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Mitochondria Disease Case Study

Learn more about mitochondrial disease.

Susan was found to have a mitochondrial disease causing pathogenic variant in high levels m.3243A>G.

m.3243 A>G is the most common heteroplasmic (see below) mtDNA disease genotype.

The name m.3243 A>G refers to a genetic change in the mitochondrial DNA where an A (Adenosine) base is changed to a G (Guanosine) at position 3243.

The clinical presentation can be hugely variable. A proportion (15%) present with MELAS syndrome ( Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes), the remainder display a variety of features including diabetes, ataxia, deafness, and myopathy. The carrier frequency of this pathogenic variant has been estimated at 140-250 per 100,000 but disease prevalence is significantly lower (40-70 fold lower). Consequently, many patients are asymptomatic or have a disease that has not been recognised as mitochondrial in etiology.

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Genomic Scenarios in Primary Care

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It transpires that distant family members of Susan had previously been diagnosed with the pathogenic variant but this hadn’t filtered through to Susan’s immediate family.

FTT and low BMI, young-onset deafness are all typical of m.3243 A>G. The IBS represents gastrointestinal dysmotility, a frequent feature, and gestational diabetes is significantly more common, reflecting impaired glucose tolerance.

Susan’s migraines diagnosis was incorrect, the visual phenomena had continued too long. These episodes were mitochondrial stroke-like episodes, a manifestation of left occipital status epilepticus. Failure to treat these increases cerebral damage and worsens outcomes.

Susan has a two year old son and wishes to have further children.

Mitochondrial conditions have implications for all maternal family members of the index case. The reproductive issues and options will be discussed further later.

For more information on m.3243 A>G you can read this review of the phenotypical heterogeneity of the UK population.

Mitochondrial Genomes, Inheritance, and Heteroplasmy

Mitochondria are intracellular organelles responsible for energy production. They can be found in almost all cells of the body but are found in greater number in those with higher energy needs (e.g. muscle). Mitochondria have their own genome, a circular piece of DNA, mtDNA, with 16,000 bases and 37 genes, compare this to the 3.3 billion base pairs in the nuclear genome.

Only 3% of the mtDNA is non-coding, compared to 93% of the nuclear DNA. The mitochondrial genome is very different to the nuclear genome and is far more similar to bacterial genomes- indeed, it is believed that mitochondria evolved from a quirk of evolution, when a bacteria lived in a symbiotic relationship within an ancestral cell. Each individual cell can have hundreds of mitochondria and not all of these necessarily have the pathogenic mutation, the proportion that do can vary from one cell type to another in the same individual. This is the concept of heteroplasmy.

The 37 genes in the mitochondrial genome encode just 13 proteins, 22 transfer RNA (tRNA) and 2 ribosomal RNA (rRNA). All 13 proteins are involved in instructing the cell to make protein subunits of the enzyme complexes of the oxidative phosphorylation (OXPHOS) system, that enable the mitochondria to ‘power’ the cell. This OXPHOS system is under dual control, both the mitochondrial and nuclear genomes.

Mitochondrial diseases affect 1-in-4000 to 1-in-6000 individuals. They are almost entirely caused by disease-causing variants in the genome of the mitochondria. Mitochondrial diseases are strictly maternally inherited. We share our mitochondrial DNA sequence with our mothers, maternal grandmother, brothers and sisters, and if female (but NOT male) our children.

The linked article gives an overview of mtDNA and mitochondrial disease.

The mitochondrial pattern of inheritance is different to X-linked inheritance. This short video explains X-linked recessive inheritance when the mother is a carrier, so you can check how the patterns of inheritance differ.

Due to this pattern of inheritance, mtDNA has been used in cases of human rights abuses, as a match can be found with maternal relatives even when these relatives may be few and distant. The article by Owens et al linked in the Further Reading section provides some historical case studies of using mtDNA in this way.