Molecular Genetic Testing

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing based on clinical findings (see Table 1). Sequence analysis is performed first, followed by deletion/duplication analysis if only one or no pathogenic variant is identified.

Use of a multigene panel that includes the nine genes in Table 2 and some or all of the other genes of interest may be considered; for example, genes:

• Known (or suspected) to be required for CoQ₁₀ biosynthesis but not identified to date as a cause of primary CoQ₁₀ deficiency (i.e., ADCK1, ADCK2, ADCK5, COQ3, COQ10a, COQ10b, FDXR, and FDX2 (FDX1L) [Desbats et al 2015a])
• Associated with secondary deficiencies of coenzyme Q₁₀ (APTX, BRAF, ETFDH) (see Differential Diagnosis)
• Associated with a specific phenotype (e.g., steroid-resistant nephrotic syndrome, ataxia)

Note: (1) The choice of the specific panel depends on the phenotype observed in the patient. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing. Because of the large (and still growing) number of genes involved, the rarity of primary coenzyme Q₁₀ deficiency, the incomplete knowledge of the coenzyme Q₁₀ biosynthetic pathway, and the continuous reduction in the cost of genomic testing, exome sequencing is an alternative to the use of single-gene testing and specific multigene panels [Desbats et al 2015a, Desbats et al 2015b]. In fact, exome sequencing may also be able to detect all possible genetic causes of both primary and secondary coenzyme Q₁₀ deficiency (see Differential Diagnosis).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Biochemical Testing

The following findings on biochemical testing can differentiate coenzyme Q₁₀ deficiency from other mitochondrial disorders with similar clinical findings, but cannot differentiate primary from secondary coenzyme Q₁₀ deficiency (see Differential Diagnosis).

• Reduced levels of CoQ₁₀ in skeletal muscle [Montero et al 2008]. Note: While coenzyme Q₁₀ measurements may be performed on cultured skin fibroblasts or blood mononuclear cells, these tissues may not be reliable in detecting secondary coenzyme Q₁₀ defects [Yubero et al 2015].
• Reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates. These enzymatic activities, which depend on endogenous coenzyme Q_10, are reduced in persons with a defect in CoQ₁₀ even when isolated complex II and III respiratory chain activities are normal [Rahman et al 2012].

Principal Clinical Manifestations

Neurologic. Central nervous system (CNS) manifestations include encephalopathy (a wide spectrum of brain involvement with different clinical and neuroradiologic features often not further specified). In some individuals encephalopathy is associated with findings on neuroimaging resembling Leigh syndrome [López et al 2006] or MELAS (with stroke-like episodes) [Salviati et al 2005]. CNS manifestations often include seizures, dystonia, spasticity, and/or intellectual disability [López et al 2006, Mollet et al 2007, Heeringa et al 2011].

The age of onset and clinical severity range from fatal neonatal encephalopathy with hypotonia [Mollet et al 2007, Jakobs et al 2013] to a late-onset slowly progressive multiple-system atrophy (MSA)-like phenotype, a neurodegenerative disorder characterized by autonomic failure associated with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. This clinical picture resembling MSA with onset in the seventh decade was reported in two multiplex families with COQ2-related coenzyme Q₁₀ deficiency [Mitsui et al 2013].

Individuals with COQ8A-related coenzyme Q₁₀ deficiency display progressive cerebellar atrophy and ataxia with intellectual disability and seizures [Lagier-Tourenne et al 2008, Mollet et al 2008].

Peripheral neuropathy with absent deep tendon reflexes has been reported in the two sibs with PDSS1-related coenzyme Q₁₀ deficiency; the age at onset and frequency of this manifestation are not known.

Given the small number of affected individuals described to date, clinical data are insufficient to make any generalizations about other neurologic manifestations (e.g., dystonia, spasticity, seizures, intellectual disability).

Renal. Steroid-resistant nephrotic syndrome (SRNS), an unusual feature of mitochondrial disorders, is a hallmark of primary CoQ₁₀ deficiency. If not treated with coenzyme Q₁₀ (see Management), SRNS usually progresses to end-stage renal disease (ESRD).

Renal involvement usually manifests as proteinuria in infancy. Affected individuals often present initially with SRNS that leads to ESRD, followed by an encephalomyopathy with seizures and stroke-like episodes resulting in severe neurologic impairment and ultimately death [Rötig et al 2000, Salviati et al 2005, Heeringa et al 2011].

Some affected individuals manifest only SRNS with onset in the first or second decade of life and slow progression to ESRD without extrarenal manifestations.

One of the two individuals in a family with COQ9-related coenzyme Q₁₀ deficiency manifested tubulopathy within a few hours after birth.

Cardiac. Hypertrophic cardiomyopathy (HCM) has been reported in:

• Neonatal-onset COQ2-related coenzyme Q₁₀ deficiency [Scalais et al 2013];
• COQ4-related coenzyme Q₁₀ deficiency manifesting as prenatal-onset HCM [Brea-Calvo et al 2015];
• COQ9-related coenzyme Q₁₀ deficiency manifesting as neonatal-onset lactic acidosis followed by a multisystem disease that included HCM [Duncan et al 2009]. The cardiac disease worsened despite treatment with CoQ₁₀.

Ocular. Retinopathy is observed in some persons with COQ2-related coenzyme Q₁₀ deficiency [Desbats et al 2016].

Optic atrophy is present in some individuals with PDSS1-related coenzyme Q₁₀ deficiency [Mollet et al 2007] and PDSS2-related coenzyme Q₁₀ deficiency [Rötig et al 2000, Rahman et al 2012]. Data regarding age of onset and course of the eye manifestations are not available.

Hearing. Sensorineural hearing loss, which is common in individuals with COQ6-related coenzyme Q₁₀ deficiency, is also observed in some individuals with COQ2-related coenzyme Q₁₀ deficiency [Author, personal observation].

Muscle findings include weakness and exercise intolerance. Muscle biopsy may show nonspecific signs of lipid accumulation and mitochondrial proliferation [Trevisson et al 2011, Desbats et al 2015b].

Prognosis. Data on the prognosis of primary CoQ₁₀ deficiency are limited due to the small number of affected individuals reported to date. It is a progressive disorder, with variable rates of progression and tissue involvement depending on the gene that is mutated and the severity of the CoQ₁₀ deficiency.

Children with severe multisystem CoQ₁₀ deficiency generally die within the neonatal period or in the first year of life.

The only child reported with COQ9-related coenzyme Q₁₀ deficiency died before age two years of a progressive multisystem disorder [Duncan et al 2009].

Of note, supplementation with high-dose oral CoQ₁₀ can change the natural history of the disease by blocking progression of the renal disease and preventing the onset of neurologic manifestations in persons with biallelic pathogenic variants in COQ2, COQ6, COQ8B, and PDSS2 [Montini et al 2008; Author, personal communication].

Phenotypes of COQ2-, COQ8A-, and COQ8B-Related Coenzyme Q₁₀ Deficiency

COQ2. The findings in affected individuals from the ten families described to date differ in severity and age of onset [Mollet et al 2007, Diomedi-Camassei et al 2007, Dinwiddie et al 2013, Jakobs et al 2013, McCarthy et al 2013, Mitsui et al 2013, Scalais et al 2013, Desbats et al 2015b, Desbats et al 2016].

The main clinical features include SRNS, which can be:

• Isolated [Salviati et al 2005, Diomedi-Camassei et al 2007, McCarthy et al 2013];
• Associated with encephalomyopathy [Salviati et al 2005] or severe multiple-system disease [Diomedi-Camassei et al 2007, Mollet et al 2007, Jakobs et al 2013];
• Associated with late-onset multiple-system atrophy with retinitis pigmentosa [Mitsui et al 2013, Desbats et al 2016].

COQ8A. Affected individuals experience onset of muscle weakness and reduced exercise tolerance between ages 18 months and three years, followed by cerebellar ataxia (the predominant clinical feature) with severe cerebellar atrophy on MRI. The disease course varies, including both progressive and apparently self-limited ataxia. The ataxia may be:

• Isolated [Lagier-Tourenne et al 2008];
• Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance [Auré et al 2004, Lagier-Tourenne et al 2008, Mollet et al 2008, Terracciano et al 2012].

COQ8B. Affected individuals generally manifest SRNS in the second decade, and frequently evolve to end-stage renal disease [Ashraf et al 2013, Korkmaz et al 2016]. In addition, four affected individuals were reported with mild intellectual disability, two with occasional seizures, and one with retinitis pigmentosa.