Hereditary Coenzyme Q Deficiency Syndromes - Ubiquinone Deficiency

Primary coenzyme Q₁₀ (CoQ10) deficiency conditions have diverse clinical manifestations that are caused by biallelic variants in genes that regulate or encode proteins involved in the coenzyme Q (CoQ) biosynthesis pathway (CoQ10 synthesis genes). Secondary CoQ10 deficiencies are caused by pathogenic variation in genes not directly related to the CoQ10 biosynthetic pathway or by nongenetic factors such as statin use or fibromyalgia. CoQ10 deficiency has a clinical presentation similar to that of many mitochondrial diseases. Unlike other mitochondrial diseases, CoQ10 deficiency is treatable, making definitive diagnosis extremely important for proper medical management. Initial laboratory testing often includes creatine kinase (CK) and lactic acid tests. These measurements are useful, but they cannot provide a definitive diagnosis. As such, genetic testing or biochemical detection of CoQ10 deficiency via muscle biopsy is necessary.

Quick Answers for Clinicians

How is laboratory testing used in coenzyme Q deficiencies?

General laboratory tests to measure creatine kinase (CK) and lactic acid can provide useful information in the initial investigation of coenzyme Q₁₀ (CoQ10) deficiency. However, these tests neither exclude the presence of CoQ10 deficiency nor reveal its etiology. The current gold standard approach for CoQ10 deficiency diagnosis is biochemical measurement of CoQ10 reduction in muscle tissue and histologic examination of muscle biopsy. CoQ10 levels in serum or plasma cannot be used to diagnose deficiency because they are affected by dietary CoQ10 sources. Genetic testing is required to accurately interpret biochemical test results and to differentiate between primary and secondary disease.

How do statins impact coenzyme Q10 levels?

Statins, or hydroxyl-methylglutaryl coenzyme A reductase inhibitors, interfere with the production of a molecular precursor in the coenzyme Q₁₀ (CoQ10) biosynthetic pathway. It has been proposed that this interference may contribute to statin-associated myalgia (SAM), although the actual mechanism of SAM is currently unclear. There are no clinical guidelines that support the use of CoQ10 supplementation for the treatment of SAM at this time.

Indications for Testing

Primary CoQ10 deficiency has a heterogeneous clinical presentation and often demonstrates multisystem involvement. Individuals who present with one or more of the following common clinical phenotypes should be considered for CoQ10 deficiency testing:

Cerebellar ataxia
Steroid-resistant nephrotic syndrome
Encephalopathy
Severe infantile multisystemic disease
Myopathy

Although these presentations are the most widely recognized, the presentation of CoQ10 deficiency may appear similar to that of several mitochondrial disorders. Patients who have tested negative for these disorders should be considered for CoQ10 deficiency testing.

Laboratory Testing

Nonspecific Tests

Initial nonspecific testing may provide evidence suggestive of CoQ10 deficiency. Clinical evaluation should inform the proper use of these tests. Muscle biopsy and/or genetic testing is necessary to provide a definitive diagnosis.

Creatine Kinase

CK is a nonspecific indicator of muscle inflammation or damage. Elevated levels may indicate CoQ10 deficiency but are not diagnostic. For example, patients who exhibit myopathy often exhibit elevated CK, but those with cerebellar ataxia do not.

Lactic Acid

Lactic acid levels in plasma are indicative of muscle-damaging processes. Elevated levels may indicate CoQ10 deficiency but are not diagnostic. CoQ10 deficiency may also be present in patients with normal lactic acid levels.

Muscle Biopsy

Tissue from a muscle biopsy is the gold standard for evaluation of CoQ10 deficiency, although skin fibroblasts, white blood cells (WBCs), cerebrospinal fluid (CSF), and urine can also be used for testing in some cases. Biopsied muscle tissue should be tested for reduced levels of CoQ10 and reduced activity of complex I+III and complex II+III of the mitochondrial respiratory chain (testing not performed at ARUP Laboratories). These tests can differentiate CoQ10 deficiency from other disorders with similar clinical findings but cannot differentiate between primary and secondary CoQ10 deficiency.

Routine morphologic studies of muscle tissue can be useful but often do not yield definitive diagnostic information. Lipid accumulation is a common finding in both primary and secondary CoQ10 deficiency.

Genetic Testing

Primary CoQ10 Deficiency

The diagnosis of primary CoQ10 deficiency can be established by identification of biallelic pathogenic variants in one of the nine CoQ10 synthesis genes (COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, COQ9, PDSS1, or PDSS2).

Secondary CoQ10 Deficiency

The diagnosis of secondary CoQ10 deficiency can be established by identification of biallelic pathogenic variants in genes that cause mitochondrial diseases, oxidative phosphorylation diseases, or other diseases that lead to CoQ10 deficiency.

Monitoring

Coenzyme Q10 Total, Plasma

Although measurement of CoQ10 in plasma is not useful for diagnosis because it is influenced by dietary sources of CoQ10, this testing can be used to monitor the progress of CoQ10 replacement therapy.