Pontine autosomal dominant microangiopathy with leukoencephalopathy: Col4A1 gene variants in the original family and sporadic stroke

• Published in: Journal of neurology Vol. 270; no. 5; pp. 2631 - 2639
• Main Authors: Roos, Jessica, Müller, Stefanie, Giese, Anne, Appenzeller, Silke, Ringelstein, Erich Bernd, Fiehler, Jens, Berger, Klaus, Rolfs, Arndt, Hagel, Christian, Kuhlenbäumer, Gregor
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2023; Springer Nature B.V
• Subjects: Adult; Binding sites; Brain stem; Cerebral Small Vessel Diseases - complications; Cerebral Small Vessel Diseases - diagnostic imaging; Cerebral Small Vessel Diseases - genetics; Collagen; Collagen Type IV - genetics; Cross-Sectional Studies; Dementia disorders; Humans; Leukoencephalopathies - diagnostic imaging; Leukoencephalopathies - genetics; Leukoencephalopathy; Magnetic resonance imaging; Medicine; Medicine & Public Health; MicroRNAs; miRNA; Mutation; Neurology; Neuroradiology; Neurosciences; Original Communication; Sequence analysis; Skull; Stroke; Stroke - complications; Stroke - diagnostic imaging; Stroke - genetics; Substantia alba; Pontine autosomal dominant microangiopathy with leukoencephalopathy; Autosomal dominant stroke; Cerebral microangiopathy; PADMAL; Sporadic stroke; Monogenic; COL4A1
• ISSN: 0340-5354; 1432-1459; 1432-1459
• DOI: 10.1007/s00415-023-11590-9

Background (1) Description of clinical and cranial MRI features in the original Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy (PADMAL) family and correlation with the segregation analysis of the causative collagen 4A1 gene ( COL4A1 ) variant. (2) Sequence analysis of the COL4A1 miRNA-binding site containing the causative variant in two independent cross-sectional samples of sporadic stroke patients. Patients and methods Sanger sequencing of the COL4A1 miRNA-binding site in the PADMAL family and 874 sporadic stroke patients. Results PADMAL shows adult-onset usually between 30 and 50 years of age with initial brainstem-related symptoms most commonly dysarthria, with progression to dementia and tetraparesis. Radiologically pontine lacunes are followed by supratentorial white matter involvement. Radiological onset may precede clinical symptoms. We found no variants in the COL4A1 miRNA-binding site of sporadic stroke patients. Conclusion Our results allow an early diagnosis of PADMAL based on cranial MRI, clinical signs, and confirmatory sequencing of the COL4A1 miRNA-29-binding site. COL4A1 miRNA-29-binding site variants do not contribute to a sizeable proportion of sporadic stroke.