Clinical Diagnosis

Mitochondrial DNA (mtDNA) deletion syndromes comprise the three following overlapping phenotypes, which may be observed in different members of the same family or may evolve in a given individual over time:

Kearns-Sayre syndrome (KSS) is a multisystemic disorder defined by the following obligatory triad:

• Onset before age 20 years
• Pigmentary retinopathy. Funduscopy reveals an atypical "salt and pepper" retinopathy; ERG often reveals retinal dystrophy; and visual field testing reveals normal visual fields. In KSS, the retinopathy is usually rod-cone dystrophy that seems to behave differently from other forms of retinitis pigmentosa [Author, personal observation].
• Progressive external ophthalmoplegia (PEO)

At least one of the following must also be present:

• Cardiac conduction block
• Cerebrospinal fluid protein concentration greater than 100 mg/dL
• Cerebellar ataxia [Kearns & Sayre 1958, Rowland et al 1983]

Other frequent but not invariable clinical manifestations of KSS include short stature, hearing loss, dementia, limb weakness, diabetes mellitus, hypoparathyroidism, and growth hormone deficiency.

Pearson syndrome is a usually fatal disorder of infancy characterized by sideroblastic anemia and exocrine pancreas dysfunction [Rötig et al 1990].

Progressive external ophthalmoplegia (PEO) is a mitochondrial myopathy with drooping of the eyelids (ptosis), paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness.

A few individuals with PEO have other manifestations of KSS but do not fulfill all the clinical criteria for the diagnosis [Rowland et al 1983]. This situation is called "KSS minus" or "PEO plus."

Leigh syndrome, characterized by lesions of the basal ganglia and brain stem, is an uncommon presentation of a mtDNA deletion.

Testing

Kearns-Sayre syndrome and progressive external ophthalmoplegia

• Lactate and pyruvate concentrations in blood and cerebrospinal fluid (CSF). Commonly elevated at rest and increase excessively in blood after moderate activity
• Electromyogram and nerve conduction studies. Consistent with a myopathy, but neuropathy may coexist
• Brain MRI. Sometimes shows leukoencephalopathy, often associated with cerebral or cerebellar atrophy or basal ganglia lesions
• Fasting serum glucose concentration to screen for diabetes mellitus
• Echocardiogram and electrocardiogram to evaluate cardiac conduction and contractility
• Muscle biopsy. Typically shows ragged-red fibers (RRF) with the modified Gomori trichrome stain and hyperactive fibers with the succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with the histochemical reaction for cytochrome c oxidase (COX).
• Biochemical studies of respiratory chain enzymes in muscle extracts. Usually show decreased activities of respiratory chain complexes containing mtDNA-encoded subunits, especially when enzyme values are referred to the activity of citrate synthase, a good marker of mitochondrial "mass" [DiMauro et al 2002]. However, depending on the mutational load, biochemical studies may also be normal.

Pearson syndrome

• Sideroblastic anemia is defined by the presence of anemia and ringed sideroblasts in the bone marrow. Ringed sideroblasts are normoblasts with excessive deposits of iron in mitochondria and are detected by iron stains of bone marrow.
• Exocrine pancreatic dysfunction is manifest clinically by 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 difficult to perform in infants.

Leigh syndrome

• Brain MRI shows characteristic T₂-weighted hyperintense lesions in the basal ganglia and midline brain stem.

Molecular Genetic Testing

Gene. Deletions of mitochondrial DNA (mtDNA), ranging in size from 1.1 to 10 kb, are associated with Kearns-Sayre syndrome, Pearson syndrome, progressive external ophthalmoplegia, and rarely Leigh syndrome.

• More than 150 different mtDNA deletions have been associated with KSS. A deletion of 4977 bp known as m.8470_13446del4977 is encountered most frequently ("common deletion") [Schon 2003].
• The same m.8470_13446del4977 and numerous other types of deletions of varying length have been identified in Pearson syndrome and PEO.

Clinical testing

• Duplication/deletion analysis identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA. A variety of methods can be used (Table 1, footnote 2).
  • Southern blot (or other methodology)
    
    Kearns-Sayre syndrome. Deletions can 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 large-scale (i.e., 1.1- to 10-kb) mtDNA deletion.
    
    Note: (1) Deletions are usually present in all tissues of individuals with KSS, and can be looked for in blood leukocytes. However, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of "deleted" mtDNA. Since mutant mtDNA may be undetectable in blood cells, muscle biopsy may be necessary. (2) Large-scale duplications of mtDNA coexist with deletions in some individuals with KSS [Poulton et al 1989].
    
    Pearson syndrome. Mitochondrial DNA deletions are usually more abundant in blood than in other tissues. The diagnosis of Pearson syndrome is reliably made in leukocyte DNA by Southern blot analysis or another type of analysis.
    
    Progressive external ophthalmoplegia (PEO). Mitochondrial DNA deletions are confined to skeletal muscle. The molecular diagnosis of PEO requires analysis of a muscle biopsy by Southern blot or another appropriate method [Moraes et al 1989].
    
    Leigh syndrome. Mitochondrial DNA deletions are detected in post-mitotic tissues such as muscle and brain, but not in blood or other replicating cells.
  • Long PCR analysis. Long PCR (also known as deletion-specific PCR) analysis detects deletions throughout the mtDNA; however, this method has high sensitivity and low specificity. Because mtDNA deletions accumulate normally with age, detection of the common deletion or of multiple deletions by PCR may lead to misdiagnosis. As a result, Southern blot analysis is the preferred method for diagnosis. It is advisable to consult with the testing laboratory about the method employed and its sensitivity and specificity.

Table 1. Summary of Molecular Genetic Testing Used in Mitochondrial DNA Deletion Syndromes

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Test Method	Mutations Detected	Mutation Detection Frequency by Phenotype 1			Test Availability
		Kearns-Sayre Syndrome	PEO	Leigh syndrome
Duplication / deletion analysis 2	Mitochondrial DNA deletions 3	90% 4	50% 4	<5%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. For KSS and Pearson syndrome, the detection rate is not 100% because rare individuals have syndromes that mimic KSS but are caused by other mtDNA mutations. For PEO, however, numerous mutations in either mtDNA or nuclear genes also cause PEO often associated with other manifestations. For Leigh syndrome, the detection rate is estimated at <5% of all Leigh syndrome [Author, personal observation].

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

3. Usually deletions, but rarely duplications, and often the two rearrangements occur together.

4. Detection frequency may depend on the methodology employed and vary among laboratories.

Testing Strategy

To confirm/establish the diagnosis in a proband. The clinical diagnosis must be confirmed by molecular studies documenting rearrangements (usually deletions, but rarely duplications, and often the two together) of mtDNA in leukocytes or muscle.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with single deletions of mtDNA. See Mitochondrial Disorders Overview.

Natural History

Genotype-Phenotype Correlations

No correlation exists between size or location of the mtDNA deletion and phenotype.

For all mtDNA mutations, clinical expressivity depends on the three following factors:

• The relative abundance of mutant mtDNA (heteroplasmy)
• The tissue distribution of the mutant mtDNAs
• The vulnerability of each tissue to impaired oxidative metabolism (threshold effect)

The tissue vulnerability threshold probably does not vary substantially among affected individuals, but variable mutational load and tissue distribution may account for the spectrum of clinical findings 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 the different clinical phenotypes. The gradual decrease in mtDNA deletions in rapidly dividing blood cells and their gradual increase in post-mitotic 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 mutation load. As a general rule, heteroplasmic levels above 80%-90% cause mitochondrial dysfunction and clinical symptoms.

Nomenclature

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

The multisystemic form is called Kearns-Sayre syndrome (KSS); in the past, KSS was also referred to as "ophthalmoplegia-plus," a term now used to describe individuals who have more than isolated myopathy but do not fulfill the canonical criteria for KSS.

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 North East of England estimated the prevalence of large-scale mtDNA deletions at 1.2:100,000 [Schaefer et al 2008].

See Mitochondrial Disorders Overview for general prevalence.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a mitochondrial DNA deletion syndrome, the following evaluations are recommended:

• Complete neurologic, cardiologic, ophthalmologic, and endocrinologic evaluations for KSS and PEO in children and adults
• Complete hematologic and gastroenterologic evaluations for Pearson syndrome in infants
• Complete neurologic, cardiac, gastrointestinal, endocrinologic, and renal evaluations for Leigh syndrome.

Treatment of Manifestations

The following are appropriate:

• Placement of cardiac pacemaker in individuals with cardiac conduction block to reduce the risk of sudden death
• Placement of eyelid slings for severe ptosis
• Cochlear implants and hearing aids for neurosensory hearing loss
• Hormone replacement for endocrinopathies
• Dilation of the upper esophageal sphincter to alleviate cricopharyngeal achalasia
• Folinic acid supplementation in individuals with KSS with low CSF folic acid
• Replacement of pancreatic enzymes in Pearson syndrome
• Administration of coenzyme Q₁₀ (50-200 mg 3x/day) and L-carnitine (330 mg 3x/day)
• Physical and occupational therapy
• Treatment of depression
• Ventilatory support for respiratory abnormalities in Leigh syndrome.

Prevention of Secondary Complications

Antioxidants may ameliorate damage from reactive oxygen species (ROS).

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

Surveillance

Surveillance includes the following:

• ECG and echocardiogram every six to 12 months to monitor cardiac conduction and contractility
• Yearly audiometry and endocrinologic evaluation

Agents/Circumstances to Avoid

Medications to avoid:

• Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolide, valproic acid, nucleoside reverse transcriptase inhibitors
• Dichloroacetate (DCA) as a lactate-lowering agent, as DCA has been proven to cause peripheral neuropathy [Kaufmann et al 2006]

Evaluation of Relatives at Risk

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

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Mitochondrial DNA 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 disease-causing mtDNA mutation.
• The mother of a proband with a mtDNA deletion syndrome is usually unaffected and does not have mtDNA deletions in her tissues.
• The mtDNA deletion is usually de novo in the proband, occurring either in the mother's oocyte or during embryogenesis.

Sibs of a proband

• The risk to the sibs of a proband is usually extremely low.
• If the mother and one child are affected, the risk to other children is very low: thus far, maternal transmission to more than one child has not been reported.

Offspring of a proband

• Affected women have a small but finite chance of having an affected child, calculated to be approximately one in 24 births [Chinnery et al 2004].
• Offspring of males with a mtDNA mutation are not at risk.

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

Related Genetic Counseling Issues

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Although prenatal testing is theoretically possible, accurate interpretation of prenatal diagnostic results of a mtDNA mutation is extremely problematic. Because of mitotic segregation, the mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues. As a consequence no laboratories offer prenatal testing.

Molecular Genetic 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 deletion" (m.8470_13446del4977) accounted for 0.1% of the approximately 150,000 mtDNAs in a human oocyte. A "bottleneck" between oocyte and embryo allows only a minority of maternal mtDNAs to populate the fetus. On rare occasions, a "deleted" mtDNA may slip through. From the blastocyst, deleted mtDNAs can enter all three germ layers and cause KSS, segregate predominantly to the hematopoietic lineage and cause Pearson syndrome, or segregate to muscle and 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 mutations are flanked by perfect direct repeats;
• Class II mutations 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 mtDNAs is a clonal expansion of a single mutation 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 wildly to form the trillions of deleted mtDNAs in the affected individual. How the selective amplification of deleted mtDNAs occurs is currently unknown, but the bottleneck concept described above may provide an answer.

Normal allelic variants. See Mitochondrial Disorders Overview.

Pathologic allelic variants. Deletions can 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 large-scale (i.e., 1.1- to 10-kb) mtDNA deletion. The "common deletion" (m.8470_13446del4977) is present in about one third of affected individuals.

Normal gene product. 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" mtDNAs are transcribed into RNA in the usual way, but the processed transcript encoding polypeptides is not translated because the deletions remove essential tRNAs needed for protein synthesis [Schon 2003].

Literature Cited

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Suggested Reading

1. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008;31:91–123. [PubMed: 18333761]
2. Hirano M. Kearns-Sayre syndrome. In: Gilman S, editor-in-chief. Medlink Neurology. San Diego: Medlink Corporation. Available at www​.medlink.com (subscription required). 2010.
3. Yamashita S, Nishino I, Nonaka I, Goto Y. Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions. J Hum Genet. 2008;53:598–606. [PubMed: 18414780]

Revision History

• 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 to live Web site
• 17 December 2003 (me) Review posted to live Web site
• 17 July 2003 (sdm) Original submission