<scp>TRIT1</scp> defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels

Muylle, Ewout; Jiang, Huafang; Johnsen, Christin; Byeon, Seul Kee; Ranatunga, Wasantha; Garapati, Kishore; Zenka, Roman M.; Preston, Graeme; Pandey, Akhilesh; Kozicz, Tamás; Fang, Fang; Morava, Éva

doi:10.1002/jimd.12550

Cited by 4 publications

(3 citation statements)

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“… 18 We collected previously reported disease-causing variants of TRIT1 (Fig. 1a ), and found that p.R327X has been previously reported as pathogenic by two independent studies, 19 , 20 while p.P24S is novel, located on the mitochondrial transit peptide sequence, and conserved in species down to arthropods (Fig. 1b ).…”

Section: Resultsmentioning

confidence: 84%

“…Only 17 patients have been reported with defects in TRIT1 gene (MIM#617873), which encodes a tRNA isopentenyltransferase modifying mitochondrial tRNAs. 18 – 20 In addition to the novel p.P24S variant, we present the first Finnish patient with the p.R327X 19 , 20 variant, previously described in two studies from France 20 and USA/China. 19 The p.R327X is the most common pathogenic TRIT1 variant in genomic databases, and three times more frequent in the Finnish population than in others, suggesting it might be a Finnish founder allele.…”

Section: Discussionmentioning

confidence: 99%

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Genetic etiology of progressive pediatric neurological disorders

Aaltio,

Etula,

Ojanen

et al. 2023

Pediatr Res

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Background The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology. Methods We studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed. Results We found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo. Conclusions The most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies. Impact Whole-exome sequencing is useful in heterogeneous pediatric neurology cohorts. Our article provides further evidence for and novel variants in several genes. De novo variants are an important cause of childhood encephalopathies.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Genetic etiology of progressive pediatric neurological disorders

Aaltio,

Etula,

Ojanen

et al. 2023

Pediatr Res

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show abstract

“…Fifteen patients with disseminated TRIT1 mutations causing different clinical manifestations have been reported, and a different and more severe phenotype was found in a child with a truncated TRIT1 mutation than in other patients, including intrauterine growth retardation, neonatal microcephaly, fibromuscular dysplasia, sensorineural hearing loss, and visual loss. 51 However, the link between these neurodevelopmental symptoms and abnormal tRNA modifications is unclear.…”

Section: Introductionmentioning

confidence: 99%

Research Advances on Deafness Genes Associated with Mitochondrial tRNA-37 Modifications

2023

Int Adv Otol

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As the most common cause of speech disorders, the etiological study of deafness is important for the diagnosis and treatment of deafness. The mitochondrial genome has gradually become a hotspot for deafness genetic research. Mitochondria are the core organelles of energy and material metabolism in eukaryotic cells. Human mitochondria contain 20 amino acids, except for tRNA Leu and tRNA Ser , which have 2 iso-receptors, the other 18 amino acids correspond to unique tRNAs one by one, so mutations in any one tRNA may lead to protein translation defects in mitochondria and thus affect their oxidative phosphorylation process resulting in the corresponding disease phenotype. Mitochondrial tRNAs are extensively modified with base modifications that contribute to the correct folding of tRNAs and maintain their stability. Defective mitochondrial tRNA modifications are closely associated with the development of mitochondrial diseases. The in-depth study found that modification defects of mammalian mitochondrial tRNAs are associated with deafness, especially the nucleotide modification defect of mt-tRNA-37. This article reviews the research on mitochondrial tRNAs, nucleotide modification structure of mitochondrial tRNA-37, and nuclear genes related to modification defects to provide new ideas for the etiological study of deafness.

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TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels

Muylle

Jiang

Johnsen

et al. 2022

J of Inher Metab Disea

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TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures, and abnormal mitochondrial function. Currently, only 13 patients have been reported. We reviewed the genetic, clinical, and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all 15 patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.

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TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels

Cited by 4 publications

References 20 publications

Genetic etiology of progressive pediatric neurological disorders

Genetic etiology of progressive pediatric neurological disorders

Research Advances on Deafness Genes Associated with Mitochondrial tRNA-37 Modifications

TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels

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