MITOCHONDRIAL DISEASEA SIMPLIFIED APPROACH TO A CHALLENGING DIAGNOSIS

N E U R O L O G Y A T M A Y O C L I N I C

M A Y O M E D I C A L L A B O R A T O R I E S . C O M / N E U R O L O G Y

A CHALLENGING DIAGNOSISMitochondrial disease is caused by mutations in

either nuclear DNA or mitochondrial DNA that

lead to a loss or decline of energy production by

the mitochondria. There are several aspects of

mitochondrial disease that can make identifying

and diagnosing these patients challenging.

} 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 may also yield different results for the same analysis.

THE MAYO CLINIC SOLUTION: EXPERTISE AND EXPERIENCEThe 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 team of genetic counselors are available to support test selection and test interpretation ensuring the most appropriate test utilization for each patient.

A SIMPLIFIED APPROACHIn addition to radiological and histological findings, the results of biochemical and molecular lab tests are a key part of the diagnostic process. Mayo Medical Laboratories (MML) offers a full menu of biochemical testing, which is often one of the first steps in diagnosing a mitochondrial disorder. MML 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.

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M I T O C H O N D R I A L D I S E A S E

BIOCHEMICAL TESTINGThe 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.

}Growth Differential Factor 15, Plasma (Mayo ID: GDF15)}Organic Acids Screen, Urine (Mayo ID: OAU)}Amino Acids, Quantitative, Plasma (Mayo ID: AAQP)}Coenzyme Q10, Total, Plasma (Mayo ID: TQ10)}Fatty Acid Profile, Mitochondrial, Serum (Mayo ID: FAPM)}Lactate, Plasma (Mayo ID: LAA) or Lactate, Body Fluid (Mayo ID: LABF)}Pyruvic Acid, Blood (Mayo ID: PYR) or Pyruvic Acid, Spinal Fluid (Mayo ID: PYRC)}Pyruvate Dehydrogenase Complex, Fibroblasts (Mayo ID: PDHC)

MOLECULAR TESTINGConfirming a mitochondrial diagnosis or identifying a specific mitochondrial syndrome requires molecular testing. MML 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.

GDF15: A NOVEL BIOMARKER FOR MITOCHONDRIAL DISEASEMitochondrial 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 and specific 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 specificity and sensitivity for mitochondrial disease with the exception of NARP and PDHC-deficient patients and a small subset of MELAS patients. GDF15 appears to have a useful role, alongside other mitochondrial disease biomarkers, such as blood lactate, in the evaluation of patients with a suspected mitochondrial disorder.

}Mitochondrial Full Genome Analysis by Next-Generation Sequencing (Mayo ID: MITOP) Next-generation sequencing is used to test for the presence of mutations within the mitochondrial genome including 13 protein coding genes, 22 tRNA genes, and 2 rRNA genes.

}Mitochondrial Nuclear Gene Panel by Next-Generation Sequencing (Mayo ID: MITON) Next-generation and Sanger sequencing are used to identify mutations within the 176 nuclear genes included on the panel.

}Combined Mitochondrial Analysis, Mitochondrial Full Genome and Nuclear Gene Panel (Mayo ID: MITOT) Next-generation sequencing is used to test for the presence of mutations within the mitochondrial genome (includes 13 protein coding genes, 22 tRNA genes, and 2 rRNA genes) and next-generation and Sanger sequencing are used to evaluate for 176 nuclear genes.

COMPREHENSIVE TEST OPTIONS FOR MITOCHONDRIAL DISEASE

FOR MORE INFORMATION ABOUT NEUROLOGY TESTING, VISIT:MayoMedicalLaboratories.com/neurology

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COLLEGIAL ACCESS TO MAYO CLINIC CLINICIANS, LABORATORIANS, AND GENETIC COUNSELORS

Mayo Medical Laboratories supports the local delivery of health care services, so when assistance is needed with testing options, result interpretation, or case review and coordination, Mayo Clinic clinicians, laboratorians, and genetic counselors are available to discuss questions with you. This rapport also provides the opportunity for general practice discussions among colleagues.

MAYO CLINIC GENETICS LABORATORY CONSULTANTS

1. LINDA HASADSRI, M.D., PH.D.

2. W. EDWARD HIGHSMITH, JR., PH.D.

3. DEVIN OGLESBEE, PH.D.

GENETIC COUNSELORS

4. ANGELA PICKART, M.S., CGC

5. AMY L. WHITE, M.S., CGC

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