Clinical and molecular characterization of three patients with Hepatocerebral form of mitochondrial DNA depletion syndrome: a case series

Abstract

BackgroundMitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis.Case presentationIn this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706–707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)).ConclusionsThese patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.

Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: Evaluation of outcomes after liver transplantation

“…However, no significant differences in body weight were noted between these two groups in the postnatal period, suggesting that MPV17-deficient patients had marked postnatal growth restrictions compared to non-MPV17 patients. Previous studies have reported that low birth weight was observed in 20-80% of patients with DGUOK mutations and also in patients with POLG mutations [15][16][17][18][19][20][21] . However, very few studies have reported MPV17-deficient patients exhibiting intrauterine growth restrictions (IUGR) 15,[21][22][23] .…”

Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease

“…Hepatocerebral MDS is one of the most common MDS diseases, and at least 50 kinds of related gene mutations have been discovered ( 62 ). This disease may occur in newborns within 6 months after birth, as characterized by vomiting, developmental delay, serious progressive liver failure, hypotonia, hyperreflexia, irritability, and hypoglycemia.…”

Deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax: a case report

“…Deoxyguanosine kinase (DGUOK) deficiency is part of hepatocerebral mitochondrial deoxyribonucleic acid (DNA) depletion syndrome (MDS). MDS represents a broad spectrum of autosomal recessive diseases characterized by reduced copy number of mitochondrial DNA (mtDNA), resulting in mitochondrial dysfunction and insufficient energy production in the affected tissues and organs [ 1 – 5 ]. The phenotypic presentations of MDS are heterogeneous with a generally early onset.…”

“…Depending on the affected organs, MDS are classified into four categories: myopathic, encephalomyopatic, hepatocerebral, and neurogastrointestinal forms. Each category results from different nuclear gene mutations [ 1 , 3 ]. The exact prevalence of MDS or DGUOK deficiency is still unknown.…”

“…The majority of affected patients develop multisystemic manifestations, commencing in the first weeks of life, such as lactic acidosis, hypoglycemia, hepatic dysfunction, and neurological damage. Later, severe myopathy, developmental delay, and nystagmus may also follow [ 1 – 5 ]. The DGUOK-related MDS affected patients usually die within the first year of life, mainly due to liver failure [ 1 , 2 ].…”