Proteomic-guided targeted treatment of leukoencephalopathy with calcification and cysts.

SNORD118

Biallelic SNORD118 variants (ribosomopathy) — ribosomal dysfunction in white matter and convergent VEGF pathway activation in the vascular compartment

Leukoencephalopathy with calcifications and cysts (LCC) is a rare ribosomopathy caused by biallelic SNORD118 variants, with no established treatment. The authors applied spatially resolved proteomics — laser-capture microdissection followed by label-free mass spectrometry — to vascular and white matter regions from four patients and four controls. Alterations were tissue-specific: vascular remodelling emerged as the primary site of cell proliferation, whereas white matter degeneration appeared driven by ribosomal dysfunction, with consistent upregulation of VEGFR1/2 and of the PKC and Ras-MEK-ERK cascades. In a 53-year-old patient carrying novel compound heterozygous SNORD118 variants, VEGF-targeted treatment with axitinib produced a radiographic and clinical response sustained beyond 35 months, the longest reported in this disease.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A single treated patient is not proof of efficacy, but the approach is exemplary: start from patient tissue to nominate a target, then repurpose an already available inhibitor. In practice this justifies discussing a VEGF inhibitor in a multidisciplinary setting for a progressive LCC patient, and above all preserving usable tissue material whenever procedures are performed in these rare encephalopathies. Whether the method transfers to other ribosomopathies remains entirely to be shown.

Analysis by Dr Thibaut Benquey