RNASET2 – Cystic Leukoencephalopathy without Megalencephaly

Ribonuclease T2 (RNASET2) is a lysosomal endoribonuclease crucial for RNA turnover. Biallelic loss-of-function variants in RNASET2 cause Cystic Leukoencephalopathy without Megalencephaly, an autosomal recessive leukodystrophy marked by early-onset psychomotor impairment, white matter cystic degeneration, intracranial calcifications, seizures and global developmental delay (PMID:27091087). Only eight families were reported prior to 2018, and recent studies have expanded the genetic and clinical spectrum.

Six unrelated probands with biallelic RNASET2 variants have been documented across two cohorts: five in a European multi-patient series and one East Asian case (PMID:27091087; PMID:29336640). Variants include the recurrent nonsense allele c.128G>A (p.Trp43Ter) and an in-frame deletion c.394_396del (p.Lys133del), confirming a loss-of-function spectrum.

All affected individuals inherit RNASET2 variants in trans under an autosomal recessive model; parents are asymptomatic carriers. No additional segregating affected relatives beyond the probands have been reported, consistent with AR inheritance.

Functional studies in RNaseT2 knockout rats demonstrate hippocampal neuroinflammation, altered lysosomal markers (reduced LAMP2, increased acid phosphatase and β-N-acetylglucosaminidase activity) and specific memory deficits, supporting pathogenicity via lysosomal dysfunction and neurodegeneration (PMID:29752287).

Mechanistically, RNASET2 deficiency leads to accumulation of undegraded RNA in lysosomes, impaired autophagy and neuroinflammation, aligning with the human white matter pathology and seizure phenotype.

Together, genetic and experimental data yield a Strong clinical validity for RNASET2 association with cystic leukoencephalopathy without megalencephaly. RNASET2 testing should be prioritized in infants presenting with congenital infection–like leukodystrophy. Key take-home: Bi-allelic RNASET2 loss-of-function variants underlie a distinct AR leukoencephalopathy, with direct implications for diagnosis and genetic counselling.

References

• European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society • 2016 • Clinical, radiological and possible pathological overlap of cystic leukoencephalopathy without megalencephaly and Aicardi-Goutières syndrome PMID:27091087
• Fetal and pediatric pathology • 2018 • Novel RNASET2 Pathogenic Variants in an East Asian Child with Delayed Psychomotor Development. PMID:29336640
• Disease models & mechanisms • 2018 • RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory. PMID:29752287

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