Remarkably different results between two studies from North America on genomic mutations and sensitivity to DNA demethylating agents for myelodysplastic syndromes

Sekeres et al. （1） conducted a multicenter randomized, controlled trial to compare whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates to azacitidine in the treatment of myelodysplastic syndromes （MDS）. In that trial, 224 patients with higher-risk MDS and 53 with chronic myelomonocytic leukemia （CMML） were enrolled and randomly assigned to the ＂azacitidine＂ group, ＂azacitidine plus lenalidomide＂ group or ＂azacitidine plus vorinostat＂ group. The researchers found that patients with MDS treated with azacitidine-based combinations had similar response rate to azacitidine monotherapy. Using genomic mutation analysis, they found that the overall response rate to azacitidine-based treatment was higher for patients with mutations in DNMT3A and lower for those with mutations in SRSF2. Whereas in another study, Welch et al. enrolled 26 patients with MDS and 90 with acute myeloid leukemia （AML） who were treated with decitabine, and they found that patients with TP53 mutations had a higher response rate, but not those with DNMT3A mutations （2）. We propose that this big discrepancy in the conclusions between the two studies might have been caused by the presence of many co-interacting factors, e.g. study aims, DNA demethylating agents, treatment protocols, and patient sources.

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.

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.