Introduction
Leukoencephalopathy, calcifications and cysts (LCC) represents a disorder of a progressive cerebral angiopathy leading to widespread white matter signal changes, cystic hemispheric and cerebellar lesions and focal brain calcifications. LCC imaging is prototypical for the disorder known as Labrune Syndrome and characterized by developmental delay, seizures, progressive spasticity and dystonia.  While Labrune Syndrome has been known for decades, its molecular association to biallelic mutations of SNORD118 was only established recently.  Over 100 patients with LCC due to SNORD118 have been reported in the literature. SNORD118 transcribes a highly conserved small nucleolar RNA (snoRNA), U8, that is essential in ribosome biogenesis.  This snoRNA is only 136 base long and overlaps the 3’UTR of the TMEM107 gene on the opposite strand.  Genomic pipelines that ignore non-coding regions could easily miss pathogenic alleles in the SNORD118.

Case Presentation
The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) evaluated the first patient, a male with symptoms of progressive left spastic hemiparesis, at age 42. The family history is negative. His travel history included an episode of severe febrile illness involving nausea, vomiting, myalgias, and diarrhea at age 12 upon returning from Mexico. Because of his travel history to a cysticercosis-endemic region and focal brain calcifications on his MRI, the patient was twice treated for neurocysticercosis with no clinical or neuroimaging improvements. At the time of our evaluation, his neurological exam revealed left spastic hemiparesis, a spastic foot drop, pseudobulbar affect (PBA), decrease in dexterity and gait difficulties.  MRI of the brain showed multiple cystic lesions, some with contrast-enhancement, areas of irregular and asymmetrical T2 hypo intensity in the periventricular white matter consistent with calcifications along with large areas of subcortical leukoencephalopathy.  Sanger sequencing and segregation in his nuclear family revealed pathogenic compound heterozygous variants in the snoRNA SNORD118 (NR_033294): n.3C>T and n.20C>T.  His neuroimaging findings in combination with the confirmed pathogenic variants in SNORD118 led to a diagnosis of LCC.

The second patient was a 53-year-old Hispanic woman admitted to the NIH Undiagnosed Diseases Program (NIH-UDP) in 2017. The family history was not contributory.  The patient has an early history of seizures that stopped by age 15. At 28, she began dragging her left leg which, over time, progressed to the right leg. Progressive dysarthria ensued, and, by age 42, she was essentially mute with profound akinesia, dystonia, pseudobulbar affect, spasticity and had become totally wheelchair bound.  She has extensive basal ganglia and dentate calcifications, significant generalized atrophy, and diffuse leukoencephalopathy. Sequencing of the nuclear pedigree identified compound heterozygous pathogenic variants in the snoRNA SNORD118 (NR_033294): n.-6G>A and n.131C>G. She had previously received an incorrect diagnosis of Multiple Sclerosis (MS) and later, Fahr’s Disease based on the presence of brain calcifications.  A molecular diagnosis of LCC was eventually established despite the atypical MRI imaging lacking brain cysts.

Diagnostic Workup
 

Conclusion
We describe two unique cases of LCC diagnosed in adulthood.  One patient experienced progressive spasticity beginning as a teenager and was erroneously treated for possible neurocysticercosis given his focal brain calcifications in the context of travel history to a cysticercosis-endemic area. The other patient suffered from progressive spasticity, akinesia, dystonia and mutism.  At the time of their evaluation by the NIH-UDP, both patients had asymmetrical spastic weakness and pseudobulbar affect. Both patients have compound heterozygous pathogenic variants in snoRNA SNORD118. Taken together, these unique cases raise awareness of LCC as a distinct phenotype, even in adults, arising from non-protein coding regions of the human genome which could be easily overlooked.  These cases also highlight the critical role of non-protein coding regions of the human genome in human health and disease.