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. 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.
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