Leigh Syndrome Associated With Mitochondrial Complex I Deficiency via the NDUFAF2 Gene

Mitochondrial complex I (CI) deficiency is characterized by a deficiency of the first and largest of the oxidative phosphorylation complexes (Fassone and Rahman 2012). Isolated mitochondrial CI deficiency is the most frequently reported childhood-onset mitochondrial disease, and may account for roughly one-third of all oxidative phosphorylation disorders (Skladal et al. 2003; Scaglia et al. 2004).

NDUFAF2-associated mitochondrial CI deficiency has been reported in fewer than 20 patients to date. The most common clinical presentation is Leigh or Leigh-like syndrome (LS or LLS). LS is a severe, progressive encephalopathy characterized by a distinct set of diagnostic criteria, which include 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; Hoefs et al. 2009). LLS, which describes a similar clinical presentation in which one or more of these diagnostic characteristics is atypical, is frequently reported in patients with pathogenic variants in NDUFAF2 (Herzer et al. 2010). In particular, lactate elevation has been reported to be sporadic or absent in some patients, and neuroradiological presentations may be atypical (Barghuti et al. 2008; Ogilvie et al. 2005).

The mitochondrial respiratory chain complex I (nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase) is composed of at least 45 structural subunits (Fassone and Rahman 2012). 38 of these subunits are encoded by nuclear DNA, and 7 are encoded by mitochondrial DNA. The resulting holoenzyme complex plays a critical role in redox-driven proton translocation, which ultimately results in synthesis of adenosine triphosphate (ATP; Sazanov 2015). Due to the many structural and accessory subunits required to support the assembly and function of complex I, mitochondrial CI deficiency is a genetically heterogeneous disorder. At least 33 genes have been linked to this disease to date (Fassone and Rahman 2012).

NDUFAF2-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. NDUFAF2, also referred to as NDUFA12L in the literature, encodes for a molecular chaperone essential to mitochondrial complex I assembly (Ogilvie et al. 2005). Approximately ten causative variants have been reported in this gene to date. The majority of these variants are nonsense changes, although one missense variant has also been described, in addition to several small and gross deletions (Human Gene Mutation Database).

At this time, due to the limited number of reported cases (<20), the clinical sensitivity of NDUFAF2-related mitochondrial complex I deficiency is difficult to predict. Rahman et al. estimate that <5% of reported autosomal recessive Leigh syndrome cases are caused by defects in NDUFAF2 (Rahman et al. 2015).

This test provides full coverage of all coding exons of the NDUFAF2 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).