Mitochondrial Combined Oxidative Phosphorylation Deficiency via the MTFMT Gene

Combined oxidative phosphorylation (OXPHOS) deficiency is a multi-systemic disorder characterized by reduced activity of two or more mitochondrial respiratory chain enzyme complexes. Combined OXPHOS deficiency accounts for roughly one-quarter to one-third of all oxidative phosphorylation disorders (Skladal et al. 2003; Scaglia et al. 2004).

Patients with MTFMT-associated oxidative phosphorylation deficiency generally present within the first year of life, although clinical presentation may range from mild (with survival into adulthood and eventual apparent clinical stability) to severe (resulting in death within the first few years of life). Although many MTFMT-deficient patients show combined oxidative phosphorylation defects in muscle tissue upon biochemical analysis, a subset of patients may present with an isolated complex I deficiency (Haack et al. 2014). Overall, affected individuals exhibit a primarily encephalomyopathic phenotype, with clinical symptoms such as lactic acidosis, hypotonia, microcephaly, developmental delays, cognitive impairment, optic atrophy, dysarthria, convulsions, ataxia and spasticity at later disease stages, stroke-like episodes, and/or acute respiratory insufficiency (Haack et al. 2014; Pena et al. 2016; Neeve et al. 2013; Tucker et al. 2011). In the majority of patients, MRI analysis often leads to a diagnosis of classical Leigh syndrome, a severe, progressive encephalopathy characterized by bilateral symmetrical lesions in the brainstem and basal ganglia; psychomotor delay or regression; isolated or combined mitochondrial complex deficiencies; elevated levels of lactate in the blood and/or cerebral spinal fluid; and neurologic manifestations such as hypotonia or ataxia (Haack et al. 2014; Rahman and Thorburn 2015; Lake et al. 2015).

Combined oxidative phosphorylation (OXPHOS) deficiency may be an autosomal recessive, X-linked, or maternally-inherited disease. Pathogenic variants in over 30 different nuclear and mitochondrial genes have been reported as causative for this disorder; the majority of these genes encode for components of the mitochondrial translation machinery.

Nuclear genes associated with autosomal recessive inheritance of combined OXPHOS deficiency include: AARS2, ATP5A1, BOLA3, C12orf65, EARS2, ELAC2, FARS2, GFER, GFM1, GTPBP3, ISCU, LYRM4, MARS2, MRPL3, MRPL44, MRPS16, MRPS22, MTFMT, MTO1, NARS2, NFU1, PARS2, PNPT1, PUS1, RMND1, SERAC1, SFXN4, TARS2, TRMT5, TSFM, TUFM, VARS2, and YARS2. AIFM1 is associated with X-linked recessive inheritance of this disease. Pathogenic defects in any of the mitochondrial-encoded tRNA genes (22 total) or rRNA genes (2 total) are expected to result in maternally-inherited combined oxidative phosphorylation deficiency (Smits et al. 2010).

Additionally, defects in the mitochondrial depletion/deletion syndrome genes (see Test #1399) or coenzyme Q10 deficiency genes (see Test #4529) may result in a combined OXPHOS deficiency in conjunction with coenzyme Q10 deficiency, quantitative mitochondrial genome depletion, or a large deletion(s) of the mitochondrial genome.

The MTFMT gene encodes for the mitochondrial methionyl-tRNA formyltransferase, responsible for formylation of the initiator Met-tRNA (Haack et al. 2014). Approximately 15 causative variants have been reported in this gene to date, including several missense and nonsense variants, one splicing variant, and several small deletions resulting in frameshifts (Human Gene Mutation Database). One particular missense change (p.Ser209Leu) appears to be prevalent among affected individuals (Haack et al. 2014).

In a cohort of 350 patients who presented with a suspected mitochondrial disorder and either isolated or combined oxidative phosphorylation deficiencies, Haack and colleagues identified causative MTFMT variants in 4 patients (~1%) (Haack et al. 2014).

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