Objective: Expanding the TELO2-related phenotype by presenting a case with prominent hyperkinetic MD.

Background: Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulate the activity of multiple protein kinases, including ATM, PRKDC, ATR and mTOR, by regulating the assembly of mTOR complex 1 (mTORC1). Bi-allelic mutations of TELO2 have been recently described and associated with syndromic post-natal neurodevelopmental disorders, epilepsy, and MDs.

Method: We report a new case with early onset MD and a review of the cases reported by literature so far.

Results: A 4-year-old boy was referred to our clinic for mild developmental delay (DD). He had been suffering since birth from failure to thrive, feeding difficulties and frequent infectious diseases. 

On examination, he showed facial dysmorphisms, mild convergent strabismus, and a complex hyperkinetic MD with dystonia and choreoathetosis of the limbs and trunk.  

Brain MRI revealed thinned corpus callosum and mild CSF space enlargement. Array-CGH and an NGS panel for MDs were unhelpful. Due to slightly increased blood lactate, mt-DNA sequencing was performed and found negative. However, enzymatic assays on fibroblasts detected a slightly reduced activity of mitochondrial complex V.  A trial with thiamine resulted in a clear clinical improvement of dyskinetic movements and motor skills. Finally, WES analysis revealed bi-allelic c.1127T>C and c.830_1282del variants in TELO2.

Since its first description, 26 patients with TELO2 defects have been reported presenting with variable clinical findings including malformations and neurological disorders. Additional features included poor growth and immunological abnormalities. Among motor signs, ataxia and gait instability were observed in 17/26 patients and MD in 17/26 patients. 

Our patient shares similar clinical findings with previously reported cases, however, with hyperkinetic MD as the dominating symptom.

Conclusion: The phenotypic spectrum of TELO2-related disorders is still evolving. Ataxia, hyperkinetic MD, and immunological abnormalities are part of the clinical picture, as seen in other conditions affecting DNA repair. Ongoing functional studies will help us to understand the pathophysiological substrate and mitochondrial abnormalities. The benefit from thiamine supplementation needs confirmation.

References: You J, Sobreira NL, Gable DL, et al. A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex. Am J Hum Genet. 2016;98(5):909-918. doi:10.1016/j.ajhg.2016.03.014

Moosa S, Altmüller J, Lyngbye T, et al. Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome. Mol Genet Genomic Med. 2017;5(5):580-584. Published 2017 Jul 28. doi:10.1002/mgg3.287

Ciaccio C, Duga V, Pantaleoni C, et al. Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant. Eur J Med Genet. 2021;64(1):104116. doi:10.1016/j.ejmg.2020.104116

Albokhari D, Pritchard AB, Beil A, et al. TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature [published online ahead of print, 2023 Feb 16]. Am J Med Genet A. 2023;10.1002/ajmg.a.63142. doi:10.1002/ajmg.a.63142

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MDS Abstracts - https://www.mdsabstracts.org/abstract/telo2-defect-presenting-with-childhood-onset-complex-hyperkinetic-md/