Leukoencephalopathy, brain calcifications, and cysts (LCC): Two unique cases

Leukoencephalopathy with brain calcifications and cysts (LCC), also known as Labrune Syndrome, is a rare cerebral microangiopathy caused by biallelic variants in the <i>SNORD118</i> gene, which encodes the small nucleolar RNA (snoRNA) U8, a critical component of ribosome biogenesis. We present LCC cases with unusually protracted diagnostic trajectories. Case 1 had symptom onset in adolescence but remained undiagnosed until adulthood, while Case 2 had a transient occurrence of seizures in childhood and developed disabling motor symptoms in adulthood. Both were initially misdiagnosed-one with neurocysticercosis, the other with Fahr's disease and multiple sclerosis-leading to inappropriate treatments. On evaluation, both probands exhibited asymmetrical spasticity with upper motor neuron weakness and pseudobulbar features. Genetic analyses confirmed compound heterozygous <i>SNORD118</i> variants, including a rare upstream non-coding change (n.-6G>A). Neuroimaging revealed extensive leukoencephalopathy and calcifications, with cysts present in only one case. Notably, the severity of neuroimaging abnormalities contrasted with the milder or delayed clinical manifestations, underscoring phenotypic variability and the insidious nature of the disease process. These cases expand the clinical and imaging spectrum of <i>SNORD118</i>-related LCC, highlight diagnostic pitfalls and demonstrate challenges in variant detection due to incomplete coverage or reporting of non-coding regions in exome and genome sequencing. Greater awareness of LCC and improved interrogation of non-coding RNAs through clinical sequencing are essential for timely and accurate diagnosis.