The mitochondrial diseases they are a highly heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They are the result of spontaneous or inherited mutations, either in mitochondrial DNA or in nuclear DNA.
These mutations lead to altered functions of proteins or RNA (ribonucleic acid) molecules that normally reside in mitochondria. The mitochondrial respiratory chain is made up of five complexes (I, II, III, IV and V) and two molecules that act as a link; coenzyme Q and cytochrome c.
The wide range of alterations in mitochondrial oxidative metabolism conditions heterogeneous conditions included under the name of mitochondrial diseases. But, to better understand what these disorders consist of, we must know what mitochondria are.
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Mitochondria are cytoplasmic organelles involved in oxidative phosphorylation. They are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth..
When mitochondria fail, less and less energy is generated within the cell causing cell damage and even cell death. If this process is repeated throughout the body, the entire systems begin to fail, and the life of the person who suffers it can be seriously compromised..
The disease mainly affects children, but the onset of the disease in adults is becoming more and more common..
Each human cell is known to contain thousands of copies of mitochondrial DNA. At birth, they are usually all identical, which is called homoplasmy. In contrast, individuals with mitochondrial disorders can harbor a mixture of mutated and wild-type mitochondrial DNA within each cell, which is called heteroplasmy..
While some mitochondrial disorders only affect a single organ, many other mitochondrial disorders involve multiple organ systems and often have neurological and myopathic features. Mitochondrial disorders can occur at any age.
In terms of prevalence, mitochondrial disorders are more common than previously believed, to the point of being one of the most common inherited metabolic disorders.
Based on available data, a conservative estimate of the prevalence of mitochondrial diseases is 11.5 per 100,000 population..
Because mitochondria perform so many different functions in different tissues, there are literally hundreds of mitochondrial diseases. Each disorder produces a spectrum of symptoms and signs that can be confusing to patients and clinicians in the early stages of diagnosis..
Due to the complex interaction between the hundreds of genes and cells that must cooperate to keep our metabolic machinery running smoothly, it is a hallmark of mitochondrial diseases that identical mitochondrial DNA mutations can produce non-identical diseases..
Thus, some of the most frequent syndromes and signs of mitochondrial pathology are the following:
The symptoms of mitochondrial diseases are very varied and depend on where the damage is located, among other things.
Some mitochondrial disorders affect only one organ, but most involve multiple systems. Therefore, the most common general symptoms of mitochondrial disease include:
Symptoms related to the central nervous system fluctuate frequently and include:
Mitochondrial disorders can be caused by defects in nuclear DNA or mitochondrial DNA. Nuclear genetic defects can be inherited in an autosomal dominant or autosomal recessive manner. Mitochondrial DNA defects are transmitted through maternal inheritance.
Mitochondrial DNA deletions generally occur de novo and therefore cause disease in only one member of the family.
The father of an affected individual is not at risk for the pathogenic variant of mitochondrial DNA, but the mother of an affected individual generally has the pathogenic mitochondrial variant and may or may not have symptoms.
With over 1,000 nuclear genes encoding mitochondrial proteins, molecular diagnosis can be challenging.
For this reason, the diagnosis of mitochondrial diseases is based on clinical suspicion, suggested by the data of the anamnesis, the physical examination, and the results of general complementary examinations. Later, specific tests for mitochondrial dysfunction are performed.
The examinations usually necessary in the process of studying the disease include:
For example, bilateral hyperintense signals in the basal nuclei have been found to be typical of Leigh syndrome..
Infarct-like lesions in the posterior cerebral hemispheres are present in MELAS syndrome, while diffusely abnormal signals from the cerebral white matter are visualized in Kearn-Sayre syndrome..
Basal ganglia calcifications are common in MELAS and Kearn-Sayre syndrome.
An initial metabolic study is also usually carried out to later carry out diagnostic confirmation tests such as morphological and histoenzymatic studies, electron microscopy, biochemical study and genetic study aimed at demonstrating alterations in mitochondrial DNA and in the future also nuclear DNA..
Regarding the genetic study, it is found that in some individuals, the clinical picture is characteristic of a specific mitochondrial disorder and the diagnosis can be confirmed by the identification of a pathogenic variant of mitochondrial DNA
Instead, in most individuals, that is not the case, and a more structured approach is needed, studying everything from family history, blood tests and / or cerebrospinal fluid lactate concentration to neuroimaging studies, cardiac evaluation, and molecular genetic testing.
Finally, in many individuals in whom molecular genetic testing does not provide much information or cannot confirm a diagnosis, a variety of different clinical trials can be performed, such as a muscle biopsy for respiratory chain function..
There is no specific curative treatment for mitochondrial diseases. Treatment of mitochondrial disease is largely supportive, palliative, and may include early diagnosis and treatment of diabetes mellitus, heart rhythm, correction of ptosis, replacement of intraocular lenses for cataracts, and cochlear implantation for sensorineural hearing loss.
General measures include:
Between the pharmacological measures they find each other:
Mitochondrial diseases normally constitute degenerative processes, although in certain cases they may have a chronic stationary course, in the form of recurrent neurological manifestations and even show spontaneous improvement until recovery, as occurs with benign COX deficiency..
The prognosis is usually better in pure myopathic forms than encephalopathic ones. The disease in children is usually more aggressive than in people in whom it manifests itself as adults.
The treatment in general does not achieve more than a slowdown of the natural process, with some exceptions among which are primary processes of deficiency in CoQ10 or carnitine.
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