AJNR Am J Neuroradiol. 2026 Sep 4:ajnr.A9624. doi: 10.3174/ajnr.A9624. Online ahead of print.
ABSTRACT
BACKGROUND AND PURPOSE: VPS11-related Hypomyelinating Leukodystrophy (VPS11-HLD), also named HLD12, is an ultrarare lysosomal-autophagic disorder characterized by severe, early-onset neurodevelopmental disability and diffuse hypomyelination. The neuroimaging spectrum of VPS11-HLD had not been systematically studied. We aimed to characterize the MRI phenotype of VPS11-HLD and identify reproducible imaging features that may aid in distinguishing it from other hypomyelinating leukodystrophies.
MATERIALS AND METHODS: Patients with VPS11-HLD from two tertiary centers were retrospectively identified between 2019 and 2025. Clinical and genetic data were retrieved from medical records. Brain MRIs were independently reviewed by two pediatric neuroradiologists, and inter-rater agreement was assessed. Imaging features and biometric measurements were compared with those of 21 individuals with other genetically confirmed HLDs using Mann-Whitney U and Fisher’s exact tests. A systematic literature review was conducted to identify previously reported cases and provide clinical and neuroimaging data.
RESULTS: Six patients (four unrelated boys and two sisters; age range 8 months to 10 years) diagnosed with a homozygous VPS11 c.2536T>G (p.Cys846Gly) variant were identified. The first MRI, obtained at a median age of 9 months (IQR 7.5,13.75), demonstrated the following findings in all patients: 1) a distinct cerebellar signature characterized by focal absence of the cerebellar cortex in the middle-anterior hemispheric portions; 2) diffuse hypomyelination; 3) a periventricular leukomalacia (PVL)-like pattern; 4) short corpus callosum with marked thinning of the posterior portion, 5) hypoplasia of the anterior commissure and 6) mild pontine volume reduction. Inter-rater agreement for MRI feature assessment was high. In a comparative analysis with 21 patients with other HLDs, the cerebellar signature was observed exclusively in VPS11-HLD (6/6 vs. 0/21, respectively, p < .001).
CONCLUSION: VPS11-HLD demonstrates a reproducible MRI pattern combining a novel, peculiar cerebellar anomaly, hypomyelination with PVL-like pattern, and extremely thin and short corpus callosum.In the context of an ultra-rare disorder, this pattern may represent a candidate neuroradiologic phenotype that could support diagnostic stratification, guide targeted genetic evaluation, and provide insight into the role of autophagy-lysosome dysfunction in myelin and cerebellar development.
PMID:42697725 | DOI:10.3174/ajnr.A9624
