First cases of MPV17 related mitochondrial DNA depletion syndrome with compound heterozygous mutations in p.R50Q/p.R50W:a case report

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.

Mitochondrial hepatopathy: Respiratory chain disorders- ‘breathing in and out of the liver’

Mitochondria,the powerhouse of a cell,are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond.Evolution supports a prokaryotic descent,and,unsurprisingly,the organelle is worthy of being labeled an organism in itself.Since highly metabolically active organs require a continuous feed of energy,any dysfunction in the structure and function of mitochondria can have variable impact,with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition.Though categorized a hepatopathy,mitochondrial respiratory chain defects are not limited to the liver in time and space.The liver involvement is also variable in clinical presentation as well as in age of onset,from acute liver failure,cholestasis,or chronic liver disease.Other organs like eye,muscle,central and peripheral nervous system,gastrointestinal tract,hematological,endocrine,and renal systems are also variably involved.Diagnosis hinges on recognition of subtle clinical clues,screening metabolic investigations,evaluation of the extrahepatic involvement,and role of genetics and tissue diagnosis.Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation.This review lists and discusses the burden of mitochondrial respiratory chain defects,including various settings when to suspect,their evolution with time,including certain specific disorders,their tiered evaluation with diagnostic algorithms,management dilemmas,role of liver transplantation,and the future research tools.

Reference Intervals of Mitochondrial DNA Copy Number in Peripheral Blood for Chinese Minors and Adults

Background： Mitocbondrial DNA （mtDNA） content measured by different techniques cannot be compared between studies, and age- and tissue-related control values are hardly available. In the present study, we aimed to establish the nonllal reference range of mtDNA copy number in the Chinese population. Methods： Two healthy cohorts of 200 Chinese minors （0.1 18.0 years） and 200 adults （18.0-88.0 years） were recruited. Then, they were further categorized into eight age groups. The absolute mtDNA copy number per cell was measured by a quantitative real-time polymerase chain reaction. We subsequently used this range to evaluate mtDNA content in tbur patients （0.5-4.0 years） with molecularly proven mitochondrial depletion syndromes （MDSs） and 83 cases of mitochondrial disease patients harboring the m.3243A〉G mutation. Results： The reference range ofmtDNA copy number in peripheral blood was 175-602 copies/cell （mean： 325 copies/cell） in minors and 164 500 copies/cell （mean： 287 copies/cell） in adults. There was a decreasing trend in mtDNA copy number in blood with increasing age, especially in 0-2-year-old and 〉50-year-old donors. The mean mtDNA copy number level among the mitochondrial disease patients with m.3243A〉G mutation was significantly higher than that ofhealtby controls. The intDNA content ofPOLG, DGUOK, TK2, and SUCLA2 genes in blood samples from MDS patients was reduced to 25%, 38%, 32%, and 24%, respectively. Conclusions： We primarily establish the refeerence intervals of mtDNA copy number, which might contribute to the clinical diagnosis and monitoring of mitochondrial disease.