SUCLA2 -Related Encephalomyopathic Form of Mitochondrial DNA Depletion Syndrome via the SUCLA2 Gene

The mitochondrial DNA depletion syndromes (MDSs) form a group of clinically and genetically heterogeneous diseases characterized by a quantitative abnormality of the mitochondrial genome in specific tissues (Suomalainen and Isohanni 2010; El-Hattab and Scaglia 2013).

The SUCLA2-related encephalomyopathic form of MDS is an infantile-onset disorder characterized by muscle hypotonia, severe psychomotor development delay, hyperkinesias, progressive neurologic deterioration, lactic acidosis, profound sensorineural deafness, mild methylmalonic aciduria (MMA), poor feeding, and postnatal growth retardation (Elpeleg et al. 2005; Carrozzo et al. 2007; Ostergaard et al. 2007). Epilepsy and ophthalmopelgia are also occasionally reported (Carrozzo et al. 2016). In contrast to patients with SUCLG1-related MDS, patients with the SUCLA2-related form do not appear to present with hepatopathy or cardiomyopathy (Carrozzo et al. 2016). 

Succinyl-coenzyme A (CoA) ligase is an enzyme of the citric acid cycle that catalyzes the reversible conversion of succinyl-CoA, phosphate, and ADP (or GDP) to succinate, coenzyme A (CoASH), and ATP (or GTP). This enzyme is composed of two subunits: an invariant alpha subunit encoded by SUCLG1 and a beta subunit encoded by either SUCLA2 or SUCLG2. Nucleotide specificity is determined by the beta subunit, resulting in the ADP- or GDP-forming isoforms of succinyl-CoA ligase, respectively.

The SUCLA2-related encephalomyopathic form of MDS is an autosomal recessive disorder caused by succinyl-CoA ligase deficiency due to defects in the SUCLA2 gene (Elpeleg et al. 2005; Carrozzo et al. 2007; Ostergaard et al. 2007). Missense changes are the most common genetic defect identified in the SUCLA2 gene, although nonsense, splicing site variants, and small indels have also been reported (Human Gene Mutation Database). Additionally, at least one full gene deletion has been described (Matilainen et al. 2015; Elpeleg et al. 2005).

The encephalomyopathic form of MDS may also be caused by pathogenic variants in SUCLG1 and RRM2B (El-Hattab and Scaglia 2013). Although they cause similar phenotypes, defects in SUCLG1 are less frequently identified compared to defects in SUCLA2 (Carrozzo et al. 2016).

Clinical sensitivity is problematic to estimate due to the genetic heterogeneity of these disorders and the scarcity of documented cases. In patients with similar phenotypes, pathogenic variants have been reported more frequently in SUCLA2 than SUCLG1 (Carrozzo et al. 2016). Analytical sensitivity for this test is likely to be high because most SUCLA2 causative variants reported to date can be detected by direct sequencing of genomic DNA.

Only one full gene deletion has been described to date (Matilainen et al. 2015; Elpeleg et al. 2005).

This test provides full coverage of all coding exons of the SUCLA2 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).