Mitochondrial diseases are a group of rare disorders that affect energy production within cells and can therefore impair the function of many organs. They affect both men and women and, in adults, are often responsible for neurological manifestations (cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, abnormal movements, and encephalopathy) as well as complex psychiatric symptoms.
These neurometabolic disorders are managed within our Adult Neurometabolic Reference Center (CRMR) in Paris, in order to ensure an optimal multidisciplinary approach (medical, dietary, neuropsychological, psychological, nursing, and medico-social support).
Table of contents
Cause
Mitochondrial diseases are caused by genetic mutations that affect the function of mitochondria, the organelles responsible for energy production in cells. To fulfil this role, mitochondria possess their own DNA, known as mitochondrial DNA (mtDNA).
Because mitochondria are transmitted to offspring exclusively through the mother, a mother carrying a mutation in mtDNA will generally pass this mutation to all of her children. An affected father does not transmit mtDNA mutations.
Each cell contains several hundred to several thousand mitochondria, each harbouring between two and ten copies of mtDNA. The proportion of mutated mtDNA may vary from one tissue to another. For this reason, several tissues may be sampled for the molecular diagnosis of a mitochondrial disease caused by an mtDNA mutation.
Nuclear DNA also plays a crucial role in mitochondrial function. Mutations in nuclear genes encoding mitochondrial proteins can lead to significant mitochondrial dysfunction and symptoms that may appear from childhood through to adulthood. In these cases, inheritance may be autosomal dominant, autosomal recessive, or X-linked, depending on the gene involved.
Symptoms
Symptoms, their severity, and the age at onset can vary greatly, even within the same family carrying the same mutation. Because of the central role of mitochondria in energy production, the organs most frequently affected are those with the highest energy demands.
The most common manifestations involve the nervous system (central and/or muscular involvement), neurosensory organs (ophthalmological and/or ENT involvement), the heart, and the endocrine system. One of the mitochondrial diseases most frequently encountered is MELAS syndrome (Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes; OMIM #540000), which is associated with a mutation in mitochondrial DNA.
MELAS syndrome may involve a wide range of symptoms, including hearing loss, diabetes, stroke-like episodes, epilepsy, cerebellar ataxia, peripheral neuropathy, muscle involvement, ophthalmological abnormalities, cardiomyopathy, and/or kidney disease.
French national care protocol for MELAS
Treatments
Current treatments are mainly symptomatic and aim to improve patients’ quality of life. Research is ongoing to develop gene therapies and targeted pharmacological treatments. Several small molecules are currently being tested in patients with mitochondrial DNA mutations.
In patients experiencing stroke-like episodes and/or epilepsy that is difficult to control, a ketogenic diet may help achieve good metabolic control and stabilise mitochondrial disease.
