Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations

Abstract

Combined respiratory chain deficiency accounts for about 30% of mitochondrial respiratory chain deficiencies and is frequently associated with mtDNA depletion, deletions or point mutations. However combined respiratory chain deficiency may also be caused by mutations in nuclear genes affecting mitochondrial translation. Here we describe a 2-year-old girl, who developed an acute, isolated, severe liver failure with mitochondrial pathology and decreased respiratory chain enzyme activities both in liver and skeletal muscle at 4 months of age. Her liver function improved significantly within a month, liver function tests returned to normal. Liver cirrhosis remained without any further complications so far. Pathogenic compound heterozygous mutations were identified in the TRMU gene. This condition is one of the few mitochondrial disorders with a life-threatening onset showing recovery later in life, therefore a prompt diagnosis and treatment of these patients has great importance in clinical practice. We suggest that TRMU deficiency should be considered in infants with acute liver disease.

Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases

“…However, regular medical follow-up is maintained, particularly because of the persistence of liver nodules that could eventually be at risk of malignant transformation. The proportion of spontaneous clinical recovery after the acute episode in our series was similar to previously reported cases (11/15) (Zeharia et al 2009;Uusimaa et al 2011;Schara et al 2011). Several hypotheses have been proposed to explain these spontaneous remissions, which are quite rare in clinical courses of mitochondrial cytopathies.…”

“…In all cases, strong decreases of complexes I and IV were noticed in the liver. The activities of complexes I and IV were diminished in all other cases of TRMU-related RC combined defects, even if other complexes may also be reduced (Zeharia et al 2009;Low et al 2008;Schara et al 2011).…”

“…Previous studies reported normal activities of complexes I, II, II þ III, and IV (Zeharia et al 2009) or deficiencies of complex IV (Zeharia et al 2009), complexes I and IV (Schara et al 2011;Low et al 2008), or complexes I, II þ III, and IV (Zeharia et al 2009). In muscle biopsy from P1, mtDNAencoded complexes I, III, and IV activities were decreased (V not determined), but, intriguingly, the nuclear-encoded complex II activity was also reduced.…”

“…The role of TRMU protein defect in mitochondrial diseases was first mentioned to modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutation (m.1555A>G) (Guan et al 2006;Yan et al 2006 injury with a decrease of mtDNA-encoded complexes in liver without mtDNA depletion (Zeharia et al 2009). Only two other cases of TRMU-related hepatopathy have been described since (Kemp et al 2011;Low et al 2008;Schara et al 2011;Uusimaa et al 2011). …”

“…Since 2009, to the best of our knowledge, only two other cases of TRMU mutations associated with neonatal hepatopathy have been described (Schara et al 2011;Uusimaa et al 2011). In this study, we report clinical, biochemical, and genetic findings in three unrelated patients affected by cholestasis, lactic acidosis, recurrent hypoglycemia, and combined respiratory chain (RC) deficiency.…”