TRNT1 deficiency: clinical, biochemical and molecular genetic features. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Wedatilake, Yehani; Niazi, Rojeen; Fassone, Elisa; Powell, Christopher; Pearce, Sarah; Plagnol, Vincent; Saldanha, José; Kleta, Robert; Chong, W; Footitt, Emma; Mills, Philippa; Taanman, Jan-Willem; Minczuk, Michal; Clayton, Peter; Rahman, Shamima
• Is Part Of: Orphanet journal of rare diseases. Volume 11:Issue 1(2016)
• Page Start: 1
• Page End: 14
• Publication Date: 2016-12
• Subjects: Mitochondrial disease -- TRNT1 -- tRNA -- Protein translation -- SIFD -- Sideroblastic anaemia; Rare diseases -- Periodicals; Genetic disorders -- Periodicals; Orphan drugs -- Periodicals; 616
• DOI: 10.1186/s13023-016-0477-0
• Languages: English
• ISSNs: 1750-1172

Abstract

Abstract Background TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs). Results We investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis. Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygousTRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a homozygousTRNT1 mutation (c.569G>T), p.Arg190Ile, (previously published). We found normal mitochondrial translation products using passage matched controls and functional perturbation of 3' CCA addition to mitochondrial tRNAs (tRNACys, tRNALeuUUR and tRNAHis ) in fibroblasts from two patients, demonstrating a pathomechanism affecting the CCA addition to mt-tRNAs. Acute management of these patients included transfusion for anaemia, fluid and electrolyte replacement and immunoglobulin therapy. We also describe three-year follow-up findings after treatment by bone marrow transplantation in one patient, with resolution of fever and reversal of the abnormal metabolic profile. Conclusions Our report highlights thatTRNT1 mutations cause a spectrum of disease ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated retinitis pigmentosa presentation. Systematic review of allTRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases.