small microscope

Mito Dx & reDx- the importance of the RIGHT Diagnosis

False positive mitochondrial diagnoses based on muscle biopsy results have become a prominent issue for discussion and consideration over the past 6 to 10 years. With the exponential advances in molecular techniques over the last three or four years, I have been able to definitively determined that a number of patients previously diagnosed with a mitochondrial disease by muscle biopsy indeed have other primary diseases as the cause for their problems.

What clinical parameters have led some of us to re-investigate previously diagnosed mitochondrial patients and, what is the purpose of doing so?

A brief historical perspective on the evolution of mitochondrial testing is warranted in this discussion for better understanding of how our diagnostic tools have progressed most recently with the advent of molecular testing.

Some of the first documented patients with mitochondrial disorders were described in the 1930's in adults who developed a neurodegenerative course resulting in their demise. In these patients, autopsy samples identified histological mitochondrial changes in their tissues suggestive of mitochondrial energy disorders as causative for their clinical course. Thirty years later, some of the first mitochondrial gene mutations were identified causing well described disorders such as MERRF and MELAS. Biochemical analysis of primarily muscle tissue to assess the mitochondrial electron transport chain also became clinically available. A disease with a presumed incidence of one in 50,000 to 100,000 was soon recognized as occurring more frequently in the general population with recent data supporting a 1 in 5000 incidence.

In the 1990's, the increased  awareness of this heterogeneous group of disorders as a potential cause of disease led to frequent evaluation of a wide spectrum of patients with a host of clinical features for possible mitochondrial disease. Many of these patients were found to have biochemical abnormalities on muscle biopsy leading  to classification as mitochondrial disease. However, with the passage of time, some of these patients did not develop the typical clinical course seen with mitochondrial disease, specifically progressive multi-system problems nor were they found initially or over time to have many of the biochemical abnormalities often seen with the disease leaving many clinicians to wonder whether primary mitochondrial disease was indeed the definitive cause for these patients problems. In addition, some patients had the predominance of a critical clinical feature seen with but often not the primary finding of mitochondrial disease leading to consideration of another disease process.

In the last five years, with the development of more advanced molecular techniques, suspicions for other diagnoses could now be confirmed with genomic testing in many cases.

Utilizing a variety of newer diagnostic techniques for the clinical concerns outlined above, we have rediagnosed dozens upon dozens of patients previously characterized as having mitochondrial disease with a host of other disorders. This is a result of approaching patients “fresh” so if the clinical presentation matches the diagnosis, fine. If not then while not “taking” away a diagnosis, through discussion with the patient, we begin investigating what may be a better candidate for the cause of their issues. Several examples are outlined below:

  1. A number of patients with myopathies found to have de novo structural muscle gene mutations with far better prognosis than mitochondrial disease.
  2. A number of patients with seizures found to have de novo seizure disorder gene mutations, some associated with improved outcome when treated with specific anticonvulsants.
  3. A number of patients with intellectual disability syndromes, typically non-progressive disorders.

Of note, however, I have also made a number of re-diagnoses in patients with simple diagnostic tools because the managing physicians concerns about other diagnoses were clouded by the abnormal mitochondrial enzymology previously reported in their patients. One dramatic case was a child with hypotonia, macrocephaly, and bowed lower extremities (symptoms were present at time of biopsy) and a previously abnormal biopsy discovered to have treatable hypophosphatemic rickets. 

What is the benefit of more clearly defining the etiology of a given individual's underlying disease process?

Certainly, from a big picture perspective carrying the wrong diagnosis prevents access to appropriate treatment, as was the case in the child with rickets, and clinical treatment trials, the latter important in cases where there is no currently effective  treatment modalities. Accurate diagnosis can also prevent unnecessary screening testing. For example, because mitochondrial disease is a progressive disorder, patients routinely undergo thousands of dollars of screening studies completed yearly to look for the various problems associated with this disease. The identification of another disorder not associated with progressive symptomatology, would prevent the collection of costly and unnecessary studies. Often, ascertaining a definitive diagnosis can impact the extended family particularly in regards to recurrence risks. Many of the seizure disorders and intellectual disability gene syndromes are associated with de novo mutations meaning the disease is linked to a sporadic change in the affected individual only and is not associated with recurrence risk for a given couple. Sadly, I encountered a young couple in their 20s who underwent permanent sterilization due to recurrence risk fears associated with mitochondrial disease only to discover later when I uncovered a de novo seizure disorder mutation in their child that instead of the one in for a 25% recurrence risk that they had been provided that they actually had no risk for having a similarly affected child in a future pregnancy. The provision of that incorrect information to this young couple lead to a life altering and permanent decision.

In summary, then, a number of individuals with presumed mitochondrial disease who undergo reevaluation based on certain clinical and laboratory features or lack there of have been found to have a variety of other disorders some of which are associated with treatment, very different prognoses and in many cases no recurrence risks for future pregnancies or other family members. As such, having the most accurate diagnosis should be sought by all patients and families for the medical benefit of the affected individual and overall benefit of the family at large.


Fran Kendall, M.D.

This post is not meant to be a recommendation or a substitute for professional advice and services rendered by qualified doctors, allied medical personnel, and other professional services. The responsibility for any use of this information, or for proper medical treatment, rests with you.