Mitochondrial Complex IV Deficiency via the SCO2 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, hypertrophic 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).

SCO2-related CIV deficiency has been reported in fewer than 100 patients to date (Pronicka et al. 2013). The most common clinical presentation for SCO2-deficient patients is a rapidly-progressive neonatal cardioencephalomyopathy; alternatively, some patients lack cardiomyopathic manifestations and instead present with an infantile enceophalomyopathy with spinal muscular atrophy-like histological patterns. Additional symptoms may include hypotonia, developmental delay, dystonia, ataxia, strabismus, and/or ptosis. Slightly milder disease courses have also been described, with patients presenting with a nonspecific encephalomyopathy at approximately one year following birth.

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 SCO2, exhibit autosomal recessive inheritance.

The SCO2 gene encodes the CIV assembly factor SCO2, a copper metallochaperone that is required for metallation of the CIV subunit MT-CO2 (Pacheau-Grau et al. 2015). Missense variants, nonsense variants, small deletions, and two large deletions have all been reported as causative in this gene to date (Human Gene Mutation Database). One of the most frequently-reported pathogenic variants in this gene is p.Glu140Lys, which is located in close proximity to a proposed copper-binding site (Papadopoulou et al. 1999; Pronicka et al. 2013; Jaksch et al. 2001). This variant is particularly common in Czech, Slovak, and Polish populations.

At this time, due to the limited number of reported cases and the absence of large cohort studies, the clinical sensitivity of SCO2-related mitochondrial complex IV deficiency is difficult to estimate in the general population. In one small cohort of 41 patients with CIV deficiency, 3 patients (7.3%) carried causative variants in the SCO2 gene (Sue et al. 2000). However, due to a founder effect, the p.Glu140Lys missense variant in SCO2 was identified in the homozygous or compound heterozygous state in 36 of 36 Polish patients (100%) (Pronicka et al. 2013).

This test provides full coverage of all coding exons of the SCO2 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).