'Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome

Tenon Hospital, Stroke Unit, Department of Neurology, Paris, France.
Neurology (Impact Factor: 8.29). 12/2009; 73(22):1873-82. DOI: 10.1212/WNL.0b013e3181c3fd12
Source: PubMed


COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. The aim of this study was to describe the cerebrovascular phenotype of HANAC.
Detailed clinical data were collected in 14 affected subjects from the 3 families. MRI and magnetic resonance angiography (MRA) were performed in 9 of them. Skin biopsies were analyzed by electron microscopy in affected subjects in the 3 families.
Only 2 of 14 subjects had clinical cerebrovascular symptoms: a minor ischemic stroke at age 47 years and a small posttraumatic hemorrhage under anticoagulants at age 48 years. MRI-MRA showed cerebrovascular lesions in 8 of 9 studied subjects (mean age 39.4 years, 21-57 years), asymptomatic in 6 of them. Unique or multiple intracranial aneurysms, all on the carotid siphon, were observed in 5 patients. Seven patients had a CSVD characterized by white matter changes (7/7) affecting subcortical, periventricular, or pontine regions, dilated perivascular spaces (5/7), and lacunar infarcts (4/7). Infantile hemiplegia, major stroke, and porencephaly were not observed. Skin biopsies showed alterations of basement membranes at the dermoepidermal junction associated with expansion of extracellular matrix between smooth vascular cells in the arteriolar wall.
The cerebrovascular phenotype in hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome associates a cerebral small vessel disease and a large vessel disease with aneurysms of the carotid siphon. It is consistent with a lower susceptibility to hemorrhagic stroke than in familial porencephaly, suggesting an important clinical heterogeneity in the phenotypic expression of disorders related to COL4A1 mutations.

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    • "E-mail: Article first published online in Wiley Online Library ( 00 Month 2014 DOI 10.1002/ajmg.a.36907 Ó 2015 Wiley Periodicals, Inc. et al., 2006; Sibon et al., 2007; Vahedi et al., 2007; Alamowitch et al., 2009; Bilguvar et al., 2009; De Vries et al., 2009, Shah et al., 2010; Livingston et al., 2011; Meuwissen et al., 2011; Tonduti et al., 2012; Lemmens et al., 2013] "
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    ABSTRACT: COL4A1 is located in humans on chromosome13q34 and it encodes the alpha 1 chain of type IV collagen, a component of basal membrane. It is expressed mainly in the brain, muscles, kidneys and eyes. Different COL4A1 mutations have been reported in many patients who present a very wide spectrum of clinical symptoms. They typically show a multisystemic phenotype. Here we report on the case of a patient carrying a novel de novo splicing mutation of COL4A1 associated with a distinctive clinical picture characterized by onset in infancy and an unusual evolution of the neuroradiological features. At three months of age, the child was diagnosed with a congenital cataract, while his brain MRI was normal. Over the following years, the patient developed focal epilepsy, mild diplegia, asymptomatic microhematuria, raised creatine kinase levels, MRI white matter abnormalities and brain calcification on CT. During the neuroradiological follow-up the extension and intensity of the brain lesions progressively decreased. The significance of a second variant in COL4A1 carried by the child and inherited from his father remains to be clarified. In conclusion, our patient shows new aspects of this collagenopathy and possibly a COL4A1 compound heterozygosity. © 2015 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.
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    • "For example, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited cause of vascular dementia [12], is caused by mutations in NOTCH3 [13], a gene preferentially expressed in vascular smooth muscle [14], [15]. Furthermore, mutations in COL4A1, a gene encoding the main component of smooth muscle basement membranes, also causes SVD in families with inherited leukoencephalopathy [16], [17], [18]. Pathways by which mutant NOTCH3 and COL4A1 lead to smooth muscle dysfunction and SVD are under active investigation. "
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    • "In addition, fibronectin stimulates the proliferation and survival of BCECs in vitro (Wang and Milner, 2006). Null mutations of either fibronectin or collagen IV are embryonic lethal due to mesoderm defects or impaired BM stability respectively; and more modest mutations in the Col4a1 gene are associated with fragile vessels, which predispose to stress-induced hemorrhage and adult-onset stroke in humans and mice (George et al., 1993; Poschl et al., 2004; Gould et al., 2006; Alamowitch et al., 2009). "
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