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

Abstract

Background: Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan. Results: We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T. Conclusions: MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

Therapy Prospects for Mitochondrial DNA Maintenance Disorders

“…Some patients with mutations in MPV17 have been treated with this strategy, but its efficacy is controversial because more than half of the transplanted children died in the post-transplantation period [ 159 ] ( accessed on 22 May 2021). A recent work has reported that liver transplant is only effective in patients with mutations in MPV17 with late onset and mild phenotype [ 160 ]. Liver transplantation has also been used in DGUOK patients since most of them show severe hepatic dysfunction.…”

MPV17-related Hepatocerebral Mitochondrial DNA Depletion Syndrome

“…p.Gln93Pro is the most common homozygous pathogenic variant found in multiple Arab families. 5 12 Nine out of 20 patients (45%) survived after LT. 5,12,14 On the other hand, a case with the same mutation as the present patient (p.Leu151fs and p.Pro98Leu) showed a good prognosis with survival for more than 20 years after LT, even though the patient experienced neurological deterioration. 12 Collectively, patients harboring p.Pro98Leu or p.Pro98Leu in at least one allele without marked neurological manifestations might have a better prognosis after LT. 12 The patient with mild neurological manifestations is being considered for a deceased donor LT owing to liver failure.…”

Hypoglycaemia Metabolic Gene Panel Testing

“…Mutations in deoxyguanosine kinase ( DGUOK ), mitochondrial inner membrane protein MPV17 , polymerase catalytic subunit ( POLG ), succinate-CoA ligase GDP/ADP-forming subunit alpha ( SUCLG1 ), twinkle MtDNA helicase ( TWNK ) and transcription factors A ( TFAM ) have been associated with hepatocerebral MDDS, with acute liver failure in infancy and hypoglycemia. DGUOK deficiency is one of the most frequent causes of hepatocerebral dysfunction ( 77 ). Recessive mutations of POLG , the main gene of mtDNA replication, are associated with a phenotype ranging from infantile hepatopathic poliodystrophy (Alpers-Huttenlocher syndrome) to sensory-ataxia neuropathy with dysarthria and ophthalmoplegia (SANDO), and spinocerebellar ataxia-epilepsy syndrome (SCAE) ( 78 , 79 ).…”