“…In this report, we demonstrate a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene in a Chinese family with cSVD. Although the new variant is different from the originally reported mutations (c.*31G > T, c.*32G > T, and c.*35C > A) in patients with 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].…”
Section: Discussioncontrasting
confidence: 68%
“…The onset age of the reported PADMAL patients was 12 to 50 years old [13][14][15][16][17][18][19]. It was 38 to 52 in our study.…”
Section: Discussionmentioning
confidence: 44%
“…These variants affect a binding site of miR-29 microRNA and lead to upregulated expression of COL4A1 [13,14]. The clinical features of both diseases include leukoencephalopathy and multiple lacunar infarcts with pontine involvements [13][14][15][16][17]. Autopsy study showed massive fibro-hyalinosis and elastosis in small arteries and arterioles with atrophy of the tunica media and concentric intimal proliferation [13].…”
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.
“…In this report, we demonstrate a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene in a Chinese family with cSVD. Although the new variant is different from the originally reported mutations (c.*31G > T, c.*32G > T, and c.*35C > A) in patients with 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].…”
Section: Discussioncontrasting
confidence: 68%
“…The onset age of the reported PADMAL patients was 12 to 50 years old [13][14][15][16][17][18][19]. It was 38 to 52 in our study.…”
Section: Discussionmentioning
confidence: 44%
“…These variants affect a binding site of miR-29 microRNA and lead to upregulated expression of COL4A1 [13,14]. The clinical features of both diseases include leukoencephalopathy and multiple lacunar infarcts with pontine involvements [13][14][15][16][17]. Autopsy study showed massive fibro-hyalinosis and elastosis in small arteries and arterioles with atrophy of the tunica media and concentric intimal proliferation [13].…”
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.
“…In 2016, mutations located in a small 3’ untranslated region (UTR) of COL4A1 were shown to cause an autosomal dominant form of adult onset cSVD called PADMAL (Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy) [ 10 ]. PADMAL is characterized by recurrent small infarcts beginning around 40 years of age and leading to a progressive or stepwise cognitive decline and motor disability [ 10 , 39 , 40 ]. The cognitive profile of patients is marked by altered executive functions, processing speed and flexibility.…”
Section: Other Mutations Involving
Col4a1
and
...mentioning
confidence: 99%
“…In some patients, WMH involving the anterior temporal lobes and external capsules have been noticed, as observed in other genetic conditions such as CADASIL or CARASIL. As in duplications, microbleeds are inconsistent or scarce, and brain hemorrhage was not previously reported in PADMAL patients [ 10 , 39 , 40 ]. Fig.…”
Section: Other Mutations Involving
Col4a1
and
...mentioning
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.
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