Late Cognitive or Mood Alterations With ‘Status Cribrosum’ and Diffuse White Matter Lesions: A New Cerebral Small Vessel Disease Phenotype Associated With Rare COL4A1 Variants Located Within Exon 23

OBJECTIVE: To report an atypical phenotype associated with two rare COL4A1 glycine missense variants located in exon 23. METHODS: Clinical, neuropsychological, and brain imaging data of four patients with such variants were reported. RESULTS: Four unrelated patients presented with late-onset cognitive alterations starting between 55 and 65 years of age. Brain magnetic resonance imaging (MRI) showed extensive white-matter hyperintensities on T2 or Flair images in all subjects, associated with multiple dilated perivascular spaces in the basal ganglia with features of status cribrosum in the three oldest individuals. None of the patients had a history of haemorrhagic stroke. Three of these patients had previously experienced mood disturbances. All had a family history of depression and/or suicide. Three of these unrelated patients shared a rare missense variant p.(Gly474Arg) in COL4A1, whereas the fourth one carried a p.(Gly486Glu) variant; these two variants affect two closely linked glycine residues encoded by exon 23 and located in a major cell-binding site of the triple helix. CONCLUSION: Missense variants affecting closely clustered glycine residues within the glycine-X-Y repeats encoded by exon 23 of COL4A1 are associated with an atypical, late-onset form of cerebral small vessel disease, characterised by diffuse leukoencephalopathy with a status cribrosum pattern and predominantly cognitive and/or neuropsychiatric manifestations.