Mitochondrial Complex I Deficiency via the NUBPL 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).

Patients with NUBPL-associated mitochondrial CI deficiency are most commonly diagnosed with a mitochondrial leukoencephalopathy (Kevelam et al. 2013). Other symptoms may include developmental delays, speech regression, ataxia, respiratory insufficiency, and/or cognitive defects. In six patients from five unrelated families, affected individuals presented with a distinct MRI pattern with predominant abnormalities of the cerebellar cortex, deep cerebral white matter, and corpus callosum.

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.

NUBPL-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. The NUBPL gene, previously known as IND1, encodes for an iron-sulfur cluster assembly factor of mitochondrial CI (Sheftel et al. 2009). Several missense variants, one splicing variant, one small deletion, one small insertion, and at least one large complex rearrangement have been described in NUBPL to date (Human Gene Mutation Database).

At this time, due to the limited number of reported cases, the clinical sensitivity of NUBPL-related mitochondrial complex I deficiency is difficult to estimate.

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

One deeper intronic variant is also covered: c.815-27T>C (Tucker et al. 2012).

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).