Mitochondrial disease: recognising more than just the tip of the iceberg

Mutations in mitochondrial DNA (mtDNA) were discovered to cause mitochondrial disease over 20 years ago.1 Initially thought to be a rare group of neurological disorders predominantly affecting children, it is now known that patients with mitochondrial disease can develop a broad range of symptoms (Box) and may present at any age from early in the neonatal period to very late in adulthood. Debilitating or fatal forms of mitochondrial disease are more frequent in children than in adults, but adult patients often have chronic multisystemic manifestations that require symptomatic treatment and regular long-term surveillance to minimise the chance of life-threatening episodes of acute illness.

Mitochondrial disease may present a diagnostic challenge to the clinician. Clinical manifestations are variable (see Box), and family histories suggestive of an inherited condition may not be obvious due to the variability in phenotypic expression that characterises this group of disorders. Moreover, the lack of a “gold standard” test for its diagnosis and the fact that mtDNA analysis is not freely available to all Australians (only in Victoria) exacerbate the difficulties in diagnosing affected individuals.

Why are mitochondrial disorders highly variable? This is due to a number of factors. First, there are hundreds of mtDNA mutations that cause a variety of different mitochondrial disease syndromes. Notably, most disease-causing mtDNA mutations are heteroplasmic. Heteroplasmy is the co-existence of both normal (wild-type) and abnormal (mutant) mtDNA within the same cell. Because there are multiple mitochondria within any given cell, the proportion of mutant mtDNA may vary between 0 and 100% within any given tissue. Thus, the tissue used for diagnosis becomes critical, with blood not being the most ideal tissue to sample.2 There is substantial evidence to indicate that the higher the heteroplasmic mtDNA mutational load within the tissue or cell, the greater the level of mitochondrial dysfunction.3,4

A minimum number of mutant genomes are required for the expression of disease, a phenomenon referred to as the threshold effect. The threshold effect is a relative concept, because the critical amount of mutation required to impair mitochondrial function will vary depending on the particular mtDNA mutation involved and the relative metabolic requirements of the tissue’s cells at any given time. Although there are occasional exceptions, higher proportions of mutant mtDNA have typically been observed in more severely affected patients.5

Finally, the proportion of mutant mtDNA may change rapidly between parent and daughter cell. This phenomenon, referred to as mitotic segregation, combined with the concept of heteroplasmy, at least partly explains why some family members may be more severely affected than others and how some patients manifest different clinical manifestations at different stages of their lives.

Several studies have now found that pathogenic mtDNA mutations occur frequently in the general population. The first true population-based study showed that the most common pathogenic mutation, known as m.3243A→ G (typically associated with MELAS — mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes — syndrome), was found in one in 500 community-based Australians.6 All mutation carriers aged over 50 years had few or minor symptoms, but none had the clinical features of MELAS syndrome. Although age and other risk factors were not accounted for in the analysis, all m.3243A→ G mutation carriers had developed sensorineural hearing loss, a common but non-specific clinical symptom that frequently affects patients with mitochondrial disease.

A second study in the United Kingdom confirmed this frequency of the m.3243A→ G mutation, reporting that it was found in one in 700 live births, although no clinical information on mutation carriers was given.7 The authors analysed a total of 10 common mitochondrial point mutations, and found a population prevalence of pathogenic mutation of more than one in 200 live births. Later, two studies investigating the population prevalence of a different point mutation, m.1555A→ G (originally associated with antibiotic-induced hearing loss), independently showed that this mutation was similarly found in one in 500 subjects.8,9 Children with this mtDNA mutation were asymptomatic, but older individuals were more likely to have developed associated symptoms. In addition to determining that mtDNA mutations were prevalent and usually unrecognised in the community,10 these findings raised questions about how and when mutation carriers become symptomatic during their lives.

Should we consider mtDNA mutation carriers in the spectrum of mitochondrial disease? Given the lack of data about the factors that contribute to disease penetrance in mutation carriers, this approach could easily be justified. Patients who develop severe disease caused by their pathogenic mtDNA mutation could represent just the “tip of the iceberg”, with the vast majority of mutation carriers remaining only mildly affected. Changes in lifestyle and use of preventive strategies to delay the onset of symptoms (such as tailored exercise programs and avoidance of metabolic and physiological stressors) should be recommended to all mutation carriers in an attempt to reduce the individual’s risk of developing symptoms, although this may be ineffective in those who are destined to develop severe clinical manifestations. Longitudinal clinical studies of mutation carriers are warranted, to determine the natural history of mitochondrial disease and identify risk factors that contribute to developing severe or life-threatening disease versus mild or no symptoms during life.

If the prevalence of mtDNA mutations in Australia is at least one in 250, then 90 000 Australians are potentially at risk of developing symptoms of a mitochondrial disorder. To raise community awareness of this genetic disorder, which robs thousands of Australians of their energy, the Australian Mitochondrial Disease Foundation will hold its annual Stay in Bed Day on 22 August 2010 (see http://www.amdf.org.au for details).