A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

Qing Li,Zaiqiang Zhang,Autongsha Wupuer,Yi Zhu,Shanshan Wang,Chengfeng Wang,Hongyan Li,Kalibinuer Wumaier,Wei Li,Xiao Hu,Wengui Yu

doi:10.1007/s12975-021-00926-0

Abstract

Pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

Highlights

Cerebral small vessel disease is a main cause of stroke, cognitive impairment, and vascular dementia [1]
We demonstrate a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene in a Chinese family with Cerebral small vessel disease (cSVD)
The new variant is different from the originally reported mutations (c.*31G > T, c.*32G > T, and c.*35C > A) in patients with Pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) [13] and the c.*32G > A mutation in patients with multi-infarct dementia of Swedish type [14], the clinical features and skin biopsy results support the diagnosis of PADMAL [13,14,15,16,17,18,19]

Summary

Introduction

Cerebral small vessel disease (cSVD) is a main cause of stroke, cognitive impairment, and vascular dementia [1]. Mutations causing overproduction of COL4A1 have been identified in patients with pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) [13] and multi-infarct dementia of Swedish type [14]. Genetic analysis showed a c.*32G > A mutation in the 3′ untranslated region of COL4A1, which was identical to the mutation described in patients with multi-infarct dementia of Swedish type [14] Another case report described a novel c.*33 T > A mutation in a patient with progressive gait disturbance and cognitive impairment [19]. Overexpression of COL4A1 appears to interrupt the integrity of the basement membrane and cause both ischemic and hemorrhagic stroke [19] These recent case reports suggest that PADMAL and multi-infarct dementia of Swedish type likely belong to a growing spectrum of the same hereditary cSVD. We report a novel c.*34G > T mutation in a Chinese PADMAL pedigree

Methods

Results

Discussion