**4.3. Multiple deletions of mtDNA**

From the clinical point of view, the multiple deletion syndromes of mtDNA are characterized by progressive external ophthalmoparesis (PEO), ptosis, and proximal muscle weakness associated with signs of involvement of other systems that include the peripheral nerves (sensory-motor neuropathy), the brain (ataxia, dementia, psychosis), the ear (sensorineural deafness), and the eye (cataracts). Genes involved in the homeostasis of the mitochondrial pool of nucleotides are associated with the presence of PEO and multiple deletions in mtDNA. They include ANT1 (encodes the adenosine nucleotide translocator), PEO1 (codes for a helicase known as Twinkle), ECGF1 (which codes for thymidine phosphorylase or TP), POLG (encodes for the catalytic subunit of mitochondrial gamma polymerase), and POLG2 (which codes for a subunit of POLG) (**Figure 8**) [14, 80, 81].

**4.5. Defects in mtDNA translation**

**4.6. Mitochondrial secondary disease**

In the translation of the 13 subunits of the respiratory chain encoded in the mtDNA, the participation of many nuclear coding factors such as polymerases, ribosomal proteins, RNA-modifying enzymes and initiation, elongation, and termination factors, among others, is necessary. These defects result in deep combined deficits of all the respiratory chain complexes. Clinically, they manifest as necrotizing leukoencephalopathies, cardiomyopathies, and hepatocerebral syndromes among others. Genes involved include GFM1 (encodes a ribosomal elongation factor), MRPS16 (encodes the 16 subunit of the mitochondrial ribosomal protein), TSFM (encodes the mitochondrial elongation factor EFTs), and TUFM (encodes the elongation factor Tu) [80, 82, 83].

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Even when a sophisticated biochemical analysis confirms mitochondrial dysfunction, it can be challenging to distinguish whether the cause of this dysfunction is a gene that directly affects the electron transport or is secondary to an unrelated genetic or environmental cause. Thus, the definitive diagnosis of mitochondrial disease cannot be based solely on biochemical findings, since the in vitro activity of the electron transport chain enzyme in a sample of patient tissue may be diminished as a consequence of other metabolic diseases or issues related to the handling of samples. Mitochondrial dysfunction that may or may not be clinically relevant is observed when the main defect lies in another metabolic pathway related to energy, such as the oxidation of fatty acids or the metabolism of amino acids. In addition, alteration of OXPHOS has been observed with decreased in vitro activity of the electron transport chain enzyme in up to 50% in tissue samples from patients with other metabolic diseases [84]. Of course, other diagnoses that have finally been confirmed in individuals with suspected mitochondrial disease and biochemical samples of mitochondrial dysfunction in vitro include disorders of copper metabolism (Menkes disease and Wilson's disease), lysosomal disorders (neuronal ceroid lipofuscinosis and Fabry disease), peroxisomal disorders, neurodegeneration associated with pantothenate kinase, holocarboxylase synthetase deficiency, molybdenum cofactor deficiency, and neonatal hemochromatosis [85]. It is increasingly accepted that the alteration of OXPHOS may contribute to the pathology in some genetic alterations that are not typically classified as mitochondrial or metabolic disorders, such as Rett syndrome, Aicardi-Goutières syndrome, various neuromuscular disorders, and Duchenne muscular dystrophy. In addition, the activities of the electron transport complexes in skeletal muscle can decrease in malnourished chil-

dren, correcting to normal values after improvement of nutrition [41, 74, 86].

Medications and toxins can also significantly alter mitochondrial function. Sodium valproate can alter mitochondrial function by inducing carnitine deficiency, depression of intramitochondrial oxidation of fatty acids, and/or inhibition of OXPHOS, which should suggest the use of an alternative anticonvulsant in mitochondrial disease, especially in patients with POLG1 mutations. Other important examples of drugs that can induce mitochondrial dysfunction are retroviral nucleoside analogs in HIV infection, as well as salicylates that can alter the hepatic mitochondria in Reye syndrome. Since there are so many nonspecific clinical features that can raise the suspicion of mitochondrial diseases, the differential diagnosis can be very broad. The clinical presentation of mitochondrial disease in children can mimic other multisystem disorders, such as congenital disorders of glycosylation or Marinesco-Sjögren syndrome, or even be confused with a syndrome of vascular or immunological stroke. Although the clinical

Mitochondrial neurogastrointestinal encephalomyopathy or MNGIE is a multisystemic disease of autosomal recessive inheritance, of presentation in young adults secondary to mutations in TP (thymidine phosphorylase). It is characterized by PEO, neuropathy, leukoencephalopathy, and severe gastrointestinal dysmotility, leading to profound cachexia and early death. The decrease in thymidine phosphorylase activity leads to a defect in the synthesis of mtDNA, causing not only multiple deletions in the mtDNA but also depletion of same and point mutations that are reflected in the muscle, even though it expresses little TP. The damage, therefore, seems to be mediated by toxins. Thus, thymidine and deoxyuridine are toxic intermediaries that accumulate in the blood of these patients, and their elimination leads to clinical improvement. Different approaches have been carried out to favor the elimination of these toxic intermediaries from the blood, by means of hemodialysis, platelet transfusion, and, finally, allogeneic bone marrow transplantation [35, 80].

Mutations in mitochondrial gamma polymerase (POLG) may occur in the form of PEO at the onset of adulthood and multiple deletions in mtDNA and be accompanied by ataxia, peripheral neuropathy, Parkinsonism, psychiatric symptoms, myoclonic epilepsy, and gastrointestinal symptoms. These disorders can have both dominant and recessive inheritances. An example of a clinical syndrome secondary to mutations in this gene is SANDO (sensory ataxic neuropathy, dysarthria, ophthalmoparesis). Mutations in POLG are also responsible for the Alpers syndrome in children, a recessively inherited disorder characterized by encephalopathy and severe hepatopathy and associated with mtDNA depletion [80].
