MPV17-Related Hepatocerebral Form of Mitochondrial DNA Depletion Syndrome via the MPV17 Gene

Mitochondrial DNA Depletion Syndromes (MDSs) are a clinically and genetically heterogeneous group of diseases characterized by a quantitative abnormality of the mitochondrial genome in specific tissues (Suomalainen and Isohanni 2010; El-Hattab et al. 2013). Patients with the hepatocerebral form of MDS commonly develop severe hepatopathy, hypotonia, and psychomotor delay.

The MPV17-related hepatocerebral form of MDS has an early disease onset that ranges from infancy to childhood. Patients present with clinical features that include liver dysfunction (typically progressing to liver failure during infancy or early childhood), neurologic manifestations (peripheral neuropathy and leukoencephalopathy), metabolic abnormalities (lactic acidosis and hypoglycemia) and failure to thrive. Less frequent clinical presentations include renal tubulopathy, hypoparathyroidism, gastrointestinal dysmotility, cyclic vomiting, and diarrhea (El-Hattab et al. 2012; El-Hattab et al. 2013).

Navajo neurohepatopathy, a recessive multisystem disorder that has a high incidence in the Native American Navajo population of the southwestern United States, is caused by a founder variant in MPV17 (Karadimas et al. 2006). This disease shares similar clinical, pathological, and biochemical features with the hepatocerebral form of MDS, but patients may present with additional symptoms such as acral mutilation, corneal anesthesia, ulceration, and scarring.

Rarely, MPV17 defects result in adult-onset peripheral neuropathy with or without hepatic involvement (Blakely et al. 2012; Garone et al. 2012). This particular form of disease is characterized by severe mtDNA depletion and cytochrome c oxidase (COX) deficiency in skeletal muscle.

The MPV17-related hepatocerebral form of MDS is an autosomal recessive disorder caused by pathogenic variants in the MPV17 gene (Spinazzola et al. 2006). MPV17 has 7 coding exons that encode a non-selective channel within the inner mitochondrial membrane that functions to maintain mitochondrial homeostasis by acting as a regulator of membrane potential (Antonenkov et al. 2015). Missense, nonsense, splicing site variants, and small deletion/insertions have been found across the whole coding region of MPV17. In addition, several large deletions have been reported (Spinazzola et al., 2008; Uusimaa et al. 2014).

Associated with less severe phenotypes and extended survival in patients, the p.R50Q variant in exon 2 is the most commonly reported cause of MPV17-related disease due to a founder effect within the Navajo community (Karadimas et al. 2006). However, this variant has also arisen independently, if less frequently, in other populations (Spinazzola et al. 2006; Spinazzola et al. 2008).

The hepatocerebral form of MDS can also be caused by defects in POLG, DGUOK, and C10orf2.

Due to the founder effect of the p.R50Q variant in the Native American Navajo population, clinical sensitivity is expected to be high in patients with Navajo ancestry who present with the hepatocerebral form of MDS (Karadimas et al. 2006). For the remainder of patients, however, too few cases have been described to estimate clinical sensitivity at this time.

This test provides full coverage of all coding exons of the MPV17 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.