TSEN54 – Pontocerebellar Hypoplasia Type 2

TSEN54 encodes the subunit 54 of the tRNA-splicing endonuclease complex, and biallelic pathogenic variants cause pontocerebellar hypoplasia type 2 (PCH2), a prenatal/early-onset autosomal recessive neurodegenerative disorder. Affected infants present with feeding and respiratory difficulties, extrapyramidal dyskinesia, severe psychomotor retardation, and progressive microcephaly. Brain imaging reveals hypoplastic cerebellar hemispheres and ventral pons with megacisterna magna on ultrasound. Early misdiagnosis as dyskinetic cerebral palsy is common due to overlapping extrapyramidal signs ([PMID:29410950]).

Genetic studies report nine probands across five unrelated families harboring TSEN54 variants: three in a sibling/unrelated cohort ([PMID:29410950]), dizygotic twins ([PMID:20803644]), two unrelated individuals ([PMID:23307886]), and two affected infants in an Iranian consanguineous pedigree ([PMID:32697043]). The c.919G>T (p.Ala307Ser) founder mutation accounts for the majority of cases.

Segregation analyses confirm autosomal recessive inheritance, with three additional affected relatives segregating TSEN54 variants in sibships, twin and consanguineous pedigrees ([PMID:29410950]; [PMID:20803644]; [PMID:32697043]).

Additional mutational spectrum includes c.355T>G (p.Tyr119Asp) in compound heterozygosity with the founder allele ([PMID:23307886]) and a novel synonymous c.1170G>A (p.Val390=) predicted to alter splicing in an Iranian family ([PMID:32697043]).

Functional evidence supports a loss-of-function mechanism: zebrafish tsen54 knockdown causes brain structural defects and increased neuronal apoptosis that are rescued by human TSEN54 mRNA ([PMID:21273289]); Drosophila Tsen54 mutants recapitulate microcephaly, brain lobe reduction, and locomotor deficits ([PMID:35132432]); yeast studies reveal TSEN54 roles in tRNA/mRNA processing linked to neurodegeneration ([PMID:36943791]).

MRI of the cerebellum and pons is critical for prompt recognition of PCH2. Genetic testing targeting TSEN54, particularly the c.919G>T founder variant, should be performed in neonates with microcephaly and extrapyramidal dysfunction. Definitive molecular diagnosis enables accurate prognosis, recurrence risk assessment, and prenatal counseling. Key take-home: TSEN54 variant analysis is essential for clinical diagnosis and management of pontocerebellar hypoplasia type 2.

References

• Frontiers in pediatrics • 2018 • TSEN54 Gene-Related Pontocerebellar Hypoplasia Type 2 Could Mimic Dyskinetic Cerebral Palsy with Severe Psychomotor Retardation [PMID:29410950]
• American journal of medical genetics. Part A • 2010 • Molecular and neuroimaging findings in pontocerebellar hypoplasia type 2 (PCH2): is prenatal diagnosis possible? [PMID:20803644]
• Journal of child neurology • 2014 • Novel mutations in TSEN54 in pontocerebellar hypoplasia type 2 [PMID:23307886]
• Molecular genetics & genomic medicine • 2020 • A homozygote variant in the tRNA splicing endonuclease subunit 54 causes pontocerebellar hypoplasia in a consanguineous Iranian family [PMID:32697043]
• Human molecular genetics • 2011 • Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia [PMID:21273289]
• Biology open • 2022 • Mutations in Drosophila tRNA processing factors cause phenotypes similar to Pontocerebellar Hypoplasia [PMID:35132432]
• Genetics • 2023 • An unknown essential function of tRNA splicing endonuclease is linked to the integrated stress response and intron debranching [PMID:36943791]

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