Mitochondrial Complex IV Deficiency via the COA8/APOPT1 Gene

Mitochondrial complex IV (CIV) deficiency is characterized by a deficiency of the fourth oxidative phosphorylation (OXPHOS) complex of the mitochondrial respiratory chain (Fassone and Rahman 2012). Primary mitochondrial CIV deficiency is estimated to account for approximately one-fifth of all OXPHOS disorders (Skladal et al. 2003; Scaglia et al. 2004).

The majority of CIV-deficient patients present with a severe, early-onset disease within the first year of life. Similar to other OXPHOS disorders, recurrent lactic acidosis is a prevalent finding in affected individuals. Patients may display significant heterogeneity in additional clinical features, which can include encephalopathy, hypertropic cardiomyopathy, hypotonia, epilepsy, microcephaly, dystonia, psychomotor delay or impairment, nystagmus, respiratory insufficiency, ataxia, muscle weakness, and/or CIV-deficient Leigh or Leigh-like syndrome (Pecina et al. 2004; Darin et al. 2003; Alfadhel et al. 2011). Leigh syndrome (LS) is a severe, progressive encephalopathy characterized by psychomotor delay or regression; isolated or combined mitochondrial complex deficiencies; elevated levels of lactate in the blood and/or cerebral spinal fluid; bilateral symmetrical lesions in the brainstem and basal ganglia; and neurologic manifestations such as hypotonia or ataxia (Rahman and Thorburn 2015; Lake et al. 2015).

COA8/APOPT1-related CIV deficiency has been reported in at least five unrelated families to date (Melchionda et al. 2014). In contrast to the majority of CIV-deficient patients, patients with defects in COA8 displayed a slightly later age at onset (~2.5-5 years of age); in at least one individual, symptoms were subclinical through early adolescence. All affected individuals underwent a period of acute regression (loss of developmental milestones/speech, episodes with somnolence and seizure, and pyramidal signs that developed into spastic tetraparesis), but stabilized and/or partially recovered after several months or years. In all cases, a distinctive cavitating leukodystrophy involving the posterior cerebral white matter and corpus callosum was identified via MRI during the acute stage of disease. Long-term survival was reported in all patients.

The cytochrome c oxidase enzyme, also referred to as mitochondrial complex IV (CIV) or COX, is the terminal oxidase of the mitochondrial respiratory chain. Over 30 genes are involved in the structure, assembly, or function of this enzyme (Kadenbach and Hüttemann 2015). Primary mitochondrial CIV deficiency has been linked to pathogenic variants in approximately half of these genes to date. Three CIV subunits (MT-CO1, MT-CO2, and MT-CO3), which form the catalytic core of the enzyme, are encoded by the mitochondrial genome. Pathogenic variants in MT-CO1, MT-CO2, and MT-CO3 are maternally inherited (Rak et al. 2016). Defects in the remaining nuclear-encoded genes, including COA8, exhibit autosomal recessive inheritance.

The biological function of COA8 is still under debate; this protein may have a pro-apoptotic role or may function in mitochondrial anti-ROS defense mechanisms (Yasuda et al. 2006; Melchionda et al. 2014). One missense, one nonsense, and one splicing variant have been identified as causative for COA8-related CIV deficiency, in addition to one small and one gross deletion (Melchionda et al. 2014).

At this time, due to the limited number of reported cases (<10), the clinical sensitivity of COA8-related mitochondrial complex IV deficiency is difficult to estimate, although it is expected to be a rare cause of this disease. Four of the five reported variants in this gene are detectable by sequencing.

This test provides full coverage of all coding exons of the COA8 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).