Background: Children with biallelic mutations in TRNT1 have multi-organ involvement with congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) as well as seizures, ataxia and sensorineural hearing loss. The TRNT1 gene encodes the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs accounting for phenotypic pleitropy. Neurodegenerative Leigh syndrome has not been previously reported.

Case summary: A Portuguese boy presented with global developmental delay, 2 episodes of infantile Leigh encephalopathy at 8 mo and 4 yr responsive to high-dose steroids, slowl neurodegeneration of cognitive, language and motor functions with optic atrophy, pigmentary retinopathy, spasticity, dystonia, and focal dyscognitive seizures, pancytopenia, transfusion dependent sideroblastic anemia, recurrent febrile infections (pulmonary, gastrointestinal), hypernatremia, with tracheostomy dependence at age 5 yr, malabsorption and TPN dependence at 9 yr, and survival to early adulthood. Neuroimaging showed symmetric hemorrhagic lesions in the thalamus, brain stem (periaqueductal grey) and cerebellum consistent with Leigh syndrome but no lactate peak on MRS.

Results: Whole exome sequencing identified a homozygous missense pathogenic variant in TRNT1, c.668T>C (p.I223T) in the affected individual.

Conclusions: This report expands the neurological phenotype of TRNT1 mutations and highlights the importance of considering this gene in the evaluation of Leigh syndrome.