Mutations in MPV17 lead to severe mitochondrial DNA depletion syndrome (MTDPS). All known p.R50W variants in MPV17 are lethal. The homozygous variant p.R50Q in MPV17 among patients with Navajo neurohepatopathy is known to allow longer survival, although heterozygous variants p.R50Q have not been reported. This is the first clinical report in compound heterozygosity MPV17 mutation (p.R50W/p.R50Q). Three siblings were admitted due to multiple hepatic nodules; none presented neurological abnormalities. However, they suffered from severe hypoglycemia and cyclic vomiting. The diagnosis of MPV17-related MTDPS was confirmed by detection of a compound heterozygous MPV17 mutation (p.R50W/p.R50Q), and striking reduction of hepatic mitochondrial DNA. One patient developed pediatric-onset of hepatocellular carcinoma. Notably, all patients survived for extended periods, including two patients who received liver transplantation, which contrasted the high mortality rate associated with p.R50W mutations, as previously reported. The p.R50Q mutation might be associated with longer survival and improved liver transplantation outcomes.
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 mtDNA deletions, or with mtDNA depletion syndrome (MTDPS)[
MPV17-related MTDPS is a very rare disease. To date, MPV17-related hepatocerebral MTDPS has been reported in 96 patients[
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[
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.
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
Family pedigree (A). Whole-exome and Sanger sequencing revealed compound heterozygous missense mutations with NM_002437.4:c.148C>T (p.R50W) and c.149G>A (R50Q) in MPV17, inherited from each of their parents (B)
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
Abdominal ultrasound showed the mass in the liver (A). EOB-enhanced magnetic resonance images indicated the washed-out portal-venous phase and liver-cell-enhance phase in S7 hepatic mass (B)
Clinical findings of three patients with MPV17-related mitochondria hepatopathy at the first visit to our hospital
Case1 | Case2 | Case3 | |
---|---|---|---|
Sex | Male | Female | Female |
Height (cm) (SD) | 109.9 (-1.3 SD) | 110 (-0.9 SD) | 88.3 (-1.8 SD) |
Weight (kg) (SD) | 17.3 (-1.1 SD) | 19.4 (-0.3 SD) | 13.6 (-0.1 SD) |
Neurology | Normal | Normal | Normal |
IQ | 68 | 92 | 113 |
Metabolism | Hypoglycemia | Hypoglycemia | Hypoglycemia |
AST (U/l) | 53 | 47 | 82 |
ALT (U/l) | 30 | 28 | 36 |
GGT (U/l) | 201 | 99 | 143 |
Alb (mg/dL) | 2.7 | 3.1 | 3.1 |
Plt (104/μL) | 21.3 | 12.3 | 28.1 |
PT (%) | 67.4 | 61.5 | 55.3 |
Lactic acid (mg/dL) | 22.0 | 19.2 | 18.6 |
Pyruvic acid (mg/dL) | 1.2 | 1.0 | 1.0 |
AFP (ng/mL) | 413 | 1332 | 3078 |
Abdominal MRI | Multifocal masses | Multifocal masses | Multifocal masses |
Liver histology | Cirrhosis/steatosis | Cirrhosis/steatosis | Not done |
Head MRI | Normal | Normal | Normal |
Child-Pugh score | 6 | 6 | 6 |
IQ: intelligence quotient; AST: aspartate alanine aminotransferase; ALT: alanine aminotransferase; GGT: gamma glutamyl transferase; Alb: albumin; Plt: platelet; AFP: alpha-feto protein; MRI: magnetic resonance imaging; PT: prothrombin time
All three patients had multiple masses with hyper-echogenic occupied lesions and low-echogenic occupied lesions measuring between 0.5 and 1.0 cm, which were negatively detected by enhanced computed tomography. Transverse T2-weighted magnetic resonance (MR) image shows numerous well-defined hypointense masses in the liver, while transverse EOB-enhanced MRI demonstrated negative arterial enhancement, portal-venous phase, and liver-cell-enhance phase studies showed high intensity with masses in all three patients.
Liver biopsies revealed advanced fibrosis with regenerative nodules and mild steatosis in Cases 1 and 2
Liver biopsies at age six showed advanced fibrosis with regenerative nodules and mild steatosis: (A) hematoxylin-eosin staining (magnification, low power field); and (B) electron microscopy (magnification, ×25,000) revealed giant mitochondria with increased inclusion bodies in hepatocytes
After obtaining approval from the institutional review board of Saiseikai Yokohama-shi Tobu Hospital and informed consent from parents, biochemical examination and molecular studies were performed.
A biochemical analysis was performed at the Department of Metabolism, Chiba Prefectural Children’s Hospital. Case 1 and 2 livers were analyzed for tissue-specific enzyme activity and mtDNA levels. Hepatic respiratory chain complex I, II, III, and IV (CI-CIV) activities were evaluated as described previously[
DNA was extracted from peripheral blood samples of the three patients and their parents. A whole-exome analysis using Hiseq 2500 (Illumina, Sana Clara, USA) identified compound heterozygous missense mutations with NM_002437.4:c.148C>T (p.R50W) and c.149G>A (p.R50Q) in MPV17, respectively, inherited from each of their parents
These results confirmed a diagnosis of MPV17-related MTDPS.
Patients were given ubiquinone carnitine as medication for mitochondrial rescue supplementation. A lipid-rich diet efficiently controlled hypoglycemia and normalized liver function for a previous case study[
Six months later, Case 2 was readmitted to our hospital because of an increasing mass measuring 2.9 cm located in segment 7, as revealed by abdominal ultrasound imaging. It showed no evidence of vascular invasion or metastasis. EOB-enhanced MR images revealed early arterial enhancement, as well as washed-out portal-venous and liver-cell-enhance phases
Explanted Case 2 liver with multiple large nodules. A histological analysis (hematoxylin-eosin staining) of the Case 2 S7 mass revealed: (A) a high nucleo-to-cytoplasm ratio (magnification, low power field); and (B) sharply delineated small aggregates of highly pleomorphic small hepatocytes, which are typical of well-differentiated hepatocellular carcinoma (magnification, high power field)
This is the first clinical report in compound heterozygous mutation (p.R50Q/p.R50W) of MPV17, and three cases were diagnosed with hepatocerebral MTDPS. In contrast with deceased outcomes of p.R50W variants previously reported, our three cases with p.R50Q/R50W mutations survived for a more extended period without neurological manifestations. One case developed HCC. Two of our cases underwent liver transplantation, and both showed positive post-transplant outcomes at the time of writing.
Clinical phenotype of patients with MPV-17-related mitochondria hepatopathy with p.R50Q, or p.R50W mutations
p.R50Q/p.R50W |
p.R50W reported |
p.R50Q reported |
|||||
---|---|---|---|---|---|---|---|
Sex | Female | 2 | (67) | 4 | (80) | 4 | (36) |
Outcome | Alive | 3 | (100) | 0 | (0) | 5 | (46) |
Liver transplantation | 2 | (66) | 1 | (20) | 5 | (46) | |
Hepatic symptoms | 3 | (100) | 5 | (100) | 11 | (100) | |
HCC | 1 | (33) | 1 | (20) | 1 | (9) | |
Hepatomegaly | 3 | (100) | 3 | (60) | 3 | (27) | |
Cirrhosis | 2 | (67) | 1 | (20) | 6 | (55) | |
Liver dysfunction | 3 | (100) | 5 | (100) | 11 | (100) | |
Liver failure | 2 | (67) | 5 | (100) | 9 | (82) | |
Cholestasis | 0 | (0) | 3 | (60) | 8 | (73) | |
Steatosis | 0 | (0) | 4 | (80) | 7 | (64) | |
Neurological symptoms | 1 | (33) | 4 | (80) | 10 | (91) | |
Ataxia | 0 | (0) | 0 | (0) | 2 | (18) | |
Corneal ulcers | 0 | (0) | 0 | (0) | 3 | (27) | |
Developmental delay | 1 | (33) | 2 | (40) | 9 | (82) | |
Dystonia | 0 | (0) | 2 | (40) | 0 | (0) | |
Hypotonia | 0 | (0) | 2 | (40) | 3 | (27) | |
Peripheral neuropathy | 0 | (0) | 0 | (0) | 8 | (73) | |
Seizures | 0 | (0) | 1 | (20) | 1 | (9) | |
MRI abnormality | |||||||
Basal ganglia | 0 | (0) | 1 | (20) | 0 | (0) | |
White matter | 0 | (0) | 2 | (40) | 5 | (46) | |
Metabolic symptoms | 3 | (100) | 3 | (60) | 10 | (91) | |
Lactic acidemia | 0 | (0) | 3 | (60) | 8 | (73) | |
Hypoglycemia | 3 | (100) | 2 | (40) | 7 | (64) | |
GI symptoms | 3 | (100) | 4 | (80) | 8 | (73) | |
Feeding difficulties | 0 | (0) | 2 | (40) | 0 | (0) | |
Failure to thrive | 3 | (100) | 4 | (80) | 8 | (73) |
The data are numbers (percentages). HCC: hepatocellular carcinoma; GI: gastrointestinal; MRI: magnetic resonance imaging
Additionally, our cases with a compound heterozygous p.R50Q/p.R50W mutation were free from neurological manifestations compared with high occurrence of neurological manifestations in p.R50W and p.R50Q mutations previously reported. Regarding neurological manifestations, in previous cases, 90% of p.R50Q homozygous variants and 80% of p.R50W homozygous variants had neurological symptoms such as ataxia, corneal ulcers, developmental delay, dystonia, hypotonia, peripheral neuropathy, and seizures. MRI abnormality was also observed in 40% patients who had p.R50Q homo and p.R50W cases, respectively. Compared with earlier cases, p.R50Q/p.R50W lacked neurological symptoms except mild intellectual disability observed in Case 1. Taken together, the fact that none of our cases showed mortality even though they had heterozygous p.R50W mutation and that they had no visible neurological manifestations suggests the p.R50Q mutation might be associated with longer survival compared with other mutations linked to severe outcomes of MPV17-related MTDPS, such as p.R50W.
Interestingly, one of our cases developed pediatric-onset HCC, increasing the number to four known patients with MPV17-related MTDPS who had this cancer
Clinical manifestations of patients with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome who developed hepatocellular carcinoma
Case 2 | Patient 1 | Patient 2 | Patient 3 | |
---|---|---|---|---|
Sex | Female | Male | Male | Female |
Ethnicity | Japan | Navajo | Caucasian | India |
MPV17 | ||||
Allele 1 | p.R50Q | p.R50Q | c.22insC | p.R50W |
Allele 2 | p.R50W | p.R50Q | NA | p.R50W |
Onset age | 4 years | Infancy | Infancy | 5 years |
LT (age) | Done (7 years) | Done (11 years) | Done (NA) | Done (9 years) |
Outcome (age) | Alive (8 years) | Alive (21 years) | Alive (9 years) | Died (10 years) |
Hepatic manifestation | Cirrhosis, HCC | LF, Cirrhosis, Steatosis, HCC | LF, Cirrhosis, HCC | LF, Cirrhosis, Steatosis, HCC |
Other manifestation | Hypoglycemia, FTT | DD, Peripheral neuropathy, MRI abnormalities, Hypoglycemia, FTT | DD, Hypotonia, Seizures, FTT | Seizures, Dystonia, MRI abnormalities, FTT |
Ref. | This report | [ |
[ |
[ |
HCC: hepatocellular carcinoma; DD: developmental delay; FTT: failure to thrive; GI: gastrointestinal; LF: liver failure; LT: liver transplantation; NA: not accessed; MRI: magnetic resonance imaging
Liver transplantation is one of the best treatments for HCC-induced cirrhotic liver. Although a recent study showed that liver transplantation for pediatric HCC patients with inherited metabolic disease has better chances of survival compared with pediatric HCC patients with non-inherited metabolic disease[
As with previous studies of MTDPS, this case report describes a small sample size and short follow-up period. Therefore, we need to perform further studies on large patient cohorts, to determine the effectiveness and outcomes of liver transplantation in MPV17-related MTDPS. Long-term follow up should be performed, including regular neurological assessment.
This case study reported the first compound heterozygous p.R50Q/p.R50W mutation of MPV17. All the three siblings survived without neurological manifestations, in contrast with total mortality accompanied by systemic organ involvements in previous MPV17 mutation p.R50W. Two of our cases underwent liver transplantation, and both showed positive post-transplant outcomes at the time of writing. The p.R50Q mutation might be associated with more prolonged survival including liver transplantation outcomes, as compared with other previously described mutations linked to severe outcomes of MPV17-related MTDPS. Screens of the
We thank Dr. Notohara Kenji at Kurashiki Central Hospital for advice on evaluating liver histopathology from adult hepatic neoplasms.
Drafted the manuscript: Umetsu S
Made a special support from the metabolic evaluation: Murayama K, Shimura M
Made a special support from genetic evaluation: Uehara T, Kosaki K
Made a special support from Liver transplantation: Uchida H, Kasahara M
Assisted with liver histopathology: Irie R, Yoshioka T
Supervised diagnosis and treatment: Kobayashi S, Sogo T, Komatsu K, Inui A, Fujisawa T
Read and approved the final manuscript: Umetsu S, Inui A, Kobayashi S, Shimura M, Uehara T, Uchida H, Irie R, Sogo T, Komatsu H, Yoshioka T, Murayama K, Kosaki K, Kasahara M, Fujisawa T
Not applicable.
This study was supported by the following grants. Kei Murayama was supported by the Practical Research Project (19ek0109273, 18ek0109177) for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development.
All authors declared that there are no conflicts of interest.
The institutional review board of Saiseikai Yokohama-shi Tobu Hospital approved, and informed consent was obtained from parent.
Written informed consent was obtained from the guardian of the patients for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
© The Author(s) 2020.