Mitochondrial Complex I Deficiency via the NDUFA1 Gene

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

The majority of CI-deficient patients present within the first year of life (Distelmaier et al. 2009). Respiratory infections, gastrointestinal disease, or long periods of fasting may trigger the initial symptoms of this disorder and stimulate additional episodes, leading to rapid deterioration of the patient’s condition. Similar to other OXPHOS disorders, recurrent lactic acidosis is a prevalent finding in patients with CI deficiency. Additional clinical symptoms, which can involve single or multiple organ systems, may be highly heterogeneous. The most common clinical presentations in patients with nuclear-encoded CI deficiency include Leigh/Leigh-like syndrome (LS/LLS), leukoencephalopathy with macrocephaly, fatal infantile lactic acidosis, hypertrophic cardiomyopathy, and hepatopathy with renal tubulopathy (Fassone and Rahman 2012; Distelmaier et al. 2009). 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).

NDUFA1-associated mitochondrial CI deficiency has been associated with either Leigh-like syndrome or myoclonic epilepsy and developmental delay (Fernandez-Moreira et al. 2007; Uehara et al. 2014). Patients presented within the first year of life, and additional symptoms included hypotonia, nystagmus, choreoathetosis, and/or seizures. Heterozygous female carriers that were reported within these families were noted to be asymptomatic. 

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 (MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6) 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). 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.

NDUFA1-associated mitochondrial complex I deficiency is inherited in an X-linked recessive pattern. NDUFA1 encodes for a subunit of the mitochondrial CI, and several pathogenic missense variants have been reported in this gene to date (Fassone and Rahman 2012; Human Gene Mutation Database).

At this time, due to the limited number of reported cases (<10), the clinical sensitivity of NDUFA1-related mitochondrial complex I deficiency is difficult to estimate. In one small cohort, Fernandez-Moreira et al. identified causative NDUFA1 variants in 2/26 patients with an isolated complex I deficiency (~7.7%) (Fernandez et al. 2007). Analytical sensitivity is likely to be high, however, as all causative variants reported to date are missense changes.

This test provides full coverage of all coding exons of the NDUFA1 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).