

  • Prevention of stressors that exacerbate the condition, such as illness, is advocated for all mitochondrial disease.

  • There is evidence that avoidance of valproic acid in POLG-1 will avert some of the effects.

  • There is evidence that avoidance of aminoglycosides in patients with mutations in mtA155G will avert hearing loss.

  • There is some evidence that use of arginine or citrulline may be protective against recurrent stroke in MELAS.

What is the evidence?






Bernier, FP, Boneh, A, Dennett, X, Chow, CW, Cleary, MA, Thorburn, DR. “Diagnostic criteria for respiratory chain disorders in adults and children”. Neurology. vol. 59. 2002. pp. 1406-1411. (This manuscript describes the criteria that are most likely to diagnose a patient with a mitochondrial disorder using a combination of clinical, biochemical, imaging, molecular and pathology findings. It is a modification of the Walker criteria [see below] which was felt to rely on features more common in adult rather than pediatric mitochondrial disorders.)PUBMED:18055683

Haas, RH, Parikh, S, Falk, MJ, Saneto, RP, Wolf, NI, Darin, N, Cohen, BH. “Mitochondrial disease: a practical approach for primary care physicians”. Pediatrics. vol. 120. 2007. pp. 1326-1333. (This manuscript presents a practical approach to diagnosis and referral and is aimed at primary care providers.)PUBMED:8864705

Walker, UA, Collins, S, Byrne, E. “Respiratory chain encephalomyopathies: a diagnostic classification”. Eur Neurol. vol. 36. 1996. pp. 260-267. PUBMED:12427891

Wolf, NI, Smeitink, JA. “Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children”. Neurology. vol. 59. 2002. pp. 1402-5. (This manuscript presents another attempt in reaching consensus in diagnosis of young children and infants.)

Ongoing controversies regarding etiology, diagnosis, treatment

The diagnosis of mitochondrial disorders is often not straightforward and takes into account clinical history, physical examination features, family history, biochemical and other laboratory findings, imaging findings and is confirmed by a molecular finding. Some clinicians advocate muscle biopsy whereas others focus on findings from the laboratories and promote early molecular testing.

While there are guidelines, there is no consensus on diagnosis and treatment which is still empiric.