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Mitochondrial DNA Deletion Syndromes

Synonym: mtDNA Deletion Syndromes

, MD and , MD.

Author Information
, MD
Department of Neurology
Columbia University Medical Center
New York, New York
, MD
Department of Neurology
Columbia University Medical Center
New York, New York

Initial Posting: ; Last Update: May 3, 2011.

Summary

Disease 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 in a given individual over time. The three phenotypes are Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO). Rarely Leigh syndrome can be a manifestation of a mtDNA deletion. KSS is a multisystem disorder defined by the triad of onset before age 20 years, pigmentary retinopathy, and PEO. In addition, affected individuals have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia. Onset is usually in childhood. Pearson syndrome is characterized by sideroblastic anemia and exocrine pancreas dysfunction and is usually fatal in infancy. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), oropharyngeal weakness, and variably severe proximal limb weakness, is relatively benign.

Diagnosis/testing. Diagnosis of mtDNA deletion syndromes relies on presence of characteristic clinical findings and, in KSS, changes on muscle biopsy (ragged-red fibers [RRF] with the modified Gomori trichrome stain, hyperactive fibers with the succinate dehydrogenase [SDH] stain, failure of both RRF and some non-RRF to stain with the histochemical reaction for cytochrome c oxidase [COX]) and decreased activity of respiratory chain complexes containing mtDNA-encoded subunits in muscle extracts. In Pearson syndrome, bone marrow examination reveals ringed sideroblasts, normoblasts with excessive deposits of iron in mitochondria detected by iron stains. Mitochondrial DNA deletion syndromes are caused by mtDNA deletions ranging in size from two to ten kilobases. Approximately 90% of individuals with KSS have a large-scale (i.e., 1.1- to 10-kb) mtDNA deletion that is usually present in all tissues; however, mutant mtDNA is often undetectable in blood cells, necessitating examination of muscle. In Pearson syndrome, mtDNA deletions are usually more abundant in blood than in other tissues. In PEO, mtDNA deletions are confined to skeletal muscle.

Management. Treatment of manifestations: Placement of cardiac pacemakers in individuals with cardiac conduction blocks, 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 and L-carnitine, physical and occupational therapy, and treatment of depression.

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 and endocrinologic evaluation.

Agents/circumstances to avoid: Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolide, valproic acid, nucleoside reverse transcriptase inhibitors. Dichloroacetate (DCA), a lactate-lowering agent, causes peripheral neuropathy.

Genetic counseling. Mitochondrial DNA deletion syndromes are caused by deletion of mtDNA and, when inherited, are transmitted by maternal inheritance. 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; therefore, the risk to the sibs of a proband is usually extremely low. Offspring of a female proband are usually not at risk of inheriting the mutation; however, exceptions occur. Offspring of males with a mtDNA mutation are not at risk. Although prenatal testing for pregnancies at increased risk is theoretically possible, interpretation of test results is difficult. If the mitochondrial deletions in the family are known, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the mitochondrial deletion of interest or custom testing.

GeneReview Scope

Mitochondrial DNA Deletion Syndromes: Included Disorders
  • Kearns-Sayre syndrome (KSS)
  • Pearson syndrome
  • Progressive external ophthalmoplegia (PEO)
  • Leigh syndrome (mtDNA deletion)

For synonyms and outdated names see Nomenclature.

Diagnosis

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:

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

Test MethodMutations DetectedMutation Detection Frequency by Phenotype 1
KSSPEOLeigh syndrome
Duplication/deletion analysis 2Mitochondrial DNA deletions 390% 450% 4<5%

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 partial or whole-gene 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.

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.

Clinical Description

Natural History

Kearns-Sayre Syndrome (KSS)

KSS is a multisystem disorder affecting predominantly the central nervous system, skeletal muscle, and heart. Onset is usually in childhood, with ptosis, ophthalmoplegia, or both. Exercise intolerance and impaired night vision may be early symptoms. Dysphagia caused by oropharyngeal weakness, incomplete opening of the upper esophageal sphincter (cricopharyngeal achalasia), or both is common [Kornblum et al 2001, Aure et al 2007]. The disease usually progresses to death in young adulthood.

Central nervous system involvement is manifest by 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. Strokes are also rare. In two individuals, strokes were attributed to cardiac emboli [Kosinski et al 1995, Provenzale & Van Landingham 1996].

Muscle involvement is manifest by PEO, ptosis, oropharyngeal and esophageal dysfunction, exercise intolerance, and proximal more than distal limb muscle weakness. The defect of extraocular movement is usually symmetric but may cause blurred or double vision.

Heart involvement is characterized by conduction block, which can lead to complete heart block if a pacemaker is not placed in a timely fashion. Cardiomyopathy, less common than cardiac conduction block, has been reported in several individuals [Aure et al 2007].

Endocrinopathies are common in KSS and include diabetes mellitus, hypoparathyroidism, irregular menses, and growth hormone deficiency. The diabetes mellitus is caused by insufficient insulin secretion rather than a defect of insulin receptor [Piccolo et al 1989]. Short stature may be the result of growth hormone deficiency.

Renal tubular acidosis can be part of KSS and in some cases is the presenting feature.

The pigmentary retinopathy of KSS affects low-light vision more prominently than visual acuity; hence, affected individuals complain of difficulty with night vision. Peripheral vision may be compromised by ptosis. Vision generally deteriorates insidiously; therefore, the age at onset is often difficult to discern (see Table 2).

Table 2. Signs and Symptoms in 86 Individuals with KSS

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 often fatal in infancy. Individuals with Pearson syndrome who survive beyond infancy develop the symptoms and signs of KSS [McShane et al 1991, Lee et al 2007].

Progressive External Ophthalmoplegia (PEO)

PEO is characterized by drooping of the eyelids (ptosis), paralysis of the extraocular muscles (ophthalmoplegia), and variably severe oropharyngeal and proximal limb weakness. The disorder is relatively benign and compatible with a normal life span.

Leigh Syndrome

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

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.

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 1 and Usher Syndrome Type 2.

Progressive external ophthalmoplegia. KSS and PEO must be differentiated from other disorders associated with ophthalmoplegia. These include (with distinguishing features):

Leigh syndrome has been associated with multiple genetic mutations causing mitochondrial dysfunction including defects of the pyruvate dehydrogenase complex and deficiencies of respiratory chain enzymes. Autosomal recessive, X-linked, and maternally inherited forms have been reported (see Mitochondrial DNA-Associated Leigh Syndrome and NARP).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

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 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals

Prenatal Testing

Prenatal testing is possible; however, 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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children's European Mitochondrial Disease Network
    Mayfield House
    30 Heber Walk
    Northwich CW9 5JB
    United Kingdom
    Phone: +44(0) 01606 43946 (Helpline)
    Email: info@cmdn.org.uk
  • 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
    11435 Cronhill Drive
    Owings Mills MD 21117-2220
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-568-0150
    Email: info@fightblindness.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • 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 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.

Pathogenic 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.

Table 3. Selected Mitochondrial DNA Deletion Syndrome Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequence
m.8470_13446del4977
(4977 bp deletion)
--NC_012920​.1

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

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

1. Variant designation that does not conform to current naming conventions

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].

References

Literature Cited

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  16. Mita S, Rizzuto R, Moraes CT, Shanske S, Arnaudo E, Fabrizi GM, Koga Y, DiMauro S, Schon EA. Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucleic Acids Res. 1990;18:561–7. [PMC free article: PMC333462] [PubMed: 2308845]
  17. Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S, Nonaka I, Koga Y, Spiro AJ, Brownell AKW, Schmidt B, Schotland DL, Zupanc M, DeVivo DC, Schon EA, Rowland LP. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989;320:1293–9. [PubMed: 2541333]
  18. Piccolo G, Aschei M, Ricordi A, Banfi P, Lo Curto F, Fratino P. Normal insulin receptors in mitochondrial myopathies with ophthalmoplegia. J Neurol Sci. 1989;94:163–72. [PubMed: 2614464]
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  22. Rowland LP, Hays AP, DiMauro S, De Vivo DC, Behrens M. Diverse clinical disorders associated with morphological abnormalities in mitochondria. In: Scarlato G, Cerri C, eds. Mitochondrial Pathology in Muscle Diseases. Padua, Italy: Piccin; 1983:141-58.
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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 online (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]

Chapter Notes

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
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