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Mitochondrial DNA Deletion Syndromes

Synonym: mtDNA Deletion Syndromes

, MD and , MD.

Author Information

Initial Posting: ; Last Update: January 31, 2019.

Estimated reading time: 26 minutes

Summary

Clinical characteristics.

Mitochondrial DNA (mtDNA) deletion syndromes predominantly comprise three overlapping phenotypes that are usually simplex (i.e., a single occurrence in a family), but rarely may be observed in different members of the same family or may evolve from one clinical syndrome to another in a given individual over time. The three classic phenotypes caused by mtDNA deletions are Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO).

  • KSS is a progressive multisystem disorder defined by onset before age 20 years, pigmentary retinopathy, and PEO; additional features include cerebellar ataxia, impaired intellect (intellectual disability, dementia, or both), sensorineural hearing loss, ptosis, oropharyngeal and esophageal dysfunction, exercise intolerance, muscle weakness, cardiac conduction block, and endocrinopathy.
  • Pearson syndrome is characterized by sideroblastic anemia and exocrine pancreas dysfunction and may be fatal in infancy without appropriate hematologic management.
  • PEO is characterized by ptosis, impaired eye movements due to paralysis of the extraocular muscles (ophthalmoplegia), oropharyngeal weakness, and variably severe proximal limb weakness with exercise intolerance.

Rarely, a mtDNA deletion can manifest as Leigh syndrome.

Diagnosis/testing.

The diagnosis of mtDNA deletion syndrome is confirmed in a proband with characteristic clinical features by identification on molecular genetic testing of a mtDNA single large-scale deletion ranging in size from 1.1 to 10 kb. Deletions are detectable in affected children in blood and urine; skeletal muscle biopsy may be required in affected adults.

Management.

Treatment of manifestations: Cochlear implants and hearing aids for sensorineural loss; eye ointment, eyelid slings, and/or ptosis repair for severe ptosis; eyeglass prisms for diplopia; dilation of the upper esophageal sphincter to alleviate cricopharyngeal achalasia; physical and occupational therapy for myopathy; prophylactic placement of cardiac pacemakers in individuals with cardiac conduction blocks; hormone replacement for endocrinopathies; folinic acid supplementation in individuals with KSS with low CSF 5-methyltetrahydrofolate; replacement of pancreatic enzymes in Pearson and KSS; transfusion therapy for individuals with Pearson syndrome with sideroblastic anemia; consideration of "mitochondrial supplement cocktails" including coenzyme Q10 and antioxidants; treatment of depression; ventilatory support for respiratory abnormalities that may occur in Leigh syndrome; consider gastrostomy tube placement if failure to thrive, choking, or aspiration risk is present.

Prevention of secondary complications: Antioxidants may ameliorate damage from reactive oxygen species; percutaneous endoscopic gastrostomy may improve nutritional intake and prevent aspiration pneumonia in individuals with severe dysphagia.

Surveillance: ECG and echocardiogram every six to 12 months and yearly audiometry, ophthalmologic, and endocrine evaluations.

Agents/circumstances to avoid: Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolide, valproic acid, and nucleoside reverse transcriptase inhibitors. Volatile anesthetic hypersensitivity may occur. Avoid prolonged propofol (>30-60 minutes).

Genetic counseling.

Mitochondrial DNA deletion syndromes are caused by a single large-scale deletion in the mtDNA genome. A mtDNA deletion may occur de novo or be transmitted through maternal (oocyte) inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband with a mtDNA deletion syndrome is usually unaffected and does not have mtDNA deletions in her somatic tissue; however, she may potentially harbor the mtDNA deletion in a population of her oocytes. If the mother of a proband is clinically unaffected, the risk to the sibs of a proband is estimated to be 1%-4% because of the possibility of maternal germline mosaicism. Offspring of a female proband have up to a 4% risk of being affected. Offspring of a male proband with a mtDNA pathogenic variant are not at risk of inheriting the variant or manifesting the condition. Prenatal testing for pregnancies at increased risk is possible; however, prenatal test results cannot reliably predict phenotype.

GeneReview Scope

Mitochondrial DNA Deletion Syndromes: Included Phenotypes 1
  • Kearns-Sayre syndrome (KSS)
  • Pearson syndrome
  • Chronic progressive external ophthalmoplegia (PEO)
  • Leigh syndrome

For additional terms, synonyms, and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

A diagnostic algorithm has been proposed by Gorman et al [2016].

Suggestive Findings

Mitochondrial DNA (mtDNA) deletion syndromes should be suspected in individuals with clinical features present in any of the following overlapping phenotypes, although an affected person may not fit into one of the defined classic phenotypes (i.e., rather than a typical defined phenotype, the clinical variability seen between Pearson and Kearns-Sayre syndrome is a spectrum).

Kearns-Sayre Syndrome (KSS)

Clinical features. Onset before age 20 years with classic triad of:

  • Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy)
  • Progressive external ophthalmoplegia (PEO) including ptosis
  • Cardiac conduction abnormality including heart block

Additional clinical features

  • Endocrinopathies: diabetes mellitus, hypoparathyroidism, pancreatic exocrine failure, hypothyroidism, adrenal insufficiency
  • Myopathy: muscle weakness, exercise intolerance, and/or fatigue
  • Dementia (cognitive decline)
  • Cerebellar ataxia
  • Sensorineural hearing loss
  • Short stature
  • Failure to thrive, feeding intolerance, and dysphagia or achalasia (bulbar weakness)
  • Renal impairment

Laboratory features

  • Cerebrospinal fluid (CSF) protein concentration exceeding 100 mg/dL (>1 g/L)
  • Elevated lactate and pyruvate in blood and CSF. Commonly elevated at rest and increased excessively in blood after moderate activity.
  • Muscle biopsy typically showing ragged-red fibers (RRF) with modified Gomori trichrome stain and hyperactive fibers with succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with histochemical reaction for cytochrome c oxidase (COX) (e.g., combined COX-, SDH+ fibers).
  • Biochemical studies of electron transport chain enzymes in muscle tissue usually showing decreased activities of complexes containing mtDNA-encoded subunits (I, III, IV), especially when enzyme values are corrected for the activity of citrate synthase that is used as a marker of mitochondrial content. However, depending on the heteroplasmy load of mtDNA deletions, biochemical studies may be unrevealing.

Electrophysiologic and imaging features

  • Electrocardiogram. Cardiac conduction block
  • Echocardiogram. Cardiomyopathy
  • Electromyogram and nerve conduction studies. Consistent with myopathy, but neuropathy may coexist
  • Brain MRI. May show leukoencephalopathy, often associated with cerebral or cerebellar atrophy and/or basal ganglia and brain stem lesions (Leigh syndrome pattern)

Pearson Syndrome

  • Sideroblastic anemia (ringed sideroblasts, which can be detected by iron stains of the bone marrow), typically transfusion-dependent until resolution in early childhood
  • Exocrine pancreas dysfunction (increased fecal fat, identified qualitatively by Sudan staining of feces or quantitatively by measuring fecal fat)
  • May be fatal in infancy

Chronic Progressive External Ophthalmoplegia (CPEO)

(Note: CPEO-plus presentations in young adults may be better classified as KSS spectrum; see Clinical Description and Nomenclature.)

  • Ptosis
  • Extraocular muscle paralysis (ophthalmoplegia)
  • Proximal limb weakness

Leigh Syndrome

  • Psychomotor regression, especially with physiologic stressors or intercurrent illnesses
  • Brain MRI showing characteristic T2-weighted hyperintense lesions in basal ganglia and midbrain/brain stem that are often bilaterally symmetric but may fluctuate over time
  • Elevated lactate in blood and/or CSF

Establishing the Diagnosis

The diagnosis of a mitochondrial DNA (mtDNA) deletion syndrome is confirmed in a proband with the above Suggestive Findings by identification on molecular genetic testing of a mtDNA single large-scale deletion ranging in size from 1.1 to 10 kb (see Table 1). Establishing a molecular diagnosis for primary mitochondrial disease is important for prognosis and genetic counseling [Lieber et al 2013, Nesbitt et al 2013].

Molecular genetic testing approaches can include deletion/duplication analysis of the mtDNA genome, use of a multigene panel, and comprehensive genomic testing.

Deletion/duplication analysis of the mtDNA genome. The occurrence of mtDNA heteroplasmy may result in variable tissue distribution of deleted mtDNA molecules. Since mtDNA deletions may be undetectable in blood, skeletal muscle biopsy may be necessary to identify a mtDNA deletion. However, with improved molecular methodologies, a single, large-scale mtDNA deletion can be found in blood and/or urine in all reported affected children, making muscle biopsy unnecessary to confirm the diagnosis in this age group [Broomfield et al 2015].

  • Sequencing of long-range PCR products or quantitative PCR analysis may reveal a pathogenic mtDNA deletion/duplication. The deletion/duplication breakpoint may then be mapped by mtDNA sequencing.
  • Next-generation sequencing can quantify the presence of one or more mtDNA deletions or duplications together with their exact breakpoints.
  • Quantitative PCR methods, such as digital droplet PCR analysis, can quantify the mtDNA deletion heteroplasmy level.

Note: Southern blot analysis was historically used for mtDNA deletion detection, but is not as sensitive as next-generation sequencing in detecting low heteroplasmy levels of mtDNA deletions, and may fail to distinguish single from multiple mtDNA deletions in the same genomic region.

Kearns-Sayre syndrome (KSS)

  • Mitochondrial DNA deletions are usually present in all tissues of individuals with KSS, and can be identified in blood leukocytes, buccal sample, or urine sediment. However, muscle biopsy may be necessary to establish the diagnosis if testing in blood leukocytes is negative, especially in older individuals.
  • Large-scale duplications of mtDNA may coexist with deletions in some individuals with KSS [Poulton et al 1989, Poulton et al 1993]. The frequency of mtDNA duplications occurring with mtDNA deletions in KSS is not known.

Pearson syndrome

  • Mitochondrial DNA deletions are usually more abundant in blood leukocytes than in other tissues.
  • Mitochondrial DNA deletions can be reliably identified in leukocyte DNA in individuals with Pearson syndrome.

Progressive external ophthalmoplegia (PEO)

  • Mitochondrial DNA deletions are confined to skeletal muscle.
  • The molecular diagnosis of PEO requires molecular analysis for a mtDNA deletion in a muscle tissue specimen, obtained by open muscle biopsy or by percutaneous needle muscle biopsy.

Leigh syndrome. Mitochondrial DNA deletions are detected in post-mitotic tissues such as muscle, but may be detected in blood leukocytes, buccal sample, or urine sediment.

A multigene nuclear panel for mitochondrial disease genes that includes combined deletion/duplication analysis of the mitochondrial genome (see Differential Diagnosis) may be considered. Note: (1) Genes included in panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing (when available) including exome sequencing, RNA sequencing, and/or genome sequencing may be considered, alone or together with mtDNA genome sequencing. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). Exome sequencing may be preferred as it enables simultaneous detection of all known mitochondrial and non-mitochondrial diseases, including the presence of more than one genetic disease affecting a given individual.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Mitochondrial DNA Deletion Syndromes

Test MethodPathogenic Variants DetectedEstimated Proportion of Probands with a Pathogenic Variant 1 Detectable by This Method Based on Clinical Phenotype
KSSPEOLeigh syndrome
Deletion/duplication analysis of mtDNA 2Variable single mtDNA deletions 3100% 4, 5100% 6, 7<5% 8
1.

See Molecular Genetics for information on allelic variants detected in mtDNA.

2.

Testing that identifies deletions/duplications not readily detectable by sequence analysis. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and Southern blotting, which is the technique traditionally used. Note: The mtDNA has homology with regions of the nuclear genome; therefore, assays that depend on hybridization must be approached with caution .

3.

Deletions ranging in size from 1.1 to 10 kb. Duplications rarely occur with deletions, but may occur alone.

4.

More than 150 different mtDNA deletions have been associated with KSS. A deletion of 4,977 bp known as m.8470_13446del4977 is the most common deletion [Schon 2003].

5.

A diagnosis of KSS requires detection of mtDNA deletion.

6.

Numerous pathogenic variants in either mtDNA or nuclear genes also cause PEO that is often associated with other clinical manifestations. However, identification of multiple (small- or large-scale) mtDNA deletions suggests an underlying nuclear gene etiology.

7.

A diagnosis of PEO requires the detection of mtDNA deletion in muscle.

8.

Large-scale mtDNA deletions are one known cause of Leigh syndrome [Rahman et al 1996]. Leigh syndrome has more than 75 monogenic causes, including pathogenic variants in nuclear and mitochondrial genes [Lake et al 2016].

Clinical Characteristics

Clinical Description

Mitochondrial DNA (mtDNA) deletion syndromes predominantly comprise three overlapping phenotypes that are usually simplex (i.e., a single occurrence in a family), but rarely may be observed in different members of the same family or may evolve from one clinical syndrome to another in a given individual over time. The three classic phenotypes caused by mtDNA deletions are Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO). Rarely, Leigh syndrome can be a manifestation of a mtDNA deletion.

"KSS spectrum" has been proposed as a phenotypic category that includes classic KSS and PEO with multisystem involvement. A retrospective analysis of an Italian cohort of 253 individuals with a single mtDNA deletion showed 6.6% had classic KSS, 31.6% met criteria for KSS spectrum, 64.5% had PEO, and 2.6% had Pearson syndrome. Likewise, in a retrospective review of the natural history of 34 children with a single large-scale mtDNA deletion (SLSMD) in the United Kingdom, the most common initial presentation was isolated ptosis (47%). 10/34 had KSS, 3/34 had PEO, 7/34 had PEO-plus ("KSS spectrum"), and 11/34 had Pearson syndrome. Three individuals did not conform to a specific mitochondrial phenotype [Broomfield et al 2015].

Kearns-Sayre Syndrome (KSS)

KSS is a multisystem disorder defined by a clinical triad consisting of onset before age 20 years, pigmentary retinopathy (sometimes referred to as "retinitis pigmentosa"), and progressive external ophthalmoplegia (PEO), plus at least one of the following: cardiac conduction defects leading to complete heart block, cerebellar ataxia, and/or elevated CSF protein. KSS predominantly affects the central nervous system, skeletal muscle, and heart. Onset is usually in childhood, with ptosis, ophthalmoplegia, or both. Exercise intolerance and impaired night vision (nyctalopia) may be early symptoms. Dysphagia caused by oropharyngeal weakness and/or incomplete opening of the upper esophageal sphincter (cricopharyngeal achalasia) is common. KSS usually progresses to death in young adulthood.

Central nervous system involvement manifests as cerebellar ataxia, impaired intellect (intellectual disability, dementia, or both), and sensorineural hearing loss. Compared to other mitochondrial encephalomyopathies (e.g., MELAS, MERRF, and NARP), KSS is notable for the extreme rarity of epilepsy. Metabolic strokes are also rare, although the Leigh syndrome overlap phenotype may occur. In a recent retrospective analysis of metabolic stroke, one individual had a SLSMD and received intravenous arginine therapy for non-focal (but worsening over baseline) ophthalmoplegia and ataxia together with new onset of atonic episodes. After intravenous arginine administration, partial improvement was seen in atonic episodes. MRI revealed bilateral symmetric basal ganglia and white matter lesions consistent with Leigh syndrome [Ganetzky & Falk 2018]. Brain MRI may yield findings of a leukoencephalopathy, Leigh syndrome, and/or cerebral and cerebellar atrophy [Friedman et al 2010, Alves et al 2018]. A secondary cerebral folate deficiency has been reported in KSS, where supplementation with folinic acid can be beneficial [Quijada-Fraile et al 2014] and may reverse white matter abnormalities seen on imaging with corresponding subjective improvement in coordination.

Skeletal muscle involvement manifests as PEO including ptosis, oropharyngeal and esophageal dysfunction, exercise intolerance, fatigue, and limb muscle weakness (proximal > distal). The defect of extraocular movement is usually symmetric but may cause blurred or double vision. Ptosis is usually asymmetric and exacerbated by fatigue.

Heart involvement is most commonly characterized by conduction block, which can be progressive and lead to complete heart block. Cardiomyopathy, less commonly than cardiac conduction block, has been reported in several individuals. Cardiac MRI is an emerging tool used to detect subclinical cardiac involvement [Kabunga et al 2015].

Endocrinopathies are common in KSS and include diabetes mellitus, exocrine pancreatic enzyme deficiencies, hypoparathyroidism, growth hormone deficiency, adrenal insufficiency, and irregular menses. Short stature may be the result of growth hormone deficiency and/or failure to thrive. Individuals may present with extreme hypocalcemia and tetany due to hypoparathyroidism [Katsanos et al 2001]. Diabetes mellitus may be caused by both insulin deficiency and insulin resistance, and is associated with higher hemoglobin A1c, lower BMI, lower rates of diabetic ketoacidosis, higher associated neuropathy and nephropathy rates, and less diabetic ophthalmologic involvement.

Renal tubular acidosis occurs in individuals with KSS and may be the presenting feature [Eviatar et al 1990]. The kidney is the most frequently affected organ over the course of disease, with tubular or glomerular dysfunction occurring in 85% (17/20) [Broomfield et al 2015]. Impaired renal function can be determined by decreased glomerular filtration rate or abnormal elevation of urinary tubulopathy markers such as retinol binding protein [Bernard et al 1987] or N-acetyl-3-glucosaminidase [Vaidya et al 2008] – potentially useful screening biomarkers in presymptomatic individuals [Herget-Rosenthal et al 2004].

Pigmentary retinopathy of KSS affects low-light vision more prominently than visual acuity, leading affected individuals to report impaired night vision (nyctalopia). Funduscopy reveals an atypical "salt and pepper" retinopathy. Electroretinogram often reveals rod-cone retinal dystrophy. Visual field testing reveals normal visual fields. Peripheral vision may be compromised by ptosis. Vision generally deteriorates insidiously, making age at onset difficult to discern (see Table 2).

Table 2.

Signs and Symptoms in 86 Individuals with Kearns-Sayre Syndrome

Sign or SymptomPresent/EvaluatedPercentage
Onset age <20 yrs86/86100%
Pigmentary retinopathy86/86100%
PEO86/86100%
Cerebellar syndrome53/6384%
Limb weakness61/6594%
Sensorineural hearing loss33/3497%
Impaired intellect25/2986%
Diabetes mellitus11/8613%
Seizures2/862%

Pearson Syndrome

Pearson syndrome is a mtDNA deletion syndrome that manifests clinically with bone marrow failure, severe transfusion-dependent sideroblastic anemia, and variable exocrine pancreatic insufficiency. Pearson syndrome features are variable and progressive. Anemia typically appears in the first year of life and may be accompanied by pancytopenia and multisystem involvement including failure to thrive, hypotonia, and metabolic derangements including lactic acidosis. Additional features may include hydrops fetalis, hepatic involvement with elevated transaminases and steatosis, microcephaly, renal Fanconi syndrome, endocrinopathies (growth hormone deficiency, hypothyroidism, hypoparathyroidism, diabetes mellitus, and adrenal insufficiency), splenic atrophy, impaired cardiac function, refractory diarrhea, and acute metabolic decompensations during intercurrent illness. Death may occur in early infancy or childhood due to metabolic decompensation, liver failure, or sepsis due to neutropenia. Survival and spontaneous recovery from bone marrow dysfunction after several years is possible, with a transition to clinical manifestations of KSS. In an Italian cohort of 11 individuals with Pearson syndrome, 64% developed neurologic sequelae and KSS [Manea et al 2009, Morel et al 2009, Williams et al 2012, Crippa et al 2015, Farruggia et al 2016].

Sideroblastic anemia is defined by the presence of anemia and ringed sideroblasts in the bone marrow. Ringed sideroblasts are normoblasts (precursors to mature red blood cells) with excessive deposits of iron in mitochondria and are detected by iron stains of bone marrow. The original report of Pearson syndrome included severe-onset transfusion-dependent macrocytic, sideroblastic anemia with a variable degree of neutropenia and thrombocytopenia (pancytopenia), normocellular bone marrow (although hypocellularity may occur), striking vacuolization of the hematopoietic progenitor cells, hemosiderosis, and ringed sideroblasts [Pearson et al 1979].

Exocrine pancreatic dysfunction due to pancreatic fibrosis is manifest clinically by failure to thrive, malabsorption, chronic diarrhea, and excessive fat excretion in the stools (steatorrhea), which can be documented qualitatively by Sudan staining of the feces or quantitatively by measuring fecal fat. The gold standard is the secretin stimulation test, which requires placing a catheter in the duodenum and is technically difficult to perform in infants. Exocrine pancreatic dysfunction is a variable feature that is not seen in up to 73% of individuals with Pearson syndrome [Farruggia et al 2016].

Chronic Progressive External Ophthalmoplegia (PEO)

CPEO is characterized by ptosis and extraocular muscle paralysis (ophthalmoplegia) that is progressive over time. CPEO, or CPEO-plus, variably also includes severe oropharyngeal and proximal limb weakness. The disorder is compatible with a normal life span.

Leigh Syndrome

Leigh syndrome typically begins in infancy and is characterized by psychomotor regression or delay with disease manifestations involving the brain stem, basal ganglia, or both.

Genotype-Phenotype Correlations

In some reported cohorts, disease progression correlates with mtDNA heteroplasmy levels as well as mtDNA deletion size and location [Grady et al 2014]. Several reports in the literature have attempted to predict disease severity, most recently in a group of 87 individuals with SLSMD in the Newcastle (UK) mitochondrial disease cohort, of whom nine had classic KSS and 54 had CPEO or "CPEO-plus myopathy." A meta-analysis of this and prior published cohorts compared the degree of COX-negative fibers on muscle biopsy (as a marker of biochemical severity), age of clinical disease onset, and disease burden (as measured by the Newcastle Mitochondrial Disease Adult Scale[NMDAS]) with the mtDNA deletion location, size, and heteroplasmy level. In both their own cohort and the larger meta-analysis, age of disease onset directly correlated with deletion size, location (e.g., including complex III and IV subunit genes MT-CYB and MT-COX), and heteroplasmy levels, factors that were significant predictors of disease progression as measured by NMDAS scores. A web tool is available for prognosis and predicted disease progression based on these factors (research.ncl.ac.uk/mitoresearch) [Grady et al 2014].

In contrast, other cohorts of individuals with SLSMD did not show a correlation between age and deletion size or inclusion of MT-CYB within the deletion.

For all mtDNA pathogenic variants, clinical expressivity depends on three factors:

  • Relative abundance of mutated mtDNA (heteroplasmy)
  • Tissue distribution of the mtDNA deletion genomes
  • Tissue vulnerability to impaired oxidative metabolism (threshold effect)

Tissue vulnerability thresholds likely do not vary substantially among affected individuals, whereas variable proportions of the mtDNA deletion and their tissue distribution may account for the wide spectrum of clinical findings that may occur in individuals with KSS.

The fact that mtDNA deletions are present in all tissues in individuals with KSS, are predominantly present in hematopoietic cells of individuals with Pearson syndrome, and are confined to skeletal muscle in PEO explains different clinical phenotypes. The gradual decrease in mtDNA deletions in rapidly dividing blood cells and their gradual increase in postmitotic tissues is an example of mitotic segregation, and explains how infants with Pearson syndrome may develop KSS later in life.

Penetrance

In mtDNA-related disorders, penetrance is a function of the proportion of abnormal mtDNA molecules. As a general rule, heteroplasmic levels above 80%-90% cause mitochondrial dysfunction and clinical symptoms. However, this is now recognized to be highly variable depending on mutation location and severity, specific tissue tested, age at which testing was performed, and testing methodology used.

Nomenclature

The general terms for the neuromuscular disorders include "progressive external ophthalmoplegia (PEO)" and "chronic progressive external ophthalmoplegia (CPEO)."

The multisystemic form of CPEO is called Kearns-Sayre syndrome (KSS). In the past, KSS was also referred to as "ophthalmoplegia-plus" (CPEO plus), a term now used to describe individuals who have more than isolated myopathy but do not fulfill classic clinical criteria for KSS. "KSS spectrum" and "CPEO-plus" are both used to indicate when an individual's clinical presentation is less severe than typical of classic KSS but includes multisystem symptoms beyond CPEO. KSS requires onset before age 20 years, although some investigators have reported individuals with CPEO-plus and a disease onset below age 20 years.

For Pearson syndrome, the term "Pearson marrow pancreas syndrome" is a synonym. The term "sideroblastic anemia and exocrine pancreatic dysfunction" is not currently used.

Leigh syndrome has also been described as "subacute necrotizing encephalomyelopathy."

Prevalence

An epidemiologic study of an adult population in the northeast of England estimated the prevalence of large-scale mtDNA deletions at 1.2:100,000 [Schaefer et al 2008, Gorman et al 2016]. The number of adults with single large-scale mtDNA deletions was reported to be 1.5:100,000 individuals (1-2.1 95% CI) [Gorman et al 2016].

Differential Diagnosis

Ataxia. See Hereditary Ataxia Overview.

Sensorineural hearing loss. See Hereditary Hearing Loss and Deafness Overview.

Pigmentary retinopathy. See Retinitis Pigmentosa Overview.

Sensorineural hearing loss and retinitis pigmentosa. See Usher Syndrome Type I and Usher Syndrome Type II.

Progressive external ophthalmoplegia. KSS and PEO must be differentiated from other disorders associated with ophthalmoplegia. The ptosis in mtDNA single-deletion disorders is typically asymmetric compared to the other causes as listed below (see Table 3), in which the ptosis is typically more symmetric as well as fluctuating.

Table 3.

Disorders with Progressive External Ophthalmoplegia to Consider in the Differential Diagnosis of KSS and PEO-Associated Ophthalmoplegia

DisorderGeneMOIDistinguishing Features of Differential Diagnosis Disorder
Non-
mitochondrial
disorders
Myasthenia gravis
(see OMIM 254200 & Congenital Myasthenic Syndromes)
See footnote 1See footnote 1
  • Fluctuating weakness & diplopia
  • Response to Tensilon & Mestinon therapy
  • Abnormal EMG/NCV repetitive stimulation
  • Absence of anti-acetylcholine receptor (AChR) & anti-MuSK antibodies in serum
Oculopharyngeal muscular dystrophyPABPN1AD
  • Late onset
  • Ptosis w/mild ophthalmoparesis
  • Severe dysphagia
  • Abnormal EMG/NCV
Oculopharyngodistal myopathy
(OMIM 164310)
UnknownAD
AR
  • Early-adulthood onset
  • Distal limb weakness
  • Frequent respiratory muscle weakness
Myotonic dystrophy type 1DMPKADMyotonia
MYH2-related myopathy
(OMIM 605637)
MYH2AR
AD
  • Childhood-onset myopathy
  • Generalized & extraocular muscle weakness
  • Minor progression
Multiple
small-scale
mtDNA
deletion
disorders 2
PEO2SLC25A4ADChildhood or adult onset of PEO w/variable myopathy, cardiomyopathy, & encephalopathy
PEO3TWNKAD
  • Adult onset (age 20-40 yrs)
  • Progressive hearing loss, cataracts, cardiomyopathy, dysphagia
  • Skeletal myopathy w/exercise intolerance, fatigue, progressive muscle weakness, myopathic EMG, RRF & ↓ COX levels on muscle biopsy
  • Psychomotor retardation, parkinsonism, gait difficulties, sensory ataxia
  • Cognitive decline, cerebral atrophy, peripheral neuropathy
  • Endocrinopathies (diabetes, infertility)
  • Mood disorders
PEO1
(see POLG-Related Disorders)
POLGAD
AR
  • Highly variable phenotypes
  • CPEO presentation: generalized myopathy, sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, cataracts, premature ovarian/testicular failure, mtDNA depletion
  • PEO caused by POLG pathogenic variants is typically adult onset.
Mitochondrial neurogastrointestinal encephalopathy diseaseTYMPAR
  • Peripheral neuropathy & gastrointestinal dysmotility
  • ↓ thymidine phosphorylase & ↑ thymidine in blood
Optic atrophy type 1OPA1ADOptic atrophy w/variable other neurologic signs
PEO5
(see RRM2B-Related Mitochondrial Disease)
RRM2BAD
AR
  • AR form may be a multisystemic severe disorder w/marked progressive weakness due to skeletal myopathy & mitochondrial DNA depletion.
  • AD form includes CPEO & variable manifestations: hearing loss, dysphagia, dysmotility, myopathy (exercise intolerance, fatigue, weakness), COX-deficient fibers & RRF on muscle biopsy, dysarthria, ataxic gait, peripheral neuropathy, mood disorders.
PEO6DNA2AD
  • PEO w/variable, slowly progressive features; onset: childhood-adulthood
  • Slender build
  • Facial muscle weakness; exertional dyspnea; obstructive sleep apnea; myopathy w/weakness, atrophy, exercise intolerance, myalgia, & cramps; gait disturbance
  • Elevated CK
mtDNA
single-
nucleotide
variants 3
Selected example: m.3243A>G 4MT-TL1Mat
  • Headaches
  • Stroke-like episodes
  • Diabetes mellitus
  • Hearing loss
  • Failure to thrive

AD = autosomal dominant; AR = autosomal recessive; CK = creatinine kinase; COX = cytochrome c oxidase; Mat = maternal; MOI = mode of inheritance; PEO = progressive external ophthalmoplegia; RRF = ragged red fibers

1.

Myasthenia gravis is a complex disorder and is thought to be associated with both genetic and non-genetic etiologies (see Melzer et al [2016]).

2.
3.
4.

Other disorders to consider

  • Leigh syndrome has been associated with multiple pathogenic variants causing mitochondrial dysfunction including defects of the pyruvate dehydrogenase complex and deficiencies of respiratory chain enzymes. Autosomal recessive, X-linked, and maternal (mtDNA) inherited forms have been reported (see Mitochondrial DNA-Associated Leigh Syndrome and NARP).
  • Diamond-Blackfan anemia (DBA) is an inherited blood disorder that causes anemia and variable congenital abnormalities. At least 18 genes have been associated with DBA. In a cohort of 362 individuals clinically diagnosed with DBA, 2.2% had a mtDNA deletion identified consistent with Pearson syndrome [Alter 2014].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a mitochondrial DNA deletion syndrome, the evaluations summarized in this section (if not already performed as part of the clinical evaluation that led to the diagnosis) are recommended:

  • Complete neurology, cardiology, ophthalmology, audiology, endocrine, and renal evaluations for KSS and PEO in children and adults. Consider gastroenterology evaluation if symptomatic.
  • Complete hematology and gastroenterology evaluations for Pearson syndrome in infants
  • Complete neurology, cardiology, ophthalmology, audiology, gastroenterology, endocrine, and renal evaluations for Leigh syndrome. Consider pulmonology and sleep evaluations if symptomatic.
  • Consultation with a clinical biochemical geneticist and/or genetic counselor

Treatment of Manifestations

The following are appropriate:

  • Augmentation therapy. Hearing aids or cochlear implants for sensorineural hearing loss
  • Placement of eyelid slings for severe ptosis with careful avoidance of and/or management of dry eye with eye ointment
  • Eyeglass prisms for diplopia
  • Dilation of the upper esophageal sphincter to alleviate cricopharyngeal/esophageal achalasia
  • Physical and occupational therapy for myopathy
  • Placement of a prophylactic cardiac pacemaker in individuals with cardiac conduction block to reduce the risk of sudden death
  • Hormone replacement for endocrinopathies
  • Folinic acid supplementation in individuals with KSS with low 5-methyltetrahydrofolate in CSF
  • Replacement of deficient pancreatic enzymes in Pearson syndrome and KSS
  • Transfusion therapy for individuals with Pearson syndrome with sideroblastic anemia
  • Consider administration of mitochondrial supplement therapies such as coenzyme Q10 and antioxidants
  • Ventilatory support for respiratory abnormalities for individuals with Leigh syndrome
  • Consider gastrostomy tube placement if failure to thrive, choking, or aspiration risk due to dysphagia

Prevention of Primary Manifestations

There are currently no preventive measures for common manifestations of mtDNA deletion. Optimizing nutrition and exercise regimen and providing medical management of recognized medical problems may stabilize care and prevent acute decompensations that are a major cause of morbidity and mortality in this population.

Prevention of Secondary Complications

Antioxidants may ameliorate damage from reactive oxygen species.

Percutaneous endoscopic gastrostomy may improve nutritional intake and prevent aspiration pneumonia in individuals with severe dysphagia.

Surveillance

In 2017, the Mitochondrial Medicine Society (MMS) published the following surveillance standards for individuals with mitochondrial disease [Parikh et al 2017]:

  • ECG and echocardiogram every six to 12 months to monitor cardiac conduction and contractility
  • Yearly evaluation by neurologist, audiologist, ophthalmologist, and endocrinologist; referral to other specialists (e.g., gastroenterologist, pulmonologist, immunologist) based on symptom occurrence
  • Evaluation by neuroophthalmologist and/or retinal specialist for CPEO, pigmentary retinopathy with appropriate surveillance testing (e.g., electroretinography, optical coherence tomography, visual fields)

Agents/Circumstances to Avoid

Medications to avoid include those potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolide, valproic acid, and nucleoside reverse transcriptase inhibitors. Volatile anesthetic hypersensitivity may occur. Avoid prolonged propofol (>30-60 minutes).

Evaluation of Relatives at Risk

Symptomatic maternal relatives should be screened for the specific mtDNA deletion.

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the specific mtDNA deletion present in the family to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. In some countries mitochondrial replacement technologies are becoming available for families in which the mother is known to harbor a pathogenic variant or deletion in mtDNA that causes severe clinical disease; such testing is not currently available on a clinical or research basis in the US.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 DNA (mtDNA) deletion syndromes are caused by deletion of mtDNA and, when inherited, are transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

  • The father of a proband is not at risk of having the mtDNA pathogenic variant.
  • The mother of a proband with a mtDNA deletion syndrome is usually unaffected. Typically, testing of maternal somatic tissues does not detect mtDNA deletions, although the mother of the proband may harbor the mtDNA deletion in a population of her oocytes (i.e., maternal germline mosaicism).
  • The mtDNA deletion is usually de novo in the proband, occurring either in the mother's oocyte or during embryogenesis.

Sibs of a proband

Offspring of a proband

Other family members. The risk to other family members of being affected or of having a mtDNA deletion is extremely low.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

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 and Preimplantation Genetic Diagnosis

Once the mtDNA deletion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible using a sensitive next-generation-sequencing methodology in a clinical diagnostic laboratory experienced with mtDNA analyses. However, accurate interpretation of prenatal diagnostic results of a mtDNA pathogenic variant or deletion is challenging. Due to mitotic segregation of mtDNA during cell division, the proportion of abnormal mtDNA in amniocytes and chorionic villi is unlikely to correspond to heteroplasmy levels in other fetal or adult tissues.

Prenatal testing using next-generation-sequencing genomic testing to detect a mtDNA deletion known to be in the proband may be offered when:

  • The mother has a known mtDNA deletion;
  • The mother does not have a mtDNA deletion detectable in her blood but had a prior child with the mtDNA deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is estimated to be 1%-4% [Falk et al 2015].

Note: Regardless of whether a pregnancy is known or not known to be at increased risk, prenatal test results cannot reliably predict the phenotype.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • International Mito Patients
  • 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
  • Foundation Fighting Blindness
    7168 Columbia Gateway Drive
    Suite 100
    Columbia MD 21046
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-423-0600
    Email: info@fightblindness.org
  • Mito Foundation (formerly the Australian Mitochondrial Disease Foundation)
    21 Mary Street
    Suite 3
    Surry Hills New South Wales 2010
    Australia
    Phone: 61-1-300-977-180
    Fax: 61-2-9999-3474
    Email: info@mito.org.au
  • MitoAction
    P.O. Box 51474
    Boston MA 02205
    Phone: 888-648-6228
    Email: support@mitoaction.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • The Charlie Gard Foundation
    United Kingdom
    Email: hello@thecharliegardfoundation.org
  • The Lily Foundation
    31 Warren Park
    Surrey CR6 9LD
    United Kingdom
    Phone: 07947 257247
    Fax: 01883 623799
    Email: liz@thelilyfoundation.org.uk
  • eyeGENE - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov
  • 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

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Mitochondrial DNA Deletion Syndromes (View All in OMIM)

157640PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1; PEOA1
256000LEIGH SYNDROME; LS
530000KEARNS-SAYRE SYNDROME; KSS
557000PEARSON MARROW-PANCREAS SYNDROME

Molecular Pathogenesis

Mitochondrial DNA deletion syndromes are almost never inherited, suggesting that these disorders are caused by de novo mtDNA deletions that occur in the mother's oocytes during germline development or in the embryo during embryogenesis. Chen et al [1995] showed that the "common mtDNA deletion" (m.8470_13446del4977) accounted for 0.1% of the approximately 150,000 mtDNA genomes in a human oocyte. A "bottleneck" between oocyte and embryo allows for only a minority (perhaps hundreds to a few thousand) of maternal mtDNA genome molecules to populate the fetus. On rare occasions, a "deleted" mtDNA may slip through. From the blastocyst, deleted mtDNAs can enter all three germ layers to cause KSS, segregate predominantly in the hematopoietic lineage to cause Pearson syndrome, or segregate in skeletal muscle to cause PEO [DiMauro & Schon 2003].

The origin of mtDNA deletions is uncertain. However, it has been noted that deletions fall into two classes [Mita et al 1990]:

  • Class I pathogenic variants are flanked by perfect direct repeats.
  • Class II pathogenic variants are not flanked by any unique elements.

Homologous recombination or slipped mispairing (i.e., unequal crossing over) may explain the origin of class I deletions. The genesis of class II deletions remains unknown. The fact that a mtDNA deletion of a given length is found in a given individual implies that the population of deleted mtDNA molecules is a clonal expansion of a single mtDNA deletion or duplication event that occurred early in oogenesis or in embryogenesis [Schon 2003]. The hypothesis of clonality implies that a single rearranged molecule present in the oocyte or the embryo multiplies excessively to form the trillions of deleted mtDNA molecules in the affected individual. How the selective amplification of deleted mtDNAs occurs is unknown, but the bottleneck concept described above may be part of the answer.

Pathogenic variants. Deletions vary in size and abundance among affected individuals, but deleted mtDNA of a given length is present in each individual. Approximately 90% of individuals with KSS have a single large-scale (i.e., 1.1-kb to 10-kb) mtDNA deletion. The "common deletion" in mtDNA (m.8470_13446del4977) is present in about one third of affected individuals.

Table 4.

Mitochondrial DNA Deletion Syndrome-Causing Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequence
m.8470_13446del4977
(4977-bp deletion)
--NC_012920​.1

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The mtDNA genome has 37 genes, encoding 13 mRNAs, 22 tRNAs, and 2 rRNAs. See Mitochondrial Disorders Overview.

Abnormal gene product. The similarly deleterious effects of different mtDNA deletions can be explained by the fact that even the smallest mtDNA deletion encompasses several tRNA genes. Thus, "deleted" mtDNA genomes are normally transcribed into RNA, but the processed transcript encoding polypeptides is not translated because the deletions remove essential tRNAs needed for protein synthesis [Schon 2003]. Larger deletions may also remove mRNAs required for synthesizing the mtDNA-encoded subunits of respiratory chain complexes I, III, IV, or V, leading to impaired mitochondrial energy production.

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Chapter Notes

Author Notes

Mitochondrial Medicine Society

www.mitosoc.org

The MMS is a group of clinicians dedicated to the evaluation, diagnosis, management, and education of mitochondrial disorders.

Author History

Salvatore DiMauro, MD; Columbia University Medical Center (2003-2019)
Marni J Falk, MD (2019-present)
Amy Goldstein, MD (2019-present)
Michio Hirano, MD; Columbia University Medical Center (2003-2019)

Revision History

  • 31 January 2019 (sw) Comprehensive update posted live
  • 3 May 2011 (me) Comprehensive update posted live
  • 19 April 2007 (sdm) Revision: prenatal testing available on a clinical basis
  • 8 February 2006 (me) Comprehensive update posted live
  • 17 December 2003 (me) Review posted live
  • 17 July 2003 (sdm) Original submission
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