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: EKG 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 and, when inherited, are transmitted by maternal 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. Typically, testing of maternal somatic tissues does not detect the mtDNA deletion, although the mother of the proband may harbor the mtDNA deletion in a population of her oocytes (i.e., maternal germline mosaicism). If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%). If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24). Maternal transmission to more than one child has not been reported to date. 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 mtDNA deletion syndromes is not clinically available, as prenatal test results cannot reliably exclude a mtDNA deletion being present in any tissue and cannot reliably predict phenotype.

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).

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 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.

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].

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].

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]:

• EKG 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 EU Clinical Trials Register 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.

Mode of Inheritance

Mitochondrial DNA (mtDNA) deletion syndromes are caused by a single large-scale deletion in the mtDNA genome 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 deletion.
• The mother of a proband with a mtDNA deletion syndrome is usually unaffected. Typically, testing of maternal somatic tissues does not detect the mtDNA deletion, 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

• If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%).
• If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24) [Chinnery et al 2004]. Maternal transmission to more than one child has not been reported to date.

Offspring of a proband

• The likelihood that an affected woman will have an affected child is low, calculated to be approximately one in 24 births [Chinnery et al 2004, Pitceathly et al 2012].
• Offspring of a male proband with a mtDNA pathogenic variant are not at risk.

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 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the mtDNA deletion has been identified in an affected family member, prenatal and preimplantation genetic testing are scientifically possible but technically prohibitive, as next-generation sequencing methodology does not accurately quantify heteroplasmy levels of mtDNA deletions and droplet digital quantitative PCR cannot reliably detect less than 10% heteroplasmy levels of mtDNA deletions. Further, prenatal testing is not clinically available because of the inability to accurately interpret the clinical prognosis based on prenatal diagnostic results of a mtDNA deletion. 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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.

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.

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

• 11 May 2023 (aa) Revision: correction to recurrence risk in Genetic Counseling
• 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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