cystic leukoencephalopathy without megalencephaly

Cystic leukoencephalopathy without megalencephaly is a neurodevelopmental condition marked by non-progressive abnormalities in the brain’s white matter, including bilateral cysts in the anterior temporal lobes. Pathogenic variants in the RNASET2 gene, which impair RNA metabolism, are responsible for the disorder. Most affected children present in early childhood with significant developmental challenges, such as global developmental delay and delayed speech. The condition is extremely rare, affecting fewer than 1 in 1,000,000 people, with fewer than 50 cases described in the medical literature.

Individuals with cystic leukoencephalopathy without megalencephaly typically exhibit profound early developmental challenges. Nearly all affected children show global developmental delay and delayed speech and language development, which are considered hallmark features. In addition, many experience spasticity, while a subset may have seizures, ataxia, and abnormal central nervous system myelination. Other less common features include nystagmus, sensorineural hearing impairment, ventriculomegaly, athetosis, microcephaly, cerebral calcification, dystonia, and an appearance sometimes described as doll-like facies. Not all individuals experience all of these features, and severity varies considerably, with the neurological involvement often impacting cognitive and motor functions.

The underlying cause of cystic leukoencephalopathy without megalencephaly is linked to pathogenic variants in the RNASET2 gene. RNASET2 plays an important role in RNA turnover and cellular processes critical for brain development. The condition is inherited in an autosomal recessive manner, which means that an affected child has received one mutated copy of the gene from each parent. This condition is more common when parents share a common ancestor, as the likelihood of both carrying the same rare variant increases. Families are encouraged to consider genetic counseling for a clearer understanding of recurrence risks and carrier testing options.

Currently, management of cystic leukoencephalopathy without megalencephaly focuses on supportive care and symptom management, as there are no treatments specifically approved for this condition. A multidisciplinary approach is recommended, with therapy teams including physical, occupational, and speech specialists working together to help optimize developmental outcomes. Regular surveillance is an essential part of long-term care, allowing healthcare providers to monitor for potential complications and adjust interventions as needed. Patients and their families are advised to discuss treatment options and management strategies with their healthcare team, and genetic counseling is recommended to provide further guidance on family planning.

The prognosis for cystic leukoencephalopathy without megalencephaly is variable, with outcomes depending on the severity of developmental impairments and the level of supportive care received. Although affected children exhibit significant early developmental challenges, many experience a period of relative stability after initial delays. With current standards of care and advances in supportive therapies, individuals may achieve improvements in quality of life and functional abilities over time. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists and genetic counselors to better understand management options and to navigate the lifelong care associated with this condition.