MELAS syndrome and the m.3243A>G mitochondrial variant: symptoms and inheritance

MELAS stands for Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes. The Lily Foundation explains that m.3243A>G simply refers to the location of the genetic change in the mitochondrial DNA, and that the same change causes a spectrum of conditions rather than one disease. At one end is MELAS, with neurological symptoms and stroke-like episodes. At the other is MIDD, maternally inherited diabetes and deafness, in which people have diabetes and progressive hearing loss without stroke-like episodes.

Stroke-like episodes are sudden changes in movement, speech or vision, often with confusion, and the charity points out that they differ from true strokes: they happen when the brain cannot generate energy at a particular site, rather than because of a blood supply problem, and they look different on brain scans. Other MELAS features include seizures, severe or recurrent headaches, memory and concentration problems, severe gut problems, muscle weakness and exercise intolerance. MELAS most often appears in childhood or early adulthood, but the Foundation emphasises it is not the most common presentation of the variant.

Each cell holds many copies of mitochondrial DNA, and in this condition some copies carry the change and some do not. The Lily Foundation calls this a mixture of good and bad mitochondrial DNA, known as heteroplasmy, and says the ratio is one factor influencing severity: someone with a lot of altered DNA may develop more symptoms. But there is huge variation between individuals with the same level of the variant, even within families, and some carriers have no symptoms at all.

Mild presentations include a predisposition to diabetes, poor bowel function or very mild deafness needing no treatment. More affected people need hearing aids or insulin, and the most severely affected can have muscle weakness, heart disease and encephalopathy. Heart rhythm problems, cardiomyopathy, balance difficulties, migraines, visual problems and chronic progressive external ophthalmoplegia (weakness of the eye muscles) are among the other features listed.

The NHS Genomics Education Programme explains that mitochondria and their DNA are inherited maternally: mothers always pass on their mitochondria and mtDNA to their children, whereas fathers never do. Both males and females are affected, the condition is inherited through the female line, and the programme says all the offspring of a woman with a variant in mtDNA would be expected to inherit the condition. A man with the variant does not pass it to his children.

Because of heteroplasmy, inheriting the variant does not predict how affected a child will be. The Lily Foundation says the same genetic change can produce different symptoms in different people, even within the same family, so a mother with mild diabetes may have a child with more serious illness, or the reverse. Other mitochondrial conditions are caused by nuclear genes and follow autosomal recessive, dominant or X-linked patterns, so a genetics service establishes which applies in each family.

The Lily Foundation lists the tests that may be used: genetic testing of blood, urine or muscle, brain imaging if neurological symptoms are present, blood and urine tests including lactate, hearing and eye assessments, and muscle biopsy in selected cases. In the UK diagnosis and ongoing care are led by the NHS Highly Specialised Services for Mitochondrial Disorders, which provide multidisciplinary teams and family support.

A clinical genetics service can explain whether testing relatives on the maternal side is appropriate, and what a result would and would not tell them given the variable effect of the variant.

There is no cure for MELAS, MIDD or other m.3243A>G-related disease. The Lily Foundation says management focuses on treating symptoms, supporting organ function, reducing complications and improving quality of life. Current plans may include diabetes care and blood sugar monitoring, hearing aids or cochlear implants, anti-seizure medicines for epilepsy, physiotherapy, occupational therapy and tailored exercise advice, speech and language therapy and nutritional guidance. During stroke-like episodes hospital treatment may be needed.

For women who carry a mitochondrial DNA variant, the NHS Genomics Education Programme records that the first UK licence for mitochondrial donation was approved by the Human Fertilisation and Embryology Authority in 2017, using an egg from a donor with healthy mitochondria in which the donor's nuclear DNA is replaced with the mother's. A clinical genetics service can explain which reproductive options are available and how they apply to a particular variant.