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The Diagnosis Process

There are many misconceptions about how the diagnosis of mitochondrial disease is made.  The diagnosis of mitochondrial disease is not a simple process for many reasons:

  1. The classification system for mitochondrial disease is incomplete and not clinically-oriented;
  2. The abnormality can vary from tissue to tissue within the same person, and perhaps within the same organ as well;
  3. There is no consistent, diagnostic abnormality for all patients with mitochondrial disease (Haas, 2007).  This includes blood and urine testing, functional assays, and radiologic abnormalities;
  4. Diagnostic abnormalities in tissue are not consistently present and may be age-dependent.  For example, the typical "ragged red fibers" (noted in certain defects especially those associated with mtDNA affecting tRNA) may not be apparent in all patients with the disease (Mancuso, 2007), or may not be evident in the muscle of young children (Nonaka, 1988).  The majority of mitochondrial patients do not show any consistent histologic abnormalities.
  5. For some disorders, like those involving the complexes within the respiratory chain, it is not possible to clearly differentiate primary defects from secondary dysfunction.  Defective oxidative phosphorylation is described in other genetic and metabolic diseases (Feillet, 2000; Hayasaka K, 1982; Haas, 2007) and  neuromuscular disorders (Bradley, 2000; Clarencon, 2006), and can occur in malnourished states (Morava, 2006) or in association with certain medications (Ponchaut, 1993);
  6. The methodology used for some testing (e.g., enzyme testing within the respiratory chain) does not always allow for reproducible results between laboratories;
  7. The science necessary for confirming a diagnosis is not sophisticated enough at this time to identify all cases.


All these reflect the fact that we do not yet have complete understanding of mitochondrial disease and its physiology.  Therefore while one must be cautious in making a diagnosis, one should also appreciate the great challenge in trying to definitively "rule out" such a diagnosis.  It creates an uncomfortable dilemma for both patients and clinicians and is a cause for significant anxiety.  Assigning a label too casually runs the risk of limiting the diagnostic thinking about that case, and can lead to inappropriate genetic and prognostic counseling.  However, maintaining too rigid a diagnostic position can also directly impact a patient's clinical care by withholding the implementation of interventions that can ameliorate symptoms, and by closing options that would otherwise allow better insurance coverage and educational services.  Such practical concerns can influence the quality of a patient's (and therefore a family's) life.

Diagnostic scoring systems have been developed to calculate the likelihood of a patient having a mitochondrial disease (Morava, 2006).  Such systems can be complicated though helpful but they operate under the assumption that the phenotypic presentation of all mitochondrial disease is clear and identifiable (since the scores are assigned based on data drawn from patients with known disease).  If one admits that our understanding of mitochondrial disease remains incomplete and our diagnostic testing ability imperfect, the utility of a diagnostic scoring system in identifying all cases must also be limited (although most effective in more obvious cases).

Perhaps the only way to make a diagnosis of a primary mitochondrial disease with absolute certainty at this time is to identify a DNA abnormality (mitochondrial or nuclear) that is known to cause disease.  Without that, the best one can do is "build a case" for a diagnosis by using several diagnostic approaches.  The more abnormalities that one finds in different categories that make sense with each other and which are consistent with an underlying energy diagnosis, the more certain one can be about a primary mitochondrial diagnosis.  These diagnostic approaches include:

  1. Biochemical testing in blood, urine, and CSF (e.g., blood and CSF lactate, lactate/pyruvate ratios, abnormal urine organic acid profiles).  This can also include testing for evidence of mitochondrial dysfunction (e.g., fatty acid oxidation dysfunction, paradoxical ketosis);
  2. Brain imaging (e.g., MRI), looking for bilateral or symmetric lesions, especially in the basal ganglia or thalamus, brain stem, white matter, or cerebellum.  Cerebral and/or cerebellar atrophy may also be observed (Wray, 1995);
  3. Histologic findings in affected tissue (usually muscle) causing abnormalities in size, shape, number, or structure of the mitochondria.
  4. Histochemical or immunohistochemical abnormalities or abnormal Western blot testing suggesting the presence of defective proteins;
  5. Enzymatic assays of respiratory chain complexes, and/or polarographic measurement of oxygen consumption by oxidative phosphorylation;
  6. Multi-system organ involvement where the organs of concern are affected in a way described in mitochondrial disease (e.g., sensorineural hearing loss, renal tubular dysfunction, gut dysmotility, autonomic dysfunction);
  7. Family history of mitochondrial disease, especially in first-degree relatives.

Findings in any one of these categories is not sufficient to make a diagnosis.  An elevated lactic acid can be found in any number of metabolic disease groups.  White matter disease is also characteristic of other disorders, such as lysosomal leukodystrophies; similarly cerebral or cerebellar atrophy has a broader differential diagnosis.  Enzymatic abnormalities may be a secondary phenomenon reflecting mitochondrial dysfunction associated with some other non-mitochondrial disease diagnosis.  Furthermore, not all patients with proven disease show biochemical features, or MRI findings, or histologic abnormalities, and perhaps enzymatic abnormalities as well.

Because mitochondrial disease is hard to diagnose and difficult to rule in or out, and because many symptoms of mitochondrial disease are non-specific (like chronic fatigue), it is important to consider in the differential diagnosis (when appropriate) disease entities with symptoms that overlap with the phenotype of energy disorders.  These include autoimmune disease, endocrinopathies, chronic infection, neuromuscular disease, and psychiatric illness, as well as other entities such as fibromylagia and chronic fatigue syndrome.  At the very minimum, especially in adult patients, these should be considered seriously before a formal mitochondrial evaluation is performed (unless the patient's phenotype strongly suggests otherwise).

When a diagnosis is made without absolute certainty, it is reasonable to have the patient re-evaluated from time to time by a geneticist or neurologist (or other specialist depending on the phenotype) to make sure other reasonable diagnoses are being considered and that mitochondrial disease remains the best working diagnosis.

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