Introduction
Ten to fifteen percent of strokes are related to an intracerebral hemorrhage (ICH). Etiologies are mainly arterial hypertension, amyloid deposition, and vascular malformations. In cases of a young age without vascular risk factors and vascular malformations, a genetic cause has to be suspected, especially a mutation in the gene coding for type IV collagen alpha 1 (COL4A1)[1].
We report a COL4A1 gene mutation in a 45-year-old woman with an isolated ICH in the absence of any other MRI abnormality, which further extends the clinical spectrum of COL4A1 mutations.
Case Report
A 45-year-old woman, without vascular risk factors, especially hypertension, or any medical history presented a coital thunderclap headache, followed by a right hemiparesis, hemihypoesthesia, and dysarthria. Usual biological analyses, including renal function, were normal. Brain MRI revealed an isolated ICH of the left putamen and internal capsule without any other abnormalities (fig. 1a, b). Microbleeds and leukoencephalopathy were absent. Brain CT scan did not find any calcification. Cerebral angiography was normal. Blood pressure monitoring, electrocardiography, transthoracic echocardiography, Holter monitoring, and a stress test were normal. The ophthalmological examination showed no retinal arteriolar tortuosity or cataracts. Renal ultrasound was normal. A second brain MRI performed 3 months later only showed the sequelae of ICH (fig. 1c, d). Inquiries among relatives were strictly negative. However, because of this unexplained and isolated ICH in a young adult, a genetic cause was strongly suspected.
Fig. 1
Brain MRI. Flair sequence (a) and gradient echo sequence(b). Initial MRI showing an ICH of the left putamen and internal capsule without any other abnormalities. Flair sequence(c) and gradient echo sequence(d). Sequelae of ICH on a further MRI 3 months later.
The entire COL4A1 gene was sequenced and a heterozygous G-to-A transition (c.2063G>A) was identified in exon 28, leading to the replacement of a highly conserved glycine residue by aspartic acid at position 688 (p.G688D) within the triple-helix domain. This mutation, never described to date, was not found in a panel of 288 control chromosomes of ethnically matched controls, and it is not present in the Exome Variant database or dbSNP137. It was predicted to be deleterious by SIFT, Polyphen, and alignGVD software.
Discussion
The spectrum of COL4A1-related disorders includes perinatal cerebral hemorrhage and porencephaly [2], cerebral small vessel disease with retinal arteriolar tortuosity and leukoencephalopathy [3], HANAC syndrome (Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps) and other eye abnormalities, including the Axenfeld-Rieger anomaly and cataract. A frequent white matter involvement is reported [3,4]. Interestingly, some HANAC patients may have a normal brain MRI. However, except for one patient who suffered from migraine, these patients were free from neurologic symptoms [5,6].
Recently, Weng et al. [7] reported COL4A1 variants in 2/96 patients with sporadic ICH. Their phenotype was not described in detail, but they did not seem to present an isolated deep ICH, as did our patient. Indeed, one 73-year-old patient had lobar ICH and microbleeds on his cerebral MRI, and the other patient with deep ICH suffered from hypertension.
Our report extends the clinical and MRI phenotypes of patients with pathogenic COL4A1 mutation. These data strongly suggest that COL4A1 genetic screening should be proposed in young patients with an isolated ICH of undetermined etiology, even without any other MRI abnormalities (microbleeds, leukoencephalopathy), or any family history of neurological manifestations.
Disclosure Statement
No financial disclosure.
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