Mitochondrial DNA (mtDNA) depletion syndrome is an autosomal inherited disease, characterized by a reduction of the mtDNA copy number in affected tissues without mutations or rearrangements in the mtDNA. MTDPS3 presents in infancy with progressive liver failure, hypoglycemia, increased lactate in body fluids, and neurologic abnormalities including hypotonia, encephalopathy, and peripheral neuropathy.
Diagnosis of the condition is based on reduced mtDNA copy number in the liver or the muscles. In addition, molecular genetic testing of the DGUOK gene is necessary to establish the specific diagnosis of the Mitochondrial DNA (mtDNA) depletion syndrome.
[See: Palestine > Mandel et al., 2001].
Mandel et al (2001) described three unrelated consanguineous Druze kindreds affected by hepatocerebral MDS. The first kindred consisted of eight subfamilies with 15 affected individuals that were studied. In addition, another nine affected individuals had died previously of liver failure. Since no method of prenatal diagnosis was available, three additional affected children were born into this kindred after the initial diagnosis. The second kindred consisted of three deceased affected individuals. The first two succumbed to a liver failure of unknown etiology, while the third died after having been diagnosed as having hepatocerebral MDS. The third kindred had one affected baby. These three kindreds were used to map the disease locus and later to identify the causative gene, DGUOK. In addition, Mandel et al (2001) mentioned two additional affected families, one of Druze and one of Moroccan origin, that although linked to the same gene did not carry any mutations in the coding region of the gene.
Al-Hussaini et al. (2014) studied 20 infants with suspected hepatocerebral mitochondrial DNA depletion syndrome referred to a tertiary care center between 2007 and 2013. They identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure encountered during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11 cases where tissue was available. Seven patients had mutations in the MPV17 gene (three novel mutations) while four patients had DGUOK mutations (of which two were novel mutations). Al-Hussaini et al. (2014) commented that liver failure associated to mutations in the MPV17 and DGUOK genes is associated with poor prognosis.