TSEN54 – Pontocerebellar Hypoplasia

TSEN54 is robustly associated with pontocerebellar hypoplasia, a severe neurodevelopmental disorder characterized by cerebellar and brainstem hypoplasia, progressive microcephaly, and diverse neurological deficits. Multiple clinical reports have documented affected patients presenting with symptoms such as hypertonia, polyhydramnios, ataxia, intellectual disability, epileptic spasms, and choreoathetosis. The clinical spectrum ranges from early neonatal demise to later-onset neurological impairment, emphasizing the broad phenotypic continuum of this condition (PMID:21824568).

Clinical genetic studies have provided strong evidence for an autosomal recessive mode of inheritance for TSEN54-associated pontocerebellar hypoplasia. Several unrelated families have been described in which segregating variants in TSEN54 are identified, with comprehensive segregation analyses supporting the link between genotype and phenotype (PMID:21368912). Detailed case series further document the presence of multiple affected relatives, underscoring the utility of genetic testing in affected families and aiding reproductive decision‑making.

The genetic evidence is compelling. Among the spectrum of variants, the recurrent missense mutation c.919G>T (p.Ala307Ser) has been identified in multiple unrelated patients, reinforcing its pathogenicity. Additional reports describe other variant classes, including splice site and loss‑of‑function changes, which consistently corroborate the autosomal recessive inheritance pattern. This consistent genotype‑phenotype association across diverse cohorts and populations provides a crucial diagnostic anchor (PMID:24938831, PMID:20952379).

Complementary functional assessments have been performed in several model systems. Zebrafish and Drosophila models, in particular, have recapitulated key aspects of the human pontocerebellar hypoplasia phenotype, including abnormal brain morphology and increased neuronal cell death. Rescue experiments, in which co‑injection of wild‑type human TSEN54 mRNA partially ameliorated the phenotype, support a loss‑of‑function mechanism underlying the disorder (PMID:21273289, PMID:35132432).

There is minimal conflicting evidence regarding the TSEN54–pontocerebellar hypoplasia association. Although the phenotypic spectrum is broad, the majority of studies converge on a model where TSEN54 mutations lead to disruption of tRNA processing and subsequent neurodevelopmental impairment. This coherence between clinical presentation, segregation data, and robust experimental findings strengthens the overall clinical validity of the association. The integration of multiple lines of evidence supports the prioritization of TSEN54 testing for patients presenting with relevant neuroimaging and clinical features.

In conclusion, both the extensive genetic case data and functional studies provide strong support for a causal relationship between TSEN54 mutations and pontocerebellar hypoplasia. The recurrent identification of the variant c.919G>T (p.Ala307Ser) in multiple independent studies reinforces its diagnostic significance. Key take‑home: The strong genetic and experimental evidence confirms TSEN54 as a critical gene for pontocerebellar hypoplasia, underscoring its clinical utility in diagnostic decision‑making and genetic counseling.

References

• Pediatric neurology • 2011 • Novel TSEN54 mutation causing pontocerebellar hypoplasia type 4 PMID:21824568
• European journal of human genetics • 2011 • TSEN54 mutations cause pontocerebellar hypoplasia type 5 PMID:21368912
• Molecular medicine reports • 2014 • A familial late‑onset hereditary ataxia mimicking pontocerebellar hypoplasia caused by a novel TSEN54 mutation PMID:24938831
• Brain : a journal of neurology • 2011 • Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia PMID:20952379
• Human molecular genetics • 2011 • Impairment of the tRNA‑splicing endonuclease subunit 54 causes neurological abnormalities 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

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