*4.1.3. Cardiac imaging*

Cardiac phenotype association with genetic MD is more common than realized; however, the mechanism of association of some mutations with specific cardiac phenotypes is not clearly understood. Since myocardial cells depend heavily upon mitochondria for its energy requirements, it is no wonder that specific MD involves specific cardiac pathology phenotype.

Although it has been widely accepted that mitochondria play a key role in cardiac pathological conditions, effectively diagnosing mitochondrial dysfunction in the clinical setting has been challenging. MDs often affect multiple organ systems in the body and clinical presentation varies; however, there are a few "tell-tale" signs and combinations that may enable clinicians to better identify MDs [148]. For example, patients with KSS, which is typically associated with single deletion mutations, may present with ptosis, retinal pigmentary abnormalities, ataxia, and cardiac conduction abnormalities [148]. In patients with myoclonic epilepsy with ragged-red fibers (MERRF), myoclonus, cerebellar ataxia, and elevated blood lactate are key symptoms in their presentations [149]. A high suspicion is important when considering a diagnosis of MD. Cardiologists who evaluate patients for hypertrophy, conduction abnormalities, and DCM should be aware of the spectrum of MD so that they can collaborate with MD specialists to make accurate diagnoses. Since there are variabilities in the MD symptom presentations, in addition to the clinical diagnosis, a multiple-parametric approach that involves histological, biochemical, and genetic testing is required to identify abnormalities of blood, urine, or cerebrospinal fluid (CSF) analyte values, microscopic irregularities, biochemical deviations on polarographic assays, or a

It is crucial to understand that not all persons with mtDNA mutations will manifest the symptoms. Nuclear DNA and mtDNA mutation screening can be performed in the consented family, but the challenge remains that only a small proportion of these nDNA mutations have been identified. The presence of family history of maternal inheritance or multisystemic diseases will be important to note. Furthermore, mitochondrial genome screening can also be

Muscle biopsy in conjunction with molecular genetic testing is required for effective diagnosis of MD [151]. A major feature of the histological result of the biopsy using the Gomori Trichrome stain shows >2% ragged red fibers that come from the sub-sarcolemmal mitochondrial accumulation. However, these ragged red fibers are present only in the late stage of the disease and commonly absent in children [132]. The key diagnostic feature is the presence of fibers that are deficient for cytochrome c oxidase (COX) activity [with >2% of COX negative fibers], reflecting low activity of complex IV of the respiratory chain, in patients less than 50 years [148, 151]. COX activity may be decreased in healthy older patients, so its use in diagnosis is limited to

**4. Clinical applications**

46 Mitochondrial Diseases

diagnostic genetic finding [150].

performed on the muscle sample [132].

*4.1.1. Genetic tests*

*4.1.2. Laboratory tests*

**4.1. Diagnosis of mitochondrial dysfunction in heart disease**

The cardiac presentation of MD patients varies; however, progressive cardiac conduction defects may develop into a complete heart block in KSS, while Wolff-Parkinson-White (WPW) syndrome can develop in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome owing to the m.3243A > G mutation [153, 154]. There is no characteristic manifestation of cardiomyopathy that differentiates MD, although HCM is common [150]. Cardiac imaging using cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) can be used to effectively evaluate the heterogeneous presentation of HCM, offering a more reliable measurement of all segments of the heart than echocardiography [155].
