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Mitochondrial Disorders Overview

Synonyms: Mitochondrial Encephalomyopathies, Mitochondrial Myopathies, Oxidative Phosphorylation Disorders, Respiratory Chain Disorders
, PhD, FRCPath, FRCP, FMedSci
Institute of Genetic Medicine
Wellcome Trust Centre for Mitochondrial Research
Newcastle University
Newcastle upon Tyne, United Kingdom

Initial Posting: ; Last Update: August 14, 2014.

Summary

Disease 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 mtDNA mutation 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 mutation. 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 exome or exome sequencing to identify mutation of 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.

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 mutant 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

Figure

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 mutant 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 mutant 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 mutant 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 mtDNA mutations);
  • 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

DisorderPrimary FeaturesAdditional Features
Alpers-Huttenlocher syndrome
  • Hypotonia
  • Seizures
  • Liver failure
  • Renal tubulopathy
Ataxia neuropathy syndromes (ANS): Including MIRAS, SCAE, SANDO, MEMSA
  • SANDO
  • Other ANS: Sensory axonal neuropathy w/variable sensory & cerebellar ataxia
  • Epilepsy
  • Dysarthria, and/or
  • Myopathy
CPEO
  • External ophthalmoplegia
  • Bilateral ptosis
  • Mild proximal myopathy
KSS
  • PEO onset at age <20 years
  • Pigmentary retinopathy
  • One of the following: CSF protein >1g/L, cerebellar ataxia, heart block
  • Bilateral deafness
  • Myopathy
  • Dysphagia
  • Diabetes mellitus
  • Hypoparathyroidism
  • Dementia
Pearson syndrome
  • Sideroblastic anemia of childhood
  • Pancytopenia
  • Exocrine pancreatic failure
  • Renal tubular defects
Infantile myopathy and lactic acidosis (fatal & non-fatal forms)
  • Hypotonia in 1st year of life
  • Feeding & respiratory difficulties
  • Fatal form may be associated with a cardiomyopathy and/or the Toni-Fanconi-Debre syndrome
Leigh syndrome
  • Subacute relapsing encephalopathy
  • Cerebellar and brain stem signs
  • Infantile onset
  • Basal ganglia lucencies
  • Maternal history of neurologic disease or Leigh syndrome
NARP
  • Late-childhood or adult-onset peripheral neuropathy
  • Ataxia
  • Pigmentary retinopathy
  • Basal ganglia lucencies
  • Abnormal electroretinogram
  • Sensorimotor neuropathy
MELAS
  • Stroke-like episodes at age <40 years
  • Seizures and/or dementia
  • Ragged-red fibers and/or lactic acidosis
  • Diabetes mellitus
  • Cardiomyopathy (initially hypertrophic; later dilated)
  • Bilateral deafness
  • Pigmentary retinopathy
  • Cerebellar ataxia
MEMSA 1
  • Myopathy
  • Seizures
  • Cerebellar ataxia
  • Dementia
  • Peripheral neuropathy
  • Spasticity
MERRF
  • Myoclonus
  • Seizures
  • Cerebellar ataxia
  • Myopathy
  • Dementia
  • Optic atrophy
  • Bilateral deafness
  • Peripheral neuropathy
  • Spasticity
  • Multiple lipomata
LHON
  • Subacute painless bilateral visual failure
  • Males:females ~4:1
  • Median age of onset 24 years
  • Dystonia
  • Cardiac pre-excitation syndromes

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. SeeScarpelli et al [2013], Morató et al [2014], and Wu et al [2014].

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 to be 5.7:100,000 over age 14 years.

Table 2. Epidemiology of Mitochondrial Disease

Study PopulationMutation or DiseaseDisease Prevalence / 100,000
(95% C.I.) 1
Northern England 2
  • Point prevalence August 1997
  • Population size = 2,122,290m
All mtDNA deletions1.33 3
(0.76-1.89)
All mtDNA single nucleotide variants5.24 3
(4.12-6.37)
m.11778G>A, m.3460G>A (LHON)3.29 3
(2.39-4.18)
m.3243A>G0.95 3
(0.47-1.43)
m.8344A>G0.25 3
(0.01-0.5)
All mtDNA mutations6.57 4
(5.30-7.83)
Northern Finland 5
  • Adult point prevalence
  • Population size = 245,201
m.3243A>G5.71
(4.53-6.89)
Western Sweden 6
  • Children age <16 = 385,616
Childhood mitochondrial encephalomyopathies4.7 7
(2.8-7.6)
Victoria, Australia 8
  • Birth prevalence: 1,710,000 births
Childhood respiratory chain disease4.7 9
(3.2-5.0)
SummaryMitochondrial disease (adults and children)~11.5

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 (www​.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 allelic 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: Nuclear DNA Mutation

Nuclear DNA Mutation
Nuclear genetic disorders of the mitochondrial respiratory chain (mutated genes encoding structural subunits)
  • Leigh syndrome with complex I deficiency (NDUFS1, NDUFS4, NDUFS7, NDUFS8, NDUFV1)
  • Leigh syndrome with complex II deficiency (SDHA)
  • Leukodystrophy with complex II deficiency (SDHAF1)
  • Cardiomyopathy and encephalopathy (complex I deficiency) (NDUFS2)
  • Optic atrophy and ataxia (complex II deficiency) (SDHA)
  • Hypokalemia and lactic acidosis (complex III deficiency) (UQCRB)
Nuclear genetic disorders of the mitochondrial respiratory chain (mutated genes encoding assembly factors)
  • Leigh syndrome (SURF1, LRPPRC)
  • Hepatopathy and ketoacidosis (SCO1)
  • Cardiomyopathy and encephalopathy (SCO2)
  • Leukodystrophy and renal tubulopathy (COX10)
  • Hypertrophic cardiomyopathy (COX15)
  • Encephalopathy, liver failure, renal tubulopathy (with complex III deficiency) (BCS1L)
  • Encephalopathy (with complex V deficiency) (ATPAF2)
Nuclear genetic disorders of the mitochondrial respiratory chain (mutated genes encoding translation factors)
  • Leigh syndrome, liver failure, and lactic acidosis (GFM1)
  • Lactic acidosis, developmental failure, and dysmorphism (MRPS16)
  • Myopathy and sideroblastic anemia (PUS1)
  • Leukodystrophy and polymicrogyria (TUFM)
  • Leigh syndrome and optic atrophy with COX deficiency (TACO1)
Nuclear genetic disorders associated with multiple mtDNA deletions or mtDNA depletion
Other disorders
  • Coenzyme Q10 deficiency (COQ2, COQ9, CABC1, ETFDH)
  • Cardiomyopathy and lactic acidosis (mitochondrial phosphate carrier deficiency) (SLC25A3)

1. Includes MIRAS, SCAE, SANDO, MEMSA

Table 3b. Genetic Classification of Human Mitochondrial Disorders: Mitochondrial DNA Mutation

Mitochondrial DNA Mutations
Rearrangements (deletions and duplications)
Single nucleotide variants 1
tRNA genes 1
  • 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)
  • 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)
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 (www​.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.

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 Illustrated 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 allelic 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 (see Organic Acidemias Overview).

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 [Barragan-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, medical geneticist, and genetic counselor.

Molecular genetic testing may be carried out on genomic DNA extracted from blood (suspected nuclear DNA mutations and some mtDNA mutations) or on genomic DNA extracted from muscle (suspected mtDNA mutations).

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 entire mitochondrial genome; whole-exome sequencing or whole-genome sequencing to identify mutation of 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 mtDNA mutations are usually carried out on skeletal muscle DNA because a pathogenic mtDNA variant may not be detected in DNA extracted from blood.

Studies for nuclear gene mutations. 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 mtDNA mutations 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 whole-exome sequencing, whole-genome sequencing, and whole 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 point mutations, 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.

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 mutant 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 mutant 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 siblings and mother are also at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • 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

Parents of a proband

  • 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 de novo mutation. The proportion of cases caused by de novo mutation 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

Parents of a proband

  • 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

Mitochondrial DNA (mtDNA) mutations. Prenatal molecular genetic testing and interpretation for mtDNA disorders is difficult because of mtDNA heteroplasmy. The percentage level of mutant mtDNA in a chorionic villus sampling (CVS) biopsy may not reflect the percentage level of mutant 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].

Nuclear DNA mutations

  • 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.

  • Children's European Mitochondrial Disease Network
    Mayfield House
    30 Heber Walk
    Northwich CW9 5JB
    United Kingdom
    Phone: +44(0) 01606 43946 (Helpline)
    Email: info@cmdn.org.uk
  • National Library of Medicine Genetics Home Reference
  • National Library of Medicine Genetics Home Reference
  • National Library of Medicine Genetics Home Reference
  • 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: info@umdf.org
  • International Foundation for Optic Nerve Disease (IFOND)
    PO Box 777
    Cornwall NY 12518
    Phone: 845-534-7250
    Fax: 845-534-7250
    Email: ifond@aol.com
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • 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
    Email: nslate@partners.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

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 mtDNA mutations is currently being explored [Craven et al 2010].

References

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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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