**5. Assessment and diagnostic process**

The main challenge to correctly establish mitochondrial dysfunction as the cause of the presentation of a specific patient is the absence of a definitive biomarker that characterizes mitochondrial disease in all patients. Thus, the diagnostic assessment is necessarily broad and of many levels, with a focus on integrated training from many sources: complete medical and family history, clinical findings that may suggest a mitochondrial disease, abnormalities of the biochemical laboratory such as lactic acidosis (which, as we analyzed earlier, is not sensitive or specific as an isolated biomarker in many mitochondrial disorders), tissue biopsy tests of the abnormal activity of the electron transport chain enzyme or an alteration of the respiratory capacity, and, if possible, the identification of a pathogenic mutation of mtDNA or nDNA. This process usually involves sophisticated tests that request invasive procedures, such as muscle or liver biopsy to obtain the tissue for assessment in specialized laboratories. These investigations may offer intermediate or ambiguous results, and the decrease in the activities of the enzymes of the electron transport chain may be secondary to non-respiratory chain disorders. To assist in the interpretation, two diagnostic schemes have been proposed for infants and children to classify the probability of a specific patient's mitochondrial disease as clear, probable, possible, or improbable. Recently, guidelines were proposed for the diagnosis and treatment of mitochondrial disorders in infants and children; however, these complex and sophisticated diagnostic algorithms are aimed for the metabolic specialist and have a limited clinical utility for the family physician who contemplates the start of the diagnostic evaluation of a specific patient [20, 21, 87].

The diagnostic evaluation typically begins with the general clinical assessment and goes through the systematic, imaging, and metabolic screening tests up to the most specific biochemical and genetic determinations. This starts with the less invasive evaluations and moves on to the biopsy-based, more invasive analyses, as needed. Obviously, the complete diagnostic process can be complicated and including the early intervention of a local specialist in metabolism can be very useful. Recommendation to a metabolic specialist should occur whenever the symptoms and signs clearly suggest a mitochondrial disease, patients are potentially unstable with the classic features of metabolic disease, there is lactic acidosis in the blood or the cerebrospinal fluid (CSF), a pattern of maternal inheritance is observed, or anomalies are identified in the initial diagnostic assessment. Referral by a primary care physician is also prudent when a more elaborate study is necessary, such as a provocation test or a muscle biopsy with the study of the enzymes of the electron transport chain [79, 88]. If a biochemical diagnosis has been established but its molecular basis remains unknown, further study and genetic counseling should be coordinated by a specialist. Mitochondrial disease is clearly not a single entity but rather a heterogeneous disorder of energy dysfunction caused by hundreds of different mutations, deletions, duplications, and other defects of nuclear and mitochondrial genes. Thus, at present, there is no accepted and gene-based diagnostic algorithm that is useful for all patients or used by all metabolic specialists. The study of nDNA mutations can be performed on any tissue, including blood. However, most of the diagnostic study of nDNA genes should not be done a priori but guided by the clinical picture, the specific headlines, and the biochemical findings in a given patient. On the contrary, the most informative study of mtDNA mutations is performed in a muscle biopsy sample, although urinary sediment and buccal cells may also be useful.

and neuroimaging features of Leigh's syndrome often clearly suggest a mitochondrial disorder, other alterations may give rise to striatal necrosis, which should be taken into account. Similarly, clinical and neuroimaging findings may sometimes suggest other leukoencepha-

**Figure 9.** Medications and toxin in mitochondria: Alteration of mitochondrial function by exogenous metabolites; the main damage affects cell respiration, but also damage in the oxidation of fatty acids is observed. This image is a

The main challenge to correctly establish mitochondrial dysfunction as the cause of the presentation of a specific patient is the absence of a definitive biomarker that characterizes mitochondrial disease in all patients. Thus, the diagnostic assessment is necessarily broad and of many levels, with a focus on integrated training from many sources: complete medical and family history, clinical findings that may suggest a mitochondrial disease, abnormalities of the biochemical laboratory such as lactic acidosis (which, as we

lopathies or degenerative disorders (**Figure 9**) [85, 86].

**5. Assessment and diagnostic process**

modification of QIAGEN's original [Torres-Sánchez ED].

170 Mitochondrial DNA - New Insights

It is important to recognize that dietary advice should always be offered in a specialized setting. In addition, although there are only a few viable therapeutic options for mitochondrial disease, it is best to be offered by clinicians with experience in these disorders [89].

What was once considered a few rare diseases to be described in clinical sessions or in the form of clinical cases in journals are today disorders that are commonly known and observed in a wide range of consultations.

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