Mitochondrial disease

A simplified approach to a challenging diagnosis

The symptoms and age of onset of even classic syndromes can vary substantially among individuals — even within the same family. Even the well-described, classic mitochondrial syndromes frequently have atypical presentations.

There are several modes of inheritance for mitochondrial disease. Mutations in mitochondrial DNA are maternally inherited. However, each cell contains many mitochondria — some with and some without the mutation — which may result in localized symptoms and varying severity at age of onset. Mutations in the nuclear DNA can be inherited in either an autosomal recessive, autosomal dominant, or X-linked manner.

Lab work can often give conflicting results. A standard biochemical workup will frequently demonstrate some normal and some abnormal results. Different specimen types also may yield different results for the same analysis.

A simplified approach

The challenge in mitochondrial diagnostics does not involve generating test results; it involves the appropriate interpretation of those results. The complexity of mitochondrial disease and the amount of clinical and lab data that is collected on each patient requires a great deal of expertise to integrate and understand. Our test interpretations are supported by a team of experts in mitochondrial disease. Our laboratory directors work closely with genetic counselors, neurologists, and medical geneticists to bring together a wealth of knowledge and experience in both laboratory and clinical practice. Our genetic counselors are available to support test selection and test interpretation, ensuring the most appropriate test utilization for each patient.

In addition to radiological and histological findings, the results of biochemical and molecular lab tests are a key part of the diagnostic process. Mayo Clinic Laboratories offers a full menu of biochemical testing, which is often one of the first steps in diagnosing a mitochondrial disorder. Mayo Clinic Laboratories also offers three molecular test options, which can confirm a mitochondrial diagnosis and identify a specific mitochondrial syndrome. Rather than a series of targeted panels or single-gene analyses, our recommended approach is to sequence the entire mitochondrial genome and/or a comprehensive nuclear gene panel. This approach is key to avoid time-consuming sequential testing odysseys.

GDF15: A novel biomarker for mitochondrial disease

Mitochondrial diseases are heterogeneous conditions related to mitochondrial respiratory chain dysfunction due to mitochondrial DNA or nuclear gene variants. Clinical manifestations range from early-onset, acute metabolic dysfunction to intermittent, and progressive, neuromyopathic decline. As manifestations are variable, clinicians need more sensitive biomarkers. GDF15 has been shown by studies on mitochondrial disease patients to be significantly elevated in plasma or serum.

Based on our experience and review of recent publications, GDF15 demonstrates high sensitivity for mitochondrial disease, with the exception of NARP and PDHC-deficient patients and a small subset of MELAS patients. High elevations of GDF15 appear to have a useful role, alongside other mitochondrial disease biomarkers, such as blood lactate, in the evaluation of patients with suspected mitochondrial disorders.

Which test should I order?

Biochemical testing

The diagnostic process for mitochondrial disease typically begins with a set of biochemical tests that, when abnormal, can be indicative of a metabolic disorder. Correlating biochemical laboratory results with the clinical presentation and other test results can further confirm suspicion of mitochondrial disease.

Molecular testing

Confirming a mitochondrial diagnosis or identifying a specific mitochondrial syndrome requires molecular testing. Mayo Clinic Laboratories offers three test options to analyze either the mitochondrial genome, a comprehensive panel of nuclear genes involved in mitochondrial disease, or both. For a complete list of genes included in our sequencing panels, please visit our online test catalog.

A Test in Focus

Linda Hasadsri, M.D., Ph.D., gives an overview of the three molecular mitochondrial tests. She discusses when this testing should be ordered, how this testing improves upon previous testing approaches, and what clinical action can be taken due to the results of this testing.

Learn more about how to order these evaluations at your institution.