These diseases are linked to the mitochondria, the cellular organelles responsible for generating most of the cell’s energy supply (ATP). Mitochondria are called the cell’s “powerhouse”. In a mitochondrial disease, the mitochondria fail to produce enough energy for the body’s systems to function. The mitochondria take part in the metabolism of lipids, amino acids, fatty acids and additional metabolites essential for the cell. Changes in the mitochondrial metabolism have repercussions mainly in early childhood illnesses, but also in aging processes and degenerative illnesses like Parkinson’s, Alzheimer’s, cardiovascular diseases and diabetes.
In mitochondrial diseases, the main problem lies in the mitochondria’s function: generating intracellular energy through the cellular respiratory chain. Failure in the mitochondria’s function can damage the cell’s activity and lead to cell death. When the production of ATP (the molecule that is responsible for providing cellular energy) is affected, this can affect all the organs. The most common damage is to organs and tissues which have the highest energy consumption, like the brain, the muscles, and the heart. The damage can manifest itself through a severe attack or a slow deterioration.
The damage can begin already in the womb. For instance the fetus might be small for the gestational age, or there might be problems in the fetus’ brain development. The damage might be observed immediately after birth, or might be gradual and manifest itself in non-specific symptoms, like slow or delayed development, a smaller than normal head circumference, muscular hypotonia, or developmental regression, especially in conjunction with feverish illnesses. A mitochondrial disease can appear in a child who was healthy until then. It can come as an attack when there’s a feverish illness, when the baby is not eating properly, and there’s a regression in the baby’s alertness and functioning, due to a lack of energy, precisely when the body is most in need of energy. The multiple-organ damage can be temporary or chronic. A specific bodily function might be lost, or there might be a regression and then a gradual return to the previous functional level, until the next attack. It is therefore evident that the clinical symptomatic manifestations are very diverse.
Mitochondrial diseases can manifest themselves in muscular weakness, in a decline in cognitive abilities or an impairment in cognitive development, a visual decline and at times even blindness, a nerve-related auditory decline, epilepsy, loss of equilibrium, heart failure, thickening of the heart muscle, hepatic failure, renal disease, and even diabetes. The range of neurological symptoms is very wide.
The genetic causes behind this group of diseases are numerous and diverse, and an exact genetic diagnosis is not always feasible.
Most of the genetic/hereditary material, the DNA, is found in the chromosomes in the cell nucleus. A small portion of the genetic material is in the mitochondria.
Mitochondrial diseases are caused by changes in dozens of genes, and therefore, the hereditary possibilities are manifold. The most common hereditary pattern is the Mendelian (classical) autosomal recessive inheritance, where both parents are carriers of a specific defective gene which is encoded in the cell nucleus. In every pregnancy there is a 25% risk of transmitting the disease to the child.
The specific hereditary pattern, which exists only in the group of mitochondrial diseases, is the maternal inheritance. In this pattern, the mother transmits the mutation to all of her children, and subsequently only the girls will transmit the mutation to their children. The manifestation of the disease will be determined by the amount of mitochondrial DNA that has the mutation
Written by Prof. Tally Lerman-Sagie, Head of Pediatric Neurology and Metabolic Diseases – Wolfson Medical Center (translated by Eric Bymel)
Updated (2019) by Miri Yanoov-Sharav, Genetic Counselor, The Institute of Genetics, Wolfson Medical Center
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