Mitochondrial Disorders Overview

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Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of
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Mitochondrial Disorders Overview

Synonyms: Mitochondrial Encephalomyopathies, Mitochondrial Myopathies, Oxidative
Phosphorylation Disorders, Respiratory Chain Disorders
Patrick F Chinnery, BMedSci, MBBS, PhD, FRCPath, FRCP, FMedSci

Department of Clinical Neurosciences
University of Cambridge
Cambridge, United Kingdom
[email protected]
Initial Posting: June 8, 2000; Last Update: August 14, 2014.
Summary
Clinical characteristics. Mitochondrial diseases are a clinically heterogeneous group of
disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be
caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA).
While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary
optic neuropathy [LHON]), many involve multiple organ systems and often present with
prominent neurologic and myopathic features. Mitochondrial disorders may present at any age.
Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a
discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive
external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and
stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic
weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However,
considerable clinical variability exists and many individuals do not fit neatly into one particular
category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including
mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene
POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features
of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis,
external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy,
sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common
central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine,
stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a
common occurrence that often goes unrecognized.
Diagnosis/testing. In some individuals, the clinical picture is characteristic of a specific

mitochondrial disorder (e.g., LHON, NARP, or maternally inherited LS), and the diagnosis can
be confirmed by identification of a pathogenic mtDNA variant on molecular genetic testing of
DNA extracted from a blood sample. In many individuals, such is not the case, and a more
structured approach is needed, including family history, blood and/or CSF lactate concentration,
neuroimaging, cardiac evaluation, and molecular genetic testing for a mtDNA or nuclear gene
pathogenic variant. Approaches to molecular genetic testing of a proband to consider are serial
testing of single genes, multi-gene panel testing (simultaneous testing of multiple genes), and/or
genomic testing (e.g., sequencing of the entire mitochondrial genome, genome sequencing, or
exome sequencing to identify a pathogenic variant in a nuclear gene). In many individuals in
whom molecular genetic testing does not yield or confirm a diagnosis, further investigation of
suspected mitochondrial disease can involve a range of different clinical tests, including muscle
biopsy for respiratory chain function.
https://www.ncbi.nlm.nih.gov/books/NBK1224/ 1/24
Genetic counseling. Mitochondrial disorders may be caused by defects of nuclear DNA or

mtDNA. Nuclear gene defects may be inherited in an autosomal recessive or autosomal
dominant manner. Mitochondrial DNA defects are transmitted by maternal inheritance.
Mitochondrial DNA deletions generally occur de novo and thus cause disease in one family
member only, with an approximate recurrence risk of 1 in 24. Mitochondrial DNA single-
nucleotide variants and duplications may be transmitted down the maternal line. The father of a
proband is not at risk of having the mtDNA pathogenic variant, but the mother of a proband
(usually) has the mitochondrial pathogenic variant and may or may not have symptoms. A male
does not transmit the mtDNA pathogenic variant to his offspring. A female harboring a
heteroplasmic mtDNA single-nucleotide variant may transmit a variable amount of mutated
mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same
family. Prenatal genetic testing and interpretation of test results for mtDNA disorders are difficult
because of mtDNA heteroplasmy. De novo tissue-specific pathogenic nucleotide variants are
rare, but associated with low recurrence risks.
Management. Treatment of manifestations: The management of mitochondrial disease is largely

supportive and may include early diagnosis and treatment of diabetes mellitus, cardiac pacing,
ptosis correction, intraocular lens replacement for cataracts, and cochlear implantation for
sensorineural hearing loss. Individuals with complex I and/or complex II deficiency may benefit
from oral administration of riboflavin; those with ubiquinone (coenzyme Q10) deficiency may
benefit from oral coenzyme Q10 therapy; and those with mitochondrial neurogastrointestinal
encephalomyopathy (MNGIE) may benefit from hematopoietic stem cell transplantation.
Definition
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of
dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is the
essential final common pathway for aerobic metabolism, and tissues and organs that are highly
dependent on aerobic metabolism are preferentially involved in mitochondrial disorders [Wallace
1999].
More than 70 different polypeptides interact on the inner mitochondrial membrane to form the
respiratory chain. The vast majority of subunits are synthesized within the cytosol from nuclear
gene transcripts, but 13 essential subunits are encoded by the 16.5-kb mitochondrial DNA
(mtDNA) [Larsson & Clayton 1995].
Figure 1 illustrates the structure of the human mitochondrial genome.
Figure 1.
The human mitochondrial genome
The 1.1-kb D-loop (noncoding region) is involved in the regulation of transcription and
replication of the molecule, and is the only region not directly involved in the synthesis of
respiratory chain polypeptides.
MT-ND1 through MT-ND6 and MT-ND4L encode seven subunits of complex I.
Cyt b is the only mtDNA-encoded complex III subunit.
MT-CO1 to MT-CO3 encode for three of the complex IV (cytochrome c oxidase, or COX)
subunits.
MT-ATP6 and MT-ATP8 encode for two subunits of complex V: ATPase6 and ATPase8,
respectively.
Two ribosomal RNA genes (MT-RNR1 and MT-RNR2, encoding 12S and 16S rRNA) and
22 transfer RNA genes are interspaced between the protein-encoding genes. These provide
the necessary RNA components for intra-mitochondrial protein synthesis.
OH and OL are the origins of heavy- and light-strand mtDNA replication.
Each human cell contains thousands of copies of mtDNA. At birth these are usually all identical
(homoplasmy). By contrast, individuals with mitochondrial disorders resulting from mutation of
mtDNA may harbor a mixture of mutated and wild-type mtDNA within each cell (heteroplasmy)
[Holt et al 1988, Holt et al 1990]. Single-cell studies and cybrid-cell studies have shown that the
proportion of mutated mtDNA must exceed a critical threshold level before a cell expresses a
biochemical abnormality of the mitochondrial respiratory chain (the threshold effect) [Schon et al
1997]. The percentage level of mutated mtDNA may vary among individuals within the same
family, and also among organs and tissues within the same individual [Macmillan et al 1993].
This is one explanation for the varied clinical phenotype seen in individuals with disorders
caused by mutation of mtDNA. For example, in individuals harboring the m.8993T>G
pathogenic variant, higher percentage levels of mutated mtDNA are seen in those presenting with
Leigh syndrome than in those presenting with neurogenic weakness with ataxia and retinitis
pigmentosa (NARP) [Uziel et al 1997, White et al 1999a].
Other important mitochondrial mechanisms controlled by nuclear genes include:
Disorders of mtDNA maintenance (mtDNA depletion or secondary pathogenic mtDNA

variants);
Disorders of mitochondrial protein synthesis;
Disorders of coenzyme Q10 biosynthesis;
Disorders of the respiratory chain complexes or their assembly.
With more than 1000 nuclear genes encoding mitochondrial proteins, the molecular diagnosis
can be challenging.
Secondary mitochondrial dysfunction in human diseases. Mitochondrial dysfunction is also

seen in a number of different genetic disorders, including ethylmalonic aciduria (caused by
mutation of ETHE1) [Tiranti et al 2009], Friedreich ataxia (FXN) [Rötig et al 1997], hereditary
spastic paraplegia 7 (SPG7) [Casari et al 1998], and Wilson disease (ATP7B) [Lutsenko &
Cooper 1998], and is also seen as part of the aging process. These are not strictly mitochondrial
diseases. The term mitochondrial disorder usually refers to primary disorders of mitochondrial
metabolism affecting oxidative phosphorylation.
Clinical Manifestations
Some mitochondrial disorders affect a single organ (e.g., the eye in Leber hereditary optic
neuropathy and the ear in nonsyndromic hearing loss with or without aminoglycoside sensitivity;
see Mitochondrial Hearing Loss and Deafness), but many involve multiple organ systems and
often present with prominent neurologic and myopathic features.
Mitochondrial disorders may present at any age [Leonard & Schapira 2000a, Leonard &
Schapira 2000b]. Until recently it was generally thought that nuclear DNA abnormalities present
in childhood and mtDNA abnormalities (primary or secondary to a nuclear DNA abnormality)
present in late childhood or adult life; however, recent advances have shown that many mtDNA
disorders present in childhood, and many nuclear genetic mitochondrial disorders present in adult
life.
Many individuals display a cluster of clinical features that fall into a discrete clinical syndrome
(Table 1) [DiMauro & Schon 2001, Munnich & Rustin 2001], such as Kearns-Sayre syndrome
(KSS), chronic progressive external ophthalmoplegia (CPEO) [Moraes et al 1989], mitochondrial
encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [Hirano et al 1992],
myoclonic epilepsy with ragged-red fibers (MERRF) [Hammans et al 1993], neurogenic
weakness with ataxia and retinitis pigmentosa (NARP) [Holt et al 1990], or Leigh syndrome (LS)
[Ciafaloni et al 1993]. However, there is often considerable clinical variability and many affected
individuals do not fit neatly into one particular category. Mutation of POLG, which has emerged
as a major cause of mitochondrial disease, illustrates this well, with an overlapping spectrum of
disease phenotypes resulting from pathogenic variants in the same gene (see POLG-Related
Disorders).
Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia,

proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic
atrophy, pigmentary retinopathy, and diabetes mellitus. Diabetes mellitus and deafness is also a
well-recognized clinical phenotype [van den Ouweland et al 1992].
The central nervous system findings are often fluctuating encephalopathy, seizures, dementia,
migraine, stroke-like episodes, ataxia, and spasticity. Chorea and dementia may also be
prominent features [Nelson et al 1995].
A high incidence of mid- and late pregnancy loss is also a common feature that often remains
unrecognized [Tay et al 2004].
Table 1.
Clinical Syndromes of Mitochondrial Diseases
Disorder Primary Features Additional Features

Hypotonia
Alpers-Huttenlocher
Seizures Renal tubulopathy
syndrome
Liver failure
SANDO
Ataxia neuropathy syndromes Epilepsy
Other ANS: Sensory axonal
(ANS): Including MIRAS, Dysarthria, and/or
neuropathy w/variable
SCAE, SANDO, MEMSA Myopathy
sensory & cerebellar ataxia
External ophthalmoplegia
CPEO Mild proximal myopathy
Bilateral ptosis
Bilateral deafness
PEO onset at age <20 years
Myopathy
Pigmentary retinopathy
Dysphagia
KSS One of the following: CSF
Diabetes mellitus
protein >1g/L, cerebellar
Hypoparathyroidism
ataxia, heart block
Dementia
Disorder Primary Features Additional Features

Sideroblastic anemia of
childhood
Pearson syndrome Renal tubular defects
Pancytopenia
Exocrine pancreatic failure
Infantile myopathy and lactic Hypotonia in 1st year of life Fatal form may be associated with
acidosis (fatal & non-fatal Feeding & respiratory a cardiomyopathy and/or the Toni-
forms) difficulties Fanconi-Debre syndrome
Subacute relapsing
encephalopathy Basal ganglia lucencies
Leigh syndrome Cerebellar and brain stem Maternal history of neurologic
signs disease or Leigh syndrome
Infantile onset
Late-childhood or adult-
Basal ganglia lucencies
onset peripheral neuropathy
NARP Abnormal electroretinogram
Ataxia
Sensorimotor neuropathy
Diabetes mellitus
Stroke-like episodes at age
Cardiomyopathy (initially
<40 years
hypertrophic; later dilated)
MELAS Seizures and/or dementia
Bilateral deafness
Ragged-red fibers and/or
lactic acidosis
Cerebellar ataxia
Myopathy Dementia
1
MEMSA Seizures Peripheral neuropathy
Cerebellar ataxia Spasticity
Dementia
Myoclonus Optic atrophy
Seizures Bilateral deafness
MERRF
Cerebellar ataxia Peripheral neuropathy
Myopathy Spasticity
Multiple lipomata
Subacute painless bilateral
visual failure
Dystonia
LHON Males:females ~4:1
Cardiac pre-excitation syndromes
Median age of onset 24
years
CPEO = chronic progressive external ophthalmoplegia

KSS = Kearns-Sayre syndrome
LHON = Leber hereditary optic neuropathy
MELAS = mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
MEMSA = myoclonic epilepsy myopathy sensory ataxia
MERRF = myoclonic epilepsy with ragged-red fibers
MIRAS = mitochondrial recessive ataxia syndrome
NARP = neurogenic weakness with ataxia and retinitis pigmentosa
SANDO = sensory ataxia neuropathy, dysarthria, ophthalmoplegia
SCAE = spinocerebellar ataxia with epilepsy

1. Also referred to as MIRAS and SCAE
Differential Diagnosis
Lactic acidosis. It is important to exclude other causes of lactic acidosis when interpreting these
values. For example, the concentration of lactate may be elevated in the plasma and CSF of
affected individuals following a seizure. CSF lactate concentration may be elevated following an
ischemic stroke.
White matter abnormalities. See Scarpelli et al [2013], Morató et al [2014], and Wu et al

[2016].
Prevalence
Mitochondrial disorders are more common than was previously thought (Table 2). Based on the
available data, a conservative estimate for the prevalence of all mitochondrial diseases is
11.5:100,000 (~1:8500). Arpa et al [2003] calculated prevalence in Spain at 5.7:100,000 for
individuals older than age 14 years.
Table 2.
Epidemiology of Mitochondrial Disease
Disease Prevalence /
Study Population Pathogenic Variant or Disease 100,000
(95% C.I.) 1
1.33 3
All mtDNA deletions
(0.76-1.89)
All mtDNA single nucleotide 5.24 3
Northern England 2 variants (4.12-6.37)
3.29 3
Point prevalence August m.11778G>A, m.3460G>A (LHON)
(2.39-4.18)
1997
0.95 3
Population size: m.3243A>G
(0.47-1.43)
2,122,290
0.25 3
m.8344A>G
(0.01-0.5)
6.57 4
All pathogenic mtDNA variants
(5.30-7.83)
Northern Finland 5
Adult point prevalence 5.71

m.3243A>G
(4.53-6.89)
Population size: 245,201
Western Sweden 6
Childhood mitochondrial 4.7 7
Children age <16:
encephalomyopathies (2.8-7.6)
385,616
Disease Prevalence /
Study Population Pathogenic Variant or Disease 100,000
(95% C.I.)
Victoria, Australia 8
4.7 9
Birth prevalence: Childhood respiratory chain disease
(3.2-5.0)
1,710,000 births
Mitochondrial disease (adults and

Summary ~11.5
children)
Note: The mitochondrial genetic code varies from the genomic genetic code given in the Quick Reference. For the
genetic code, gene structure, and other features of the mitochondrial genome see MITOMAP: A Human
Mitochondrial Genome Database. Variants are named according to current nomenclature guidelines (varnomen
.hgvs.org). The reference sequence for the human mitochondrial DNA is NC_012920.1 (www.mitomap.org).
1. C.I. = confidence interval
2. Chinnery et al [2000]
3. The prevalence of mtDNA disease is based on affected adults (age 16-65 yrs for males; 16-60 yrs for
females).
4. The prevalence of mtDNA pathogenic variants is based on all individuals under retirement age (<65 yrs for
males; <60 yrs for females).
5. Majamaa et al [1998]
6. Darin et al [2001]
7. Point prevalence 1 January 1999
8. Skladal et al [2003]
9. Birth prevalence measured between 1987 and 1996
Causes
Mitochondrial disorders can be caused by mutation of nuclear DNA or mitochondrial DNA
[Koopman et al 2012].
The classification of mitochondrial disease is difficult. Although a purely clinical classification

can be helpful (Table 1), many individuals do not fall into one specific disease category. The
situation is made all the more complex by the poor correlation between genotype and phenotype.
For example, among a group of clinically indistinguishable individuals with external
ophthalmoplegia, some may have a large deletion of mtDNA, others a single nucleotide variant
of mtDNA (e.g., m.3243A>G), and still others a heterozygous pathogenic variant in a nuclear
gene causing secondary mtDNA abnormalities (e.g., ANT1 pathogenic variants).
Recent advances in our understanding of the molecular genetic basis of mitochondrial disease
have helped in the classification of these disorders by nuclear DNA mutation (Table 3a) and
mitochondrial DNA mutation (Table 3b). Nonetheless, the genetic approach to classification also
has certain drawbacks:
It is currently not possible to identify the pathogenic variant in a significant number of

affected individuals, particularly children [Lieber et al 2013]
The same pathogenic variant may cause a range of very different clinical syndromes (e.g.,
the m.3243A>G single nucleotide variant may cause CPEO, diabetes mellitus and
deafness, or a severe encephalopathy with recurrent strokes and epilepsy).
The rate of new gene discovery using genomic testing methods (e.g., exome sequencing)
makes it difficult for any one resource to maintain a comprehensive list of all genes known
to impair mitochondrial function.
Table 3a.
Genetic Classification of Human Mitochondrial Disorders: Mutation of Nuclear DNA
Mutation of Nuclear DNA

Leigh syndrome with complex I deficiency
(NDUFS1, NDUFS4, NDUFS7, NDUFS8,
NDUFV1)
Leigh syndrome with complex II deficiency
(SDHA)
Nuclear genetic disorders of the mitochondrial Leukodystrophy with complex II deficiency
respiratory chain (mutated genes encoding (SDHAF1)
1
structural subunits) Cardiomyopathy and encephalopathy
(complex I deficiency) (NDUFS2)
Optic atrophy and ataxia (complex II
deficiency) (SDHA)
Hypokalemia and lactic acidosis (complex
III deficiency) (UQCRB)
Leigh syndrome (SURF1, LRPPRC)
Hepatopathy and ketoacidosis (SCO1)
Cardiomyopathy and encephalopathy
(SCO2)
Leukodystrophy and renal tubulopathy
Nuclear genetic disorders of the mitochondrial
(COX10)
respiratory chain (mutated genes encoding
Hypertrophic cardiomyopathy (COX15)
assembly factors) 1
Encephalopathy, liver failure, renal
tubulopathy (with complex III deficiency)
(BCS1L)
Encephalopathy (with complex V
deficiency) (ATPAF2)
Leigh syndrome, liver failure, and lactic
acidosis (GFM1)
Lactic acidosis, developmental failure, and
Nuclear genetic disorders of the mitochondrial dysmorphism (MRPS16)
respiratory chain (mutated genes encoding Myopathy and sideroblastic anemia (PUS1)
1
translation factors) Leukodystrophy and polymicrogyria
(TUFM)
Leigh syndrome and optic atrophy with
COX deficiency (TACO1)
Mutation of Nuclear DNA

Autosomal progressive external
ophthalmoplegia (POLG, POLG2, TWNK,
SLC25A4)
Mitochondrial neurogastrointestinal
encephalomyopathy (thymidine
phosphorylase deficiency) (TYMP)
Alpers-Huttenlocher syndrome (POLG)
Ataxia neuropathy syndromes 2 (POLG,
TWNK, OPA1)
Infantile myopathy / spinal muscular
atrophy (TK2)
Nuclear genetic disorders associated with
Encephalomyopathy and liver failure
multiple mtDNA deletions or mtDNA depletion
(DGUOK)
Hypotonia, movement disorder, and/or
Leigh syndrome with methylmalonic
aciduria (SUCLA2)
Hypotonia, encephalopathy, renal
tubulopathy, lactic acidosis (RRM2B)
Mitochondrial encephalomyopathy with
combined RC deficiency (AIF1)
Reversible hepatopathy (TRMU)
Myopathy with cataract and combined RC
deficiency (GFER)
Coenzyme Q10 deficiency (COQ2, COQ9,
CABC1, ETFDH)
Barth syndrome (TAZ)
Other disorders
Cardiomyopathy and lactic acidosis
(mitochondrial phosphate carrier
deficiency) (SLC25A3)
1. See Nuclear Gene-Encoded Leigh Syndrome Overview.

2. Includes MIRAS, SCAE, SANDO, MEMSA
Table 3b.
Genetic Classification of Human Mitochondrial Disorders: Mutation of Mitochondrial DNA
Mutation of Mitochondrial DNA

Chronic progressive external ophthalmoplegia
Rearrangements (deletions
Kearns-Sayre syndrome
& duplications)
Diabetes and deafness
Protein-encoding genes
Leber hereditary optic neuropathy (LHON) (m.11778G>A,
Single-nucleotide
m.14484T>C, m.3460G>A)
variants 1
Neurogenic weakness with ataxia and retinitis pigmentosa / Leigh
syndrome (m.8993T>G, m.8993T>C)
Mutation of Mitochondrial DNA

MELAS (m.3243A>G, m.3271T>C, m.3251A>G)
MERRF (m.8344A>G, m.8356T>C)
Chronic progressive external ophthalmoplegia (m.3243A>G,
m.4274T>C)
tRNA genes 1 Myopathy (m.14709T>C, m.12320A>G)
Cardiomyopathy (m.3243A>G, m.4269A>G)
Diabetes and deafness (m.3243A>G, m.12258C>A)
Encephalomyopathy (m.1606G>A, m.10010T>C)
Nonsyndromic sensorineural deafness (m.7445A>G)
rRNA genes 1 Aminoglycoside-induced nonsyndromic deafness (m.1555A>G)
For the genetic code, gene structure, and other features of the mitochondrial genome see MITOMAP: A Human
Mitochondrial Genome Database. Variants are named according to current nomenclature guidelines (varnomen
.hgvs.org). The reference sequence for the human mitochondrial DNA is NC_012920.1 (www.mitomap.org).
1. Mitochondrial DNA nucleotide positions refer to the L-chain.
Establishing the Diagnosis of a Mitochondrial Disorder

Mitochondrial dysfunction should be considered in the differential diagnosis of any progressive
multisystem disorder. A full evaluation for a mitochondrial disorder is often warranted in
children with a complex neurologic picture or a single neurologic symptom and other system
involvement.
Findings that can suggest a mitochondrial disorder include clinical phenotype (physical
examination including neurologic examination), mode of inheritance (family history), and extent
of the phenotype (biochemical and histologic findings). Molecular genetic testing of DNA
extracted from a blood sample is used to establish the diagnosis.
Physical Examination and Neurologic Evaluation

Approach when a specific diagnosis is suspected. Establishing the diagnosis of a specific
inherited disorder that affects mitochondrial function can be relatively straightforward if a person
has a recognizable phenotype (Table 1) that is supported by the family history and if molecular
genetic testing of a single gene based on these phenotypic findings identifies a known pathogenic
variant in the gene of interest.
When the clinical picture is classic for a nuclear DNA-inherited syndrome (Table 3a) and
the gene is known (e.g., mitochondrial neurogastrointestinal encephalomyopathy,
autosomal PEO with multiple secondary deletions, or a classic POLG-related disorder
[including MIRAS and Alpers-Huttenlocher syndrome]) the clinician should proceed with
molecular genetic studies (see Molecular Genetic Testing).
When the presentation is classic for a maternally (mitochondrial) inherited mitochondrial

syndrome such as MELAS, MERRF, or Leber hereditary optic neuropathy (Table 3b),
appropriate mtDNA studies should be obtained first (see Molecular Genetic Testing).
Family History
A three-generation family history can suggest a mode of inheritance and/or a diagnosis and can
help in directing molecular genetic testing.
Mode of Inheritance
Mitochondrial inheritance (Table 3b). A family history in which males and females are
affected, affected females transmit the disease to all their children, and affected males do not
transmit the disease to their children suggests mitochondrial inheritance.
The range of clinical features associated with mtDNA mutation is broad and the family history
may include many oligosymptomatic family members (e.g., some with diabetes mellitus or mild
sensorineural deafness as the only feature).
Autosomal recessive inheritance (Table 3a). A family history in which only sibs are affected
(i.e., a single generation in the family) and/or when the parents are consanguineous suggests
autosomal recessive inheritance.
Autosomal dominant inheritance (Table 3a). A family history in which males and females in
multiple generations are affected suggests autosomal dominant inheritance.
A clear autosomal dominant pattern of inheritance may be seen in individuals with PEO.
X-linked inheritance. A family history in which affected individuals are male and are related to
each other through females suggests X-linked inheritance.
Simplex case. If only one member of a family is known to be affected, possibilities to consider
are de novo mutation, decreased penetrance of a pathogenic variant associated with an autosomal
dominant mitochondrial disorder, a single occurrence of an autosomal recessive or an X-linked
disorder in a family, or an acquired (non-genetic) cause.
Most adults with PEO or KSS represent simplex cases.
Many individuals with a childhood-onset encephalomyopathy represent simplex cases

which may be caused by the presence of biallelic pathogenic variants in a nuclear gene or a
mtDNA pathogenic variant.
See the GeneReviews Glossary for more discussion of mitochondrial, autosomal recessive,
autosomal dominant, and X-linked patterns of inheritance.
Approach when a mitochondrial disorder is suspected, but clinical findings do not suggest a
specific diagnosis. The difficulty arises when no pathogenic variant is identified (despite
suspicion of a specific disorder) or when the clinical abnormalities are complex and not easily
matched to those of more common mitochondrial disorders.
Clinical tests are used to support a diagnosis of mitochondrial disease [Kaufmann et al 2009].
Other Investigations to Establish the Extent of the Phenotype

When the clinical picture is nonspecific but highly suggestive of a mitochondrial disorder, the
clinician should start with measurement of plasma or CSF lactic acid concentration, ketone
bodies, plasma acylcarnitines, and urinary organic acids.
Plasma/CSF Lactate/pyruvate
Measurement of plasma lactate concentration is indicated in individuals with features of a

myopathy or CNS disease. Fasting blood lactate concentrations above 3 mm/L support a
diagnosis of mitochondrial disease.
Measurement of CSF lactate concentration is indicated in individuals with suspected CNS

disease. Fasting CSF lactate concentrations above 1.5 mm/L support a diagnosis of
mitochondrial disease.
Note: Normal plasma or CSF lactic acid concentration does not exclude the presence of a
mitochondrial disorder.
Magnetic resonance spectroscopy and exercise testing may also be of use to detect an elevated
lactate level in brain or muscle at rest, or a delay in the recovery of the ATP peak in muscle after
exercise.
Neuroimaging is indicated in individuals with suspected CNS disease. CT may show basal
ganglia calcification and/or diffuse atrophy. MRI may show focal atrophy of the cortex or
cerebellum, or high signal change on T2-weighted images, particularly in the occipital cortex
[Scaglia et al 2005]. There may also be evidence of a generalized leukoencephalopathy
[Barragán-Campos et al 2005]. Cerebellar atrophy is a prominent feature in children [Scaglia et
al 2005].
Neurophysiologic studies
Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy

or seizures. Encephalopathy may be associated with generalized slow wave activity on the
EEG. Generalized or focal spike and wave discharges may be seen in individuals with
seizures.
Peripheral neurophysiologic studies are indicated in individuals with limb weakness,

sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show
myopathic features. Nerve conduction velocity (NCV) may be normal or may show a
predominantly axonal sensorimotor polyneuropathy.
Magnetic resonance spectroscopy (MRS) and exercise testing (with measurement of blood
concentration of lactate) may be used to detect evidence of abnormal mitochondrial
function non-invasively.
Glucose. An elevated concentration of fasting blood glucose may indicate diabetes mellitus.
Cardiac. Both electrocardiography and echocardiography may indicate cardiac involvement

(cardiomyopathy or atrioventricular conduction defects).
Molecular Genetic Testing

Establishing a molecular genetic diagnosis has important implications for the counseling of
individuals with mitochondrial disease [Lieber et al 2013, Nesbitt et al 2013]. For example,
infantile cytochrome oxidase deficiency may be caused by biallelic pathogenic variants in the
nuclear genes SURF1 or SCO2 or by a maternally inherited single nucleotide variant of mtDNA
(e.g., m.8993T>G). CPEO may be caused by a de novo deletion (e.g., caused by a large deletion
of mtDNA) or maternally inherited (e.g., the mtDNA m.3243A>G pathogenic variant).
The ordering of molecular genetic tests and interpretation of results is complex and may require
the support of an experienced laboratory, clinical geneticist, and genetic counselor.
Molecular genetic testing may be carried out on genomic DNA extracted from blood (suspected
nuclear DNA pathogenic variants and some pathogenic mtDNA variants) or on genomic DNA
extracted from muscle (suspected pathogenic mtDNA variants).
Approaches to molecular genetic testing of a proband to consider are serial testing of single
genes, multi-gene panel testing (simultaneous testing of multiple genes), and genomic testing
(e.g., sequencing the mitochondrial genome; exome sequencing or genome sequencing to

identify a pathogenic variant in a nuclear gene).
Single-Gene and Multi-Gene Panel Testing
In contrast to genomic testing, serial testing of single genes and multi-gene panel testing rely on
the clinician developing a hypothesis about which specific gene or set of genes to test.
Hypotheses may be based on (1) mode of inheritance, (2) distinguishing clinical features, and/or
(3) other discriminating features.
Studies for pathogenic mtDNA variants are usually carried out on skeletal muscle DNA
because a pathogenic mtDNA variant may not be detected in DNA extracted from blood.
Long-range PCR or quantitative PCR analysis may reveal a pathogenic mtDNA

rearrangement. The deletion or duplication breakpoint may then be mapped by mtDNA
sequencing.
Targeted analysis for pathogenic variants featuring a panel of mitochondrial genes may be
performed.
If a recognized single nucleotide variant is not identified, the entire mitochondrial genome
may be sequenced.
Studies for nuclear gene pathogenic variants. For multi-gene panels:
The genes included and the methods used in multi-gene panels vary by laboratory and over
time.
The testing method used in some multi-gene panels may not detect mtDNA variants at low
levels of heteroplasmy in blood, or mtDNA deletions and, therefore, would not be useful if
a disorder (or disorders) caused by pathogenic mtDNA variants were suspected.
Genomic Testing
If single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an
individual with features of a mitochondrial disorder, genomic testing may be considered. Such
testing includes exome sequencing, genome sequencing, and mitochondrial sequencing.
Note: (1) False negative rates vary by genomic region; therefore, genomic testing may not be as
accurate as targeted single gene testing or multi-gene molecular genetic testing panels. (2) Most
laboratories confirm positive results using a second, well-established method. (3) Certain DNA
variants may not be detectible through genomic testing, such as large deletions or duplications
(>8-10 bp in length), triplet repeat expansions, and epigenetic alterations [Biesecker & Green
2014].
Exome sequencing has been shown to be very effective in defining the genetic basis of
mitochondrial disorders caused by mutation of nuclear genes [Taylor et al 2014]. To determine
the molecular basis of multiple respiratory chain complex deficiencies, Taylor et al [2014]
studied 53 individuals who met the following criteria:
Evidence of histochemical and/or biochemical diagnosis of mitochondrial disease in a

clinically affected tissue (skeletal muscle, liver, or heart) confirming decreased activities of
multiple respiratory chain complexes based on published criteria
Absence of large-scale mtDNA rearrangements, mtDNA depletion, and mtDNA single-

nucleotide variants, in persons in whom decreased levels of mtDNA were confirmed in
muscle (mtDNA depletion)
Exclusion of major nuclear gene rearrangements by comparative genomic hybridization

arrays in those with congenital structural abnormalities
Of the 53 probands, presumptive causal variants were identified in 28 (53%; 95%CI, 39%-67%)
and possible causal variants were identified in four (8%; 95%CI, 2%-18%). Together these
accounted for 32 probands (60% 95%CI, 46%-74%) and involved 18 different genes.
Other (Non-Molecular Genetic) Testing

In many individuals in whom molecular genetic testing does not yield or confirm a diagnosis,
further investigation of suspected mitochondrial disease can involve a range of different clinical
tests, including muscle biopsy for respiratory chain function.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the
nature, inheritance, and implications of genetic disorders to help them make informed medical
and personal decisions. The following section deals with genetic risk assessment and the use of
family history and genetic testing to clarify genetic status for family members. This section is not
meant to address all personal, cultural, or ethical issues that individuals may face or to
substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Mitochondrial disorders may be caused by mutation of a mtDNA gene or mutation of a nuclear
gene.
Mitochondrial DNA variants are transmitted by maternal inheritance (mitochondrial

inheritance) [Thorburn & Dahl 2001].
Nuclear gene variants may be inherited in an autosomal recessive, autosomal dominant, or

X-linked manner.
Risk to Family Members — Mitochondrial Inheritance

Parents of a proband
Single mtDNA deletions
Mitochondrial DNA deletions generally occur de novo and thus affect only one
family member.
When single mtDNA deletions are transmitted, inheritance is from the mother.
The predisposition to form multiple mtDNA deletions can be inherited as an

autosomal dominant or an autosomal recessive trait.
Mitochondrial DNA single-nucleotide variants and duplications
Mitochondrial DNA single-nucleotide variants and duplications may be transmitted

through the maternal line.
The father of a proband is not at risk of having the mtDNA pathogenic variant.
The mother of a proband (usually) has the mtDNA pathogenic variant and may or
may not have symptoms.
Sibs of a proband
The risk to the sibs depends on the genetic status of the mother: if the mother has the
mtDNA pathogenic variant, all sibs are at risk of inheriting it.
When a proband has a single mtDNA deletion, the current best estimate of the recurrence
risk to sibs is 1/24 [Chinnery et al 2004].
Offspring of a proband
Offspring of males with a mtDNA pathogenic variant will not inherit the variant.
All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the
pathogenic variant.
A female harboring a heteroplasmic mtDNA single nucleotide variant may transmit

a variable amount of mutated mtDNA to her offspring, resulting in considerable
clinical variability among sibs within the same nuclear family [Poulton & Turnbull
2000].
For the m.8993T>G, m.8993T>C, m.3243A>G, m.8344A>G, and m.11778G>A

mtDNA pathogenic variants, the risk of having clinically affected offspring appears
to be related to the percentage level of mutated mtDNA in the mother's blood
[Chinnery et al 1998, White et al 1999a, Chinnery et al 2001]. However, these data
were obtained retrospectively and should not be directly used for genetic counseling.
Other family members of a proband. The risk to other family members depends on the genetic
status of the proband's mother: if she has a mtDNA pathogenic variant, her sibs and mother are
also at risk.
Risk to Family Members — Autosomal Recessive Inheritance

The parents of an affected child are obligate heterozygotes and therefore each carry one
pathogenic variant.
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, the sibs of an affected individual have a 25% chance of inheriting both
pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant
and being a carrier, and a 25% chance of inheriting both normal alleles and being
unaffected.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. All offspring are obligate heterozygotes.
Risk to Family Members — Autosomal Dominant Inheritance
One parent of the proband may have the same pathogenic variant as the proband; that
parent may or may not have symptoms.
A proband may have the disorder as the result of a de novo pathogenic variant. The
proportion of cases caused by a de novo pathogenic variant is unknown.
Note: The family history may appear to be negative because of failure to recognize the disorder
in family members, early death of the parent before the onset of symptoms, or late onset of the
disease in the affected parent.
Sibs of a proband. The risk to the sibs depends on the genetic status of the parents: if one parent
has the same pathogenic variant, the risk to the sibs is 50%.
Offspring of a proband. Each offspring of a proband has a 50% chance of inheriting the
pathogenic variant.
Risk to Family Members — X-Linked Inheritance

The father of an affected male will not have the disease nor will he be a carrier of the
pathogenic variant.
Women who have an affected son and another affected male relative are obligate
heterozygotes.
Sibs of a proband. The risk to sibs depends on the carrier status of the mother:
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each
pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female
sibs who inherit the pathogenic variant will be carriers and will usually not be affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs
is low but greater than that of the general population because of the possibility of maternal
germline mosaicism.
Offspring of a proband. All the daughters of an affected male are carriers; none of his sons will
be affected.
Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible
future use. Because it is likely that testing methodology and our understanding of genes, allelic
variants, and diseases will improve in the future, consideration should be given to banking DNA
of affected individuals.
Prenatal Testing
Mutation of mitochondrial DNA (mtDNA). Prenatal molecular genetic testing and
interpretation for mtDNA disorders is difficult because of mtDNA heteroplasmy. The percentage
level of mutated mtDNA in a chorionic villus sampling (CVS) biopsy may not reflect the
percentage level of mutated mtDNA in other fetal tissues, and the percentage level may change
during development and throughout life [Hellebrekers et al 2012].
The interpretation of a CVS result is difficult for most heteroplasmic mtDNA pathogenic
variants. However, the variants m.8993T>G and m.8993T>C show a more even tissue
distribution and the percentage level of these two variants does not appear to change significantly
over time [White et al 1999b]. Successful prenatal molecular diagnosis has been carried out for
these two pathogenic variants [Harding et al 1992, White et al 1999a] using DNA extracted from
fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or CVS
(usually performed at ~10-12 weeks' gestation) [Hellebrekers et al 2012].
Mutation of nuclear DNA
Molecular genetic testing. If the pathogenic variant(s) have been identified in an affected
family member, prenatal testing for pregnancies at increased risk may be available from a
clinical laboratory that offers either testing of this gene or custom prenatal testing.
Biochemical genetic testing. Once the specific biochemical abnormality has been
identified in an affected family member, prenatal biochemical testing for pregnancies at
risk for respiratory chain complex defects is possible using biochemical testing of cultured
amniocytes obtained from amniocentesis usually performed at about 15 to 18 weeks'
gestation [Poulton & Turnbull 2000].
Preimplantation genetic diagnosis (PGD) may be an option for some families in which the
pathogenic variant(s) have been identified.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support
organizations and/or registries for the benefit of individuals with this disorder and their families.
GeneReviews is not responsible for the information provided by other organizations. For
information on selection criteria, click here.
National Library of Medicine Genetics Home Reference

Leber hereditary optic neuropathy

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Neuropathy, ataxia, and retinitis pigmentosa
United Mitochondrial Disease Foundation (UMDF)

8085 Saltsburg Road
Suite 201
Pittsburg PA 15239
Phone: 888-317-8633 (toll-free); 412-793-8077
Fax: 412-793-6477
Email: [email protected]
www.umdf.org
Australian Mitochondrial Disease Foundation (AMDF)

Suite 4, Level 6, 9-13 Young Street
Sydney
Australia
Phone: 1-300-977-180
Fax: 02-9999-3474
www.amdf.org.au
International Foundation for Optic Nerve Disease (IFOND)

PO Box 777
Cornwall NY 12518
Phone: 845-534-7250
Fax: 845-534-7250
www.ifond.org
Muscular Dystrophy Association - USA (MDA)

222 South Riverside Plaza
Suite 1500
Chicago IL 60606
Phone: 800-572-1717
www.mda.org
The Lily Foundation

31 Warren Park
Surrey CR6 9LD
United Kingdom
Phone: 07947 257247
Fax: 01883 623799
www.thelilyfoundation.org.uk
Mitochondrial Disease Registry and Tissue Bank

Massachusetts General Hospital
185 Cambridge Street
Simches Research Building 5-238
Boston MA 02114
Phone: 617-726-5718
Fax: 617-724-9620
RDCRN Patient Contact Registry: North American Mitochondrial Disease

Consortium
Patient Contact Registry
Management
Treatment of Manifestations
The management of mitochondrial disease is largely supportive [Chinnery & Turnbull 2001].
The clinician must have a thorough knowledge of the potential complications of mitochondrial
disorders to prevent unnecessary morbidity and mortality.
Management issues may include early diagnosis and treatment of diabetes mellitus, cardiac
pacing, ptosis correction, intraocular lens replacement for cataracts, and cochlear implantation
for sensorineural hearing loss.
A variety of vitamins and co-factors have been used in individuals with mitochondrial disorders,
although a Cochrane systematic review has shown that evidence supporting their use is lacking
[Chinnery et al 2006].
Food supplements such as ubiquinone (coenzyme Q10, ubidecarenone) are generally well
tolerated and some individuals report a subjective benefit on treatment.
Individuals with complex I and/or complex II deficiency may benefit from oral
administration of riboflavin.
The role of exercise therapy in mitochondrial myopathy is currently being evaluated [Taivassalo
et al 2001, Taivassalo et al 2006, Murphy et al 2008].
Coenzyme Q10 is specifically indicated in persons with defects of CoQ10 biosynthesis.
Idebenone shows promise for the treatment of Leber hereditary optic neuropathy.
Some secondary causes of mitochondrial dysfunction, such as ethylmalonic aciduria, may have
specific treatments [Tiranti et al 2009].
Those with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) may benefit from

hematopoietic stem cell transplantation.
Prevention Strategies Under Investigation

The possibility of nuclear transfer as a means of preventing transmission of pathogenic mtDNA
variants is currently being explored [Craven et al 2010].
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Chapter Notes
Revision History
14 August 2014 (me) Comprehensive update posted live
16 September 2010 (me) Comprehensive update posted live
18 December 2003 (me) Comprehensive update posted to live Web site
8 June 2000 (tk, pb) Overview posted to live Web site
20 April 2000 (eh) Original submission
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4/30/2018 Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf

Patrick F Chinnery, BMedSci, MBBS, PhD, FRCPath, FRCP, FMedSci

Initial Posting: June 8, 2000; Last Update: August 14, 2014.

Diagnosis/testing. In some individuals, the clinical picture is characteristic of a specific

Genetic counseling. Mitochondrial disorders may be caused by defects of nuclear DNA or

Management. Treatment of manifestations: The management of mitochondrial disease is largely

Figure 1 illustrates the structure of the human mitochondrial genome.

The human mitochondrial genome

MT-ND1 through MT-ND6 and MT-ND4L encode seven subunits of complex I.

Cyt b is the only mtDNA-encoded complex III subunit.

OH and OL are the origins of heavy- and light-strand mtDNA replication.

Other important mitochondrial mechanisms controlled by nuclear genes include:

Disorders of mtDNA maintenance (mtDNA depletion or secondary pathogenic mtDNA

Disorders of mitochondrial protein synthesis;

Disorders of coenzyme Q10 biosynthesis;

Disorders of the respiratory chain complexes or their assembly.

Secondary mitochondrial dysfunction in human diseases. Mitochondrial dysfunction is also

Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia,

Disorder Primary Features Additional Features

Disorder Primary Features Additional Features

CPEO = chronic progressive external ophthalmoplegia

SCAE = spinocerebellar ataxia with epilepsy

White matter abnormalities. See Scarpelli et al [2013], Morató et al [2014], and Wu et al

Adult point prevalence 5.71

Mitochondrial disease (adults and

The classification of mitochondrial disease is difficult. Although a purely clinical classification

It is currently not possible to identify the pathogenic variant in a significant number of

Mutation of Nuclear DNA

Mutation of Nuclear DNA

1. See Nuclear Gene-Encoded Leigh Syndrome Overview.

Mutation of Mitochondrial DNA

Mutation of Mitochondrial DNA

Establishing the Diagnosis of a Mitochondrial Disorder

Physical Examination and Neurologic Evaluation

When the presentation is classic for a maternally (mitochondrial) inherited mitochondrial

Most adults with PEO or KSS represent simplex cases.

Many individuals with a childhood-onset encephalomyopathy represent simplex cases

Other Investigations to Establish the Extent of the Phenotype

Measurement of plasma lactate concentration is indicated in individuals with features of a

Measurement of CSF lactate concentration is indicated in individuals with suspected CNS

Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy

Peripheral neurophysiologic studies are indicated in individuals with limb weakness,

Cardiac. Both electrocardiography and echocardiography may indicate cardiac involvement

Molecular Genetic Testing

(e.g., sequencing the mitochondrial genome; exome sequencing or genome sequencing to

Single-Gene and Multi-Gene Panel Testing

Long-range PCR or quantitative PCR analysis may reveal a pathogenic mtDNA

Studies for nuclear gene pathogenic variants. For multi-gene panels:

Evidence of histochemical and/or biochemical diagnosis of mitochondrial disease in a

Absence of large-scale mtDNA rearrangements, mtDNA depletion, and mtDNA single-

Exclusion of major nuclear gene rearrangements by comparative genomic hybridization

Other (Non-Molecular Genetic) Testing

Mitochondrial DNA variants are transmitted by maternal inheritance (mitochondrial

Nuclear gene variants may be inherited in an autosomal recessive, autosomal dominant, or

Risk to Family Members — Mitochondrial Inheritance

Single mtDNA deletions

The predisposition to form multiple mtDNA deletions can be inherited as an

Mitochondrial DNA single-nucleotide variants and duplications