Clinicians may be able to avoid unnecessary fear and inappropriate care by categorizing patients as “diagnosis uncertain” instead of “possible” mitochondrial disease when suspected cases have not yet been genetically confirmed, a review study suggests.
In addition, a definitive diagnosis requires the detection of a disease-related genetic defect, according to the researchers who conducted the study, which was titled “Diagnosis of ‘possible’ mitochondrial disease: an existential crisis” and published in the Journal of Medical Genetics.
Despite recent progress, the variable disease manifestations and the limitations of currently available testing methods still make diagnosis of mitochondrial disease challenging. Terms such as “unlikely,” “probable,” and “possible” mitochondrial disease were proposed prior to genetic testing and relied on biochemical functional tests.
Still, suspicion for the possibility of mitochondrial disease is appropriate in the presence of multisystem involvement or so-called “red flags,” such as stroke-like episodes in a non-vascular (blood vessel) distribution, as seen in mitochondrial encephalomyopathy, lactic acidosis and stroke (MELAS) syndrome.
However, genetic testing has shown that non-mitochondrial disorders may present with symptoms suggesting mitochondrial disease, leading to misdiagnosis. These disorders may also be associated with mitochondrial dysfunction — impaired function of mitochondria, which provide energy to cells — on biochemical testing. Clinicians therefore need to be cautious when considering mitochondrial disease and ensure that even “red flag” features are in the correct context of coexisting symptoms, family history, and course of disease.
Biochemical screening in blood, urine, and cerebrospinal fluid — the liquid surrounding the brain and spinal cord — remains the first method of choice in cases of suspected mitochondrial disease. Mitochondrial DNA (mtDNA) and whole genome sequencing are among other currently used options. Although it is still important to better understand the relevance of any variants found in blood, tissue analysis should no longer be considered when genetic testing is available.
Biochemical testing for parameters such as lactate, amino acids, and organic acids has less-than-optimal sensitivity and specificity. The growing number of other genetic disorders also with widespread mitochondrial dysfunction, such as spinal muscular atrophy, further cautions against the use of biochemical analysis, the researchers added.
Rapid and relatively low-cost sequencing technologies have enabled genetic diagnosis in an increasing number of patients with mitochondrial disease. The list of genes in the cell nucleus associated with mitochondrial disease has been growing. However, the ability to detect pathogenic mutations in suspected primary disease (as opposed to secondary, when mitochondrial dysfunction is also found in other disorders) via genetic studies has still not been perfected.
Genetic testing of mtDNA in white blood cells has limitations such as the tissue specificity of mutations and mistakenly attributing common mtDNA alterations as the cause of a patient’s symptoms. As a result, analysis in tissues such as the skeletal muscle or the liver may be needed, as well as assessing mtDNA copy number compared with reference values.
Despite its limitations, “the need for genetic confirmation of a [mitochondrial disease] diagnosis is becoming a necessity,” the scientists wrote. Accurate diagnosis with this type of testing “allows care providers and affected families to better understand the condition, for the provision of appropriate genetic counselling, and for the development of targeted therapies.”
With the growing number of clinical, biochemical, and genetic data on primary mitochondrial disease, a definitive diagnosis “should only be provided when a confirmed pathogenic genetic defect has been identified,” they said. Patients with biochemical and clinical evidence for such diagnosis should still be periodically re-evaluated, according to them.
Having a diagnosis of a “possible” or “suspected” mitochondrial disease may lead to not being periodically reassessed for a more specific diagnosis with up-to-date tools. It might also be misleading to patients and families, who may fear the progressive nature and complications associated with these disorders, the scientists said. “Possible” mitochondrial disease may also lead to inappropriate care and overmedication as well as not looking for alternative causes for new symptoms.
In the absence of a confirmed genetic diagnosis, clinicians should use labels to make it clear that diagnosis is uncertain, the researchers recommend. Using “genetic diagnosis uncertain” along with a specific description of the identified alterations is preferable to using “possible,” “probable,” or “suspected” mitochondrial disease, they said. This would keep clinicians and patients engaged in finding a definitive diagnosis and avoid fear of a degenerative disease.
Also, categorizing patients as high-risk for a primary mitochondrial disease could allow for close monitoring of related comorbidities (coexisting conditions). In especially suggestive cases, it may be appropriate to manage patients as if they have a genetically confirmed disease until — and if — their clinical status changes, the investigators suggested.