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.

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 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.

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].