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We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual.

Original publication

DOI

10.1016/j.ajhg.2020.01.005

Type

Journal article

Journal

American journal of human genetics

Publication Date

02/2020

Volume

106

Pages

256 - 263

Addresses

University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria; Institute of Human Genetics, Technical University München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum, 85764 Neuherberg, Germany.

Keywords

Cerebellum, Humans, Nervous System Malformations, Cataract, Phosphorus-Oxygen Lyases, Phosphotransferases (Alcohol Group Acceptor), Pedigree, Developmental Disabilities, Amino Acid Sequence, Sequence Homology, Phosphorylation, Homozygote, Phenotype, Mutation, Alleles, Child, Preschool, Infant, Female, Male, Whole Exome Sequencing