Mitocondria

Genetic diseases of mitochondrial DNA

The diseases caused by damage in the mitochondrial genome have in common that they are produced by a deficiency in ATP biosynthesis, since all the information that this DNA contains is focused on the synthesis of protein components of the Oxphos system. The manifestations of these diseases are extremely varied and can affect all the organs and tissuessince ATP synthesis is produced in all of them and at any age. These diseases can imply a series of very concrete clinical, morphological and biochemical aspects that give rise to well-described syndromes but, for the most part, principally in pediatric ages, the symptoms of which are not very informative. It is only the presence of neurological abnormalities, sometimes accompanied by an increase inlactic acid and other secondary clinical
symptoms that affect diverse organs, that give any guidance to the diagnosis of a mitochondrial disease.17 Among the most common clinical manifestations are one or more of the following: motor disorders, cerebrovascular accidents, convulsions, dementia, exercise intolerance, ptosis, opthalmoplegia, pigmentary retinopathy, optical atrophy, blindness,deafness, cardiomyopathy, hepatic and pancreatic malfunctions, diabetes, growth defects, sideroblastic anemia, intestinal pseudo-obstruction, nephropathies, metabolic acidosis and others which are more secondary.
The presence of one or more of these symptoms then requires a morphologic, histochemical and biochemical study to ensure the nature of these diseases. Thus, the following are often found: red-ripped fibers (accumulation of mitochondria that are abnormal in size and number) in muscular biopsies stained with Gomori trichrome and fibers that are non-reactive to histochemical staining of c cytochrome oxidase; defects in one or more respiratory chain complexes; and metabolic disorders with lactate or piruvate elevation or generalized amino-aciduria caused by a respiratory chain malfunctionthat includes an increase in reductor equivalents in mitochondria and cytoplasm, and an alteration in the Krebs cycle function given the excess NADH, which provokes an accumulation of piruvate and its later conversion into lactate which is distributed in the blood. However, the absence of some of these characteristics should not rule out the possibility of a mitochondrial disease, especially inpediatric patients. In addition, family studies can be decisive if the existence of maternal inheritance of the disease is proven. The genetic study of the patient and his or her maternal relatives can finally confirm that we are faced with this type of problem. Actually, today the development and speed of the molecular genetic techniques allow, at times, confirmation of the disease before havingdone many of the previously mentioned tests. The complexity of the diagnosis of these diseases makes it necessary for patients to visit highly specialized centers where clinical, metabolic, pathologic, biochemical and genetic evaluations can be carried out, and that very diverse types of specialists be involved in the diagnosis.
Since the first diseases caused by mtDNA damage were described in1988,7-9 over 150 mutations have been found (as well as 100 deletions and around 50 specific mutations) that are associated with human diseases. Interest in their study has grown enormously due to the large number of patients diagnosed with these disorders and to the fact that they appear at any life period, from newborns to adults of all ages. In addition, many of these mutations are transmittedthrough the maternal line, as indicated previously, which means an individual’s diagnosis can have implications for many generations in one family.
In spite of the importance that mitochondrial diseases have acquired recently and that they are responsible for a considerable level of morbidity, until now no exhaustive studies have been done on their prevalence in the general population. There are...