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Mitochondrial Disease Factsheet

Clinical features
Mitochondrial disease is a broad term for numerous conditions that are caused by disruption in mitochondrial production or function. Mitochondrial conditions can be quite variable, even within the same family with respect to symptoms, severity, age of onset, and course. Disorders involving mitochondria generally affect tissues in the body with high-energy requirements (e.g., brain, muscle, kidneys) and can have global expression in terms of growth retardation, fatigue, and reduced tolerance to exercise. Other common features include neurologic disease, myopathy, hearing loss, optic atrophy, cardiomyopathy, and diabetes. Because the mitochondria are involved in energy production, mitochondrial disorders may mimic metabolic disease with crises following metabolic or energetic stress, such as infection, emotional stress, and exercise. Some mitochondrial disorders affect a single organ e.g., the eye), while others are multisystemic. Many disorders are associated with discreet clusters of specific symptoms, such as: NARP: Neurogenic weakness with ataxia and retinitis pigmentosa Alpers-Huttenlocher syndrome: Hypotonia, seizures, headaches, liver failure MERRF: Myoclonic epilepsy with ragged-red fibers

However, the expression of a particular mitochondrial disorder may vary widely from individual to individual. Many disorders present in childhood, but other can present at any age.

Diagnosis
Due to the overlap of features with other conditions and array of evaluation options, diagnosing mitochondrial disease is rarely straightforward. The diagnostic evaluation for mitochondrial disease is often a stepwise process that may include multiple different assessment techniques. The pathway depends on the patients presentation and if there is a suspicion for specific conditio ns. For some mitochondrial conditions, a clinical diagnosis can be made based on the patients clinical features and history. For oth ers, genetic testing is the most appropriate first line test and will be diagnostic. In yet other cases, imagining, ophthalmology, audiology, metabolic, and/or muscle biopsy assessment are involved in diagnosis. Often times a combined approach is taken to increase the diagnostic yield.

Genetics
Mitochondrial diseases are caused by mitochondrial DNA (mtDNA) mutations or by mutations in nuclear genes that are involved in mitochondria production. There are 37 mitochondrial genes and over 1,000 nuclear genes currently reported to be involved in mitochondrial function. During cell division, mitochondria are randomly distributed among the cytoplasm of daughter cells. This results in varying amounts of mitochondria from cell to cell. If a cell receives virtually all mutant mitochondria (increasing the likelihood of disease), or all normal mitochondria, it is said to be homoplasmic. If a cell receives both normal and mutant mitochondrial genomes, it is called heteroplasmic. In the course of further cell divisions because of random segregation of mitochondria to daughter cells, the proportion of mutant-tonormal mitochondria can alternate above and below a disease-causing threshold. That is why mitochondrial diseases can affect different tissues at different times and may present very differently even among members of the same family.

Published October 2013 NCHPEG All rights reserved

Inheritance & Genetic Counseling


Genetic counseling for mitochondrial disease recurrence risks can be complicated, especially for mtDNA mutations. Referral to a genetic professional is typically recommended for such families. For mtDNA mutations Mutations, deletions, and duplications in the mtDNA are maternally inherited. Mitochondria are inherited almost exclusively through the egg, so children of an affected woman have almost a 100% chance of inheriting the condition and children of an affected man have almost no chance of being affected. However, the severity of disease in a child of an affected woman can be highly variable, depending on the ratio of mitochondria with the mutation to mitochondria without the mutation in the childs cells. For nuclear DNA mutations These conditions are mainly inherited in an autosomal recessive pattern but can also be inherited in an autosomal dominant pattern. In autosomal recessive disorders, two carriers have a 25% chance (1 in 4) to have a child with the condition. In autosomal dominant disorders, an affected individual has a 50% chance (1 in 2) to pass on the condition to a child.

Clinical testing
Clinical testing may include a combination of molecular genetic testing (mtDNA and/or nuclear DNA), imagining, ophthalmology, audiology, metabolic, and/or muscle biopsy assessment. The specific testing pathway will depend on the patients presentation and if there is a suspicion for specific conditions.

Management
The specific management plan for mitochondrial disease is informed by the individuals type of mitochondrial disease and presenting features. Some conditions are treated with Coenzyme Q10 and other supplements, although evidence about the benefits of such treatment is limited.

Published October 2013 NCHPEG All rights reserved

References
Centre for Genetics Education: Mitochondrial Inheritance Fact Sheet at http://www.genetics.edu.au/Publications-andResources/Genetics-Fact-Sheets/Mitochondial-Inheritance-Complex-Patterns-of-Inheritance-2-FS12 GeneReviews: Mitochondrial Disorders Overview at http://www.ncbi.nlm.nih.gov/books/NBK1224/ Haas RH, Parikh S, Falk MJ. 2007. Mitochondrial Disease: A Practical Approach for Primary Care Physicians. Pediatrics 120:1326-33. McFarland R, Yaylor RW, Turnbull DM. 2010. A neurological perspective on mitochondrial disease. Lancet Neurol 9:829-40. Scaglia F, Towbin JA, Craigen WJ et al. 2004. Clinical Spectrum, Morbidity, and Mortality in 113 Pediatric Patients with Mitochondrial Disease. Pediatrics 114:925-31.

Published October 2013 NCHPEG All rights reserved