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

Mitochondrial DNA Depletion Syndromes (MDSs) are a group of clinically and genetically heterogeneous diseases characterized by a quantitative abnormality of the mitochondrial genome in specific tissues (Suomalainen and Isohanni. 2010. PubMed ID: 20444604; El-Hattab and Scaglia. 2013. PubMed ID: 23385875). Patients with the hepatocerebral form of MDS commonly develop severe hepatopathy, hypotonia, and psychomotor delay.

The DGUOK-related hepatocerebral form of MDS can be classified into two subgroups depending on age of onset and organ involvement. The majority of patients present with the neonatal-onset, multi-organ form of disease, while the remaining patients present with an isolated hepatic disease later in infancy or childhood (El-Hattab and Scaglia. 2013. PubMed ID: 23385875; El-Hattab et al. 2016. PubMed ID: 20301766). Progressive hepatic dysfunction is the most common cause of death for this disorder regardless of age at onset.

Individuals with the neonatal-onset, multi-organ form of DGUOK-associated MDS present with lactic acidosis and hypoglycemia in the first week of life, rapidly followed by the development of hepatic disease and neurologic dysfunction (El-Hattab et al. 2016. PubMed ID: 20301766). Indications of hepatic dysfunction may include elevated transaminases such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Other clinical features include typical rotary nystagmus, developmental regression, severe myopathy and cholestasis. Liver failure occurs at the neonatal or infantile stage, in combination with ascites, edema, and coagulopathy.

In contrast, the isolated hepatic form of disease results in mild hypotonia and renal involvement, which may manifest as proteinuria and aminoaciduria (Dimmock et al. 2008. PubMed ID: 18825706). Less frequently reported characteristics include neonatal hemochromatosis and adult-onset mitochondrial myopathy occasionally accompanied by progressive external ophthalmoplegia (PEO) (Hanchard et al. 2011. PubMed ID: 21478040; Ronchi et al. 2012. PubMed ID: 23043144).

The DGUOK-related form of MDS is neither a common nor rare cause of hepatocerebral MDS, with ~130 individuals reported worldwide to date. Currently, there is no treatment for this disorder beyond management of symptoms, which may include routine monitoring of development and nutritional supplementation (El-Hattab et al. 2016. PubMed ID: 20301766). Liver transplantation as a possible treatment is controversial; survival rates longer than five years are mediocre (36%) and patients may still develop neurological manifestations. Some long-term survivors demonstrated good quality of life in one study (Grabhorn et al. 2014. PubMed ID: 24478274).

The DGUOK -related hepatocerebral form of MDS is an autosomal recessive disorder caused by pathogenic variants in the DGUOK gene (Mandel et al. 2001. PubMed ID: 11687800). DGUOK spans 7 coding exons and encodes a mitochondrial deoxyguanosine kinase that plays an essential role in the purine nucleoside salvage pathway.

Nonsense and splicing variants, in addition to small deletion and insertions, have been found across the entire coding region of DGUOK, although the majority of causative variants reported are missense. Several variants that result in loss of the initial methionine have also been reported, as well as several large deletions that encompass one or more exons (Freisinger et al. 2006. PubMed ID: 16908739; Wang et al. 2012. PubMed ID: 22494545; Mudd et al. 2012. PubMed ID: 22137549; Lee et al. 2009. PubMed ID: 19103789; Yamazaki et al. 2014. PubMed ID: 24266892). Recurrent pathogenic variants in DGUOK appear to be rare, with the majority reported as private familial variants. One of the most common pathogenic variants in this gene is c.679G>A (p.Glu227Lys, NM_080916.2), which has been reported in at least four cases to date (Salviati et al. 2002. PubMed ID: 12205643; Deng et al. 2016. PubMed ID: 27324545; Lee et al. 2009. PubMed ID: 19103789; Ünal et al. 2017. PubMed ID: 28493820) and is present in the gnomAD database at a minor allele frequency of up to ~0.02% in one sub-population (https://gnomad.broadinstitute.org/variant/2-74184339-G-A).

Carriers of DGUOK pathogenic variants appear to be asymptomatic (El-Hattab and Scaglia. 2013. PubMed ID: 23385875). In one study utilizing a zebrafish model of disease, a frameshift mutation was introduced into the paralog dguok; the presumably null (-/-) zebrafish were viable, although no antibody was available to check for remaining protein product (Munro et al. 2019. PubMed ID: 30428046). Compared to wild type zebrafish, the dguok -/- zebrafish demonstrated no abnormal phenotype until adulthood, when they displayed reduced fertility and regression of movement. However, even juvenile dguok -/- zebrafish had significantly reduced levels of mtDNA compared to wild type. The OGEE (Online Gene Essentiality) database lists the DGUOK gene as nonessential for tissue culture (http://ogee.medgenius.info/browse/).

The hepatocerebral form of MDS can also be caused by defects in POLG, MPV17 and TWNK (El-Hattab and Scaglia. 2013. PubMed ID: 23385875).

Clinical sensitivity is difficult to predict accurately for DGUOK-related hepatocerebral mtDNA depletion syndrome, as no large cohort studies have been described. However, several small cohorts have been studied. Al-Hussaini et al. reported that four of 20 infants (20%) with a suspected diagnosis of hepatocerebral mtDNA depletion syndrome carried pathogenic variants in DGUOK (Al-Hussaini et al. 2014. PubMed ID: 24321534). Additionally, in a cohort of 20 Japanese patients with the more general diagnosis of mtDNA depletion syndrome, Yamazaki et al. identified three patients (15%) with DGUOK defects (Yamazaki et al. 2014. PubMed ID: 24266892).

Autosomal recessive, adult-onset progressive external ophthalmoplegia due to pathogenic variants in DGUOK is expected to be a rare cause of disease, as only a few patients have been described in the literature to date (Ronchi et al. 2012. PubMed ID: 23043144).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the DGUOK 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.

We also sequence the documented splicing variant c.444-62C>A, which was reported as a founder mutation in a North African population (Brahimi et al. 2009. PubMed ID: 19394258).