From the Guidelines
The workup for primary mitochondrial diseases should begin with a thorough clinical evaluation, including a detailed family history, physical examination, and neurological assessment, as these conditions can affect any part of the body and present with a wide range of symptoms 1. When evaluating a patient with suspected primary mitochondrial disease, it is essential to consider the diverse clinical presentations and the potential involvement of multiple organ systems.
Key Components of the Workup
- Initial laboratory testing should include:
- Complete blood count
- Comprehensive metabolic panel
- Lactate and pyruvate levels (both blood and CSF)
- Plasma amino acids
- Urine organic acids
- Acylcarnitine profile
- Elevated lactate-to-pyruvate ratio is often seen in mitochondrial disorders, and this finding can guide further diagnostic testing 1.
Diagnostic Procedures
- Muscle biopsy remains a crucial diagnostic procedure, allowing for:
- Histological examination (looking for ragged red fibers with modified Gomori trichrome stain)
- Electron microscopy (to identify abnormal mitochondrial structure)
- Biochemical analysis of respiratory chain enzyme activities
- Neuroimaging with MRI can reveal characteristic patterns such as stroke-like lesions in MELAS or bilateral basal ganglia lesions.
Genetic Testing and Functional Studies
- Genetic testing has become increasingly important and includes:
- Mitochondrial DNA analysis for point mutations and deletions
- Nuclear DNA testing for mitochondrial-related genes
- Next-generation sequencing panels targeting hundreds of mitochondrial-related genes
- Functional studies may include:
- Fibroblast oxygen consumption rates
- ATP production assays
- Exercise testing to demonstrate reduced endurance and abnormal lactate production A tailored diagnostic approach is necessary, as mitochondrial diseases can affect multiple organ systems with varying severity, and early diagnosis is crucial for appropriate management, genetic counseling, and targeted therapies to improve symptoms and prevent complications 1.
From the Research
Work-up for Primary Mitochondrial Diseases
The work-up for primary mitochondrial diseases involves a combination of clinical evaluation, molecular testing, and other diagnostic modalities.
- Clinical symptoms can range from non-specific fatigue, exercise intolerance, and weakness to syndromic phenotypes 2
- A "genetics first" approach can reduce diagnostic delay and improve management, where the diagnostic pathway can be an invasive or noninvasive combination of targeted or comprehensive molecular testing 2
- Molecular testing can provide an efficient path toward diagnosis, as molecular detection techniques have improved and become less costly 2
- Diagnosis should be made in the context of clinical and molecular data, potentially supplemented with histochemical and biochemical evidence 2
Diagnostic Challenges
Primary mitochondrial diseases are clinically heterogeneous and present diagnostic challenges due to the highly variable genotype-phenotype correlation.
- Multiple testing modalities exist to identify mitochondrial diseases, but most of these tests are nonspecific, or results are associated with other diseases 2
- It is often tempting to assign a patient's phenotype to 'mitochondrial disease', but secondary mitochondrial dysfunction (SMD) is often challenging to distinguish from primary mitochondrial disease (PMD) 3
- Rapid advances in molecular testing, made possible by next generation sequencing, have been effective at least in some cases in establishing accurate diagnoses to distinguish between PMD and SMD 3
Blood Biomarkers
Blood biomarkers can be used to assess mitochondrial dysfunction.
- Biomarkers of three classes have been identified: 1) functional markers measured in blood cells, 2) biochemical markers of serum/plasma and 3) DNA markers 4
- Combining biomarkers that cover different aspects of mitochondrial impairment is probably a good strategy to reveal underlying mitochondrial dysfunction 4
- A biomarker panel may assist in the diagnosis of primary mitochondrial disease patients and enable selection of patients who could benefit from therapies targeting mitochondria 4
Consensus-Based Recommendations
Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.
- The Mitochondrial Medicine Society has published consensus statements on patient care standards for primary mitochondrial disease 5 and diagnosis and management of mitochondrial disease 6
- These statements are intended for physicians who are engaged in the diagnosis and management of patients with primary mitochondrial disease 5, 6