||Coenzyme Q10 (Leukocytes) (MET04) is used for diagnosis of Coenzyme Q10 (CoQ10) deficiency that is inherited or acquired. Coenzyme Q10 (Leukocytes) (MET04) may also be used for assessment of Variants of Uncertain Significance (VUS) identified during genetic testing (e.g. Next Generation Sequencing or Capillary Sequencing Testing). CLINICAL Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized. Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial respiratory chain responsible for oxidative phosphorylation, where it functions as an electron carrier and acts as an antioxidant. It is found in all cell membranes and is carried by lipoproteins in the circulation. Approximately 60% of CoQ10 is associated with low-density lipoprotein (LDL), 25% with high-density lipoprotein (HDL), and 15% with other lipoproteins. CoQ10 is present in the body in both the reduced and oxidized forms, with the antioxidant activity of CoQ10 dependent not only on its concentration, but also on its reduction-oxidation (redox) status. Primary CoQ10 deficiency, although rare, is characterized by neurological symptoms (seizures, developmental delay, ataxia, etc) and muscle weakness. CoQ10 has been implicated in other disease processes, including Parkinson disease, diabetes, and Alzheimer disease, as well as in aging and oxidative stress. CoQ10 may also play a role in hydroxymethylglutaryl-CoA reductase inhibitor (statin) therapy; changes in CoQ10 may be relevant to statin-induced myalgia. At least 5 different phenotypes of primary CoQ10 deficiency have been described: Encephalomyopathy (elevated serum creatine kinase [CK], recurrent myoglobinuria, lactic acidosis) -Childhood-onset cerebellar ataxia and atrophy (neuropathy, hypogonadism) -Multisystemic infant form (nystagmus, optic atrophy, sensorineural hearing loss, dystonia, rapidly progressing nephropathy) -Glomerulopathy -Myopathy (exercise intolerance, fatigue, elevated serum CK) Treatment with CoQ10 in patients with mitochondrial cytopathies can improve mitochondrial respiration in both brain and skeletal muscle. DIAGNOSIS In many cases, a single test is insufficient for diagnosis of mitochondrial disease. However, detection of a known pathogenic variant in an individual may be diagnostic. The clinical outcome of the processfor diagnosis of mitochondrial disease is recommended to be a statement of how probable it is that the patient has a primary mitochondrial disease on a scale ranging from “unlikely” to “definite.” In between are “possible” and “probable” mitochondrial disease designations. In some individuals, the clinical picture is characteristic of a specific mitochondrial disorder (e.g., LHON, NARP, or maternally inherited LS), and the diagnosis can be confirmed by identification of a mtDNA mutation on molecular genetic testing of DNA extracted from a blood sample. In many individuals, such is not the case, and a more structured approach is needed, including family history, blood and/or CSF lactate concentration, neuroimaging, cardiac evaluation, and molecular genetic testing for a mtDNA or nuclear gene mutation. Approaches to molecular genetic testing of a proband to consider are serial testing of single genes, multi-gene panel testing (simultaneous testing of multiple genes), and/or sequencing of the entire mitochondrial genome. In many individuals in whom molecular genetic testing does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function. MANAGEMENT Treatment with CoQ10 in patients with mitochondrial cytopathies can improve mitochondrial respiration in both brain and skeletal muscle.