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

Jessica Roos; Stefanie Müller; Anne Giese; Silke Appenzeller; Erich Bernd Ringelstein; Jens Fiehler; Klaus Berger; Arndt Rolfs; Christian Hagel; Gregor Kuhlenbäumer

doi:10.1007/s00415-023-11590-9

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

J Neurol. 2023 May;270(5):2631-2639. doi: 10.1007/s00415-023-11590-9. Epub 2023 Feb 14.

Authors

Affiliations

¹ Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Arnold-Heller Str. 3, D24105, Kiel, Germany.
² Institute of Health Informatics, University College London, London, UK.
³ Department of Neurology, University Medical Center, Hamburg-Eppendorf, Germany.
⁴ Comprehensive Cancer Center Mainfranken, University Hospital, Würzburg, Germany.
⁵ Medical Faculty, University of Münster, Münster, Germany.
⁶ Department of Diagnostic and Interventional Neuroradiology, University Medical Center, Hamburg-Eppendorf, Germany.
⁷ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
⁸ Arcensus Gmbh, Rostock, Germany.
⁹ Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Germany.
¹⁰ Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Arnold-Heller Str. 3, D24105, Kiel, Germany. gregor.kuhlenbaeumer@uksh.de.

Abstract

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.

Keywords: Autosomal dominant stroke; COL4A1; Cerebral microangiopathy; Monogenic; PADMAL; Pontine autosomal dominant microangiopathy with leukoencephalopathy; Sporadic stroke.

MeSH terms

Adult
Cerebral Small Vessel Diseases* / complications
Cerebral Small Vessel Diseases* / diagnostic imaging
Cerebral Small Vessel Diseases* / genetics
Collagen Type IV / genetics
Cross-Sectional Studies
Humans
Leukoencephalopathies* / diagnostic imaging
Leukoencephalopathies* / genetics
MicroRNAs*
Mutation
Stroke* / complications
Stroke* / diagnostic imaging
Stroke* / genetics

Substances

COL4A1 protein, human
Collagen Type IV
MicroRNAs