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Page 2 of 10 Umetsu et al. Hepatoma Res 2020;6:1 I http://dx.doi.org/10.20517/2394-5079.2019.030

Keywords: Mitochondrial DNA depletion syndrome, MPV17, compound heterozygous mutation, liver transplantation

INTRODUCTION
The causes of mitochondrial disorders are defects in mitochondrial DNA (mtDNA) or in nuclear genes
that affect mtDNA biogenesis and maintenance. Defects in nuclear genes can result in the accumulation of
[1-3]
mtDNA deletions, or with mtDNA depletion syndrome (MTDPS) . The latter is an autosomal recessive
[4-6]
disease associated with decreased mtDNA copy number in clinically affected tissues . The disease has
three known phenotypes: hepatocerebral, myopathic, and encephalomyopathy. Hepatocerebral MTDPS is
[8]
[7]
[9]
linked to pathogenic variants in DNA polymerase gamma , Twinkle (PEO1) , deoxyguanosine kinase ,
[4]
and mtDNA maintenance protein MPV17 .
MPV17-related MTDPS is a very rare disease. To date, MPV17-related hepatocerebral MTDPS has been
reported in 96 patients [4,5,10-30] . Disease prognosis is severe, given that ~80% of patients die from liver failure
during early childhood . Hepatic cirrhosis has been diagnosed in 20 patients, while three patients had
[30]
hepatocellular carcinoma (HCC) [10,15,25] . Neurological manifestations were also reported in 91% of patients
with developmental delays, and 74% of patients with generalized hypotonia. These patients also experienced
MR imaging (MRI) abnormalities; metabolic manifestations, including hypoglycemia and lactic acidosis;
failure to thrive; feeding difficulties; and retinaltubulopathy.

Currently, 48 pathogenic variants of MPV17 are known, occurring exclusively in a few families. Five
cases with p.R50W mutations (three homozygous and two heterozygous) died of liver failure during early
childhood [4,12,25,30] . Previous case studies identified homozygous variant p.R50Q in MPV17 among patients
with Navajo neurohepatopathy (NNH) [10,15,29] . One specific homozygous mutation, p.R50Q, has been
reported in several Navajo individuals from the southwestern United States and is the cause of NNH. This
condition clinically manifests as severe sensory and motor neuropathy, corneal anesthesia, ulcers, cerebral
leukoencephalopathy, failure to thrive, and metabolic acidosis. To date, compound heterozygous variant
p.R50Q with other mutations has not been reported in MPV17-related MTDPS.

In this case report, we describe for the first time three patients with MTDPS who possessed the compound
heterozygous MPV17 variant p.R50Q/p.R50W. Unlike deceased outcomes of p.R50W variants as previously
reported, our three cases with p.R50Q/R50W mutations survived without signs of typical neurological
manifestations.

CASE REPORT
Patients
The proband was a 6-year-old male (Case 1) and the first child of healthy, nonconsanguineous parents with
no hereditary history of the disease (for family pedigree, see Figure 1A). The child was delivered via caesarian
section after a dinochorionic and diamniotic pregnancy. Case 2 was the first girl of a twin of Case 1. A second
girl (Case 3) was born three years after Cases 1 and 2, delivered without any complication. Cases 1-3
showed similar clinical manifestation: all patients suffered from severe hypoglycemia and cyclic vomiting.
During infancy, Cases 1 and 3 presented with liver failure; although there was a mild spontaneous
remission, acute liver failure was repeated through episodes of febrile infection. Case 2 presented with liver
dysfunction only.

In Case 1, the patient developed recurrent vomiting with hypoglycemia at the age of six, and abdominal
ultrasound found multiple liver masses. Each patient was admitted to our hospital due to multiple hepatic
nodules, detected by abdominal ultrasound at age six in Case 2, and at age three in Case 3 [Figure 2A].