Late-onset dementia with leukoencephalopathy and a COL4A2 gene variant, causal link or fortuitous association: a case...

Cerebral small vessel disease can manifest as vascular dementia, typically associated with vascular risk factors or cerebral amyloid angiopathy, and more rarely associated with hereditary conditions. We present a case of late-onset dementia, associated with a likely pathogenic COL4A2 variant.

A 74-year-old woman presented with cognitive decline and behavioral changes, without personal history of cerebral infarcts or intracerebral hemorrhage. Brain MRI revealed an extensive leukoencephalopathy affecting periventricular and deep white matter, including subcortical white matter in the anterior temporal lobes and the orbitofrontal regions. Genetic analysis identified a heterozygous glycine substitution within the triple-helical domain of COL4A2, as commonly observed in patients with COL4A1/A2 collagenopathy.

COL4A2 pathogenic variants have been associated with various neurological and extraneurological phenotypes and an incomplete penetrance. The diffuse vascular leukoencephalopathy detectable on this patient's MRI is consistent with the ones observed in COL4A1/COL4A2 mutated patients. However, the clinical phenotype of this patient, limited to cognitive decline and behavioral changes occurring in the absence of any overt stroke, is unusual. These data suggest that this phenotype is either caused by the COL4A2 variant or is fortuitously associated with this variant or is the result of another cause for which this COL4A2 variant acts as a modifier. Memory clinic physicians should consider genetic analyses in the diagnostic workup of vascular leukoencephalopathies, but they should also interpret cautiously the causality between clinico-radiological phenotypes and molecular pathogenic variants, specifically when dealing with variants with possible incomplete penetrance.