Introduction
A COL4A1 mutation is known to induce numerous phenotypes, including renal, hepatic, ophthalmological, neurological, muscular, and vascular abnormalities. Disease onset mainly occurs between the fetal period and young adulthood, although asymptomatic subjects and sporadic late-onset intracerebral hemorrhages have also been described [1].
We report the case of a late diagnosis of COL4A1 mutation in an elderly patient presenting unusual vascular cognitive impairment (VCI) in conjunction with numerous vascular risk factors. Initial imaging was nonspecific, showing vascular leukoencephalopathy and one microbleed. The patient was given anticoagulant treatment with MRI follow-up, which showed a rapid accumulation of microbleeds before the occurrence of an intracerebral hemorrhage.
Observation
We report the case of a 71-year-old man with numerous cardiovascular risk factors (hypertension, atrial fibrillation, hypercholesterolemia, and hypothyroidism) who was admitted to the Regional Memory Research Centre (CMRR) of Besançon University Hospital for evaluation of two episodes of transient global amnesia and cognitive complaints. Neurological examination was normal. Neuropsychological examination using the RAPID battery tests [2] showed normal overall cognitive efficiency, attention deficit, fatigability, and mild executive disorders. The neuropsychological results are shown in table 1. No loss of autonomy was reported. The patient was diagnosed with multidomain mild cognitive impairment [3].
MRI examination showed leukoencephalopathy (Fazekas scale: 6) [4] including pontic white matter abnormalities, and one right frontal microbleed (BOMBS: 1) [5] (fig. 1). No aneurism was observed. The diagnosis of VCI was therefore made [6].
Fig. 1
a Pedigree of the family. Oph = Ophthalmic abnormalities; ICH = intracerebral hematoma. Initial (b, c) and follow-up (d) MRI examinations performed 3 months after disease onset during anticoagulant treatment showed leukoencephalopathy with brainstem and hemispheric involvement (FLAIR; b), initially one right frontal microbleed (T2*; c), and occurrence of multiple pontic and basal microbleeds during follow-up (T2*; d).
The patient's family history included retinal vascular abnormalities (arteriolar tortuosity), intracerebral hematoma, and intraocular hemorrhages in a number of the patient's relatives. No other specific family history, such as renal or hepatic abnormalities, was reported (fig. 1a). Genetic analysis was thus performed. Written informed consent was obtained from the patient.
Coumadin treatment for atrial fibrillation with a dilated left atrium was introduced 3 months after the first consultation before the genetic test results were known. Systematic MRI follow-up was performed 3 months after the first consultation, during which the symptoms of the patient remained stable, and showed multiple cortical, basal, and pontic microbleeds on T2* (BOMBS: 26; fig. 1). Four months after the first examination, the patient presented an acute onset of headaches, bilateral ataxia, dysarthria, dysphagia, and left paresthesia (National Institute of Health Stroke Scale: 6). CT scan showed a left mesencephalic intracerebral hemorrhage that occurred during treatment, but without coumadin overdose (international normalized ratio: 2.2). Coumadin treatment was stopped. Renal function progressively decreased with hematuria. Renal sonography showed no abnormalities. No muscular disorders occurred. The creatine kinase level was not high. VCI was still present, but no vascular dementia occurred (daily life activities remained preserved) after follow-up at 6 months.
Sequencing of the 52 coding exons of COL4A1 was performed and detected a typical deleterious mutation in exon 24 (c.1528G>A, p. Gly51Arg), affecting a glycine residue adjacent to several major integrin-binding sites within the cyanogens bromide-derived fragment CB3[IV] of the COL4A1 triple helix. It is typical of mutations affecting collagens and is absent from the Exome Variant Server database (http://evs.gs.washington.edu/EVS/). This mutation is located in the region that codes a 30-amino acid segment, associated with the HANAC phenotype (hereditary angiopathy with nephropathy, aneurysm and cramps) characterized by hematuria, renal cysts, muscle cramps with high levels of creatine-kinase, and frequently bilateral aneurysms of the internal carotid artery [7].
Discussion
This case report highlights unusual onset and vascular risk factor management of an elderly patient with a COL4A1 mutation. The occurrence of VCI in an elderly patient with numerous vascular risk factors is common, but episodes of atypical transient global amnesia are an unusual VCI onset. VCI and transient global amnesia are not reported in the COL4A1 phenotype. Therefore, it is difficult to consider VCI as an onset symptom of the COL4A1 mutation in this patient. Moreover, initial neuroimaging findings showing vascular leukoencephalopathy with only one microbleed were not specific to the COL4A1 mutation: there were no porencephalic lesions, few hemorrhagic lesions, mild-to-moderate leukopathy, and no aneurism. It is probable that this mutation was initially presymptomatic and that family history was the main reason for the diagnosis. Family ophthalmologic history was, in this case, a useful ‘red flag' for COL4A1 mutation screening, as suggested by Vahedi and Alamowitch [1], despite the initial cardiovascular risk factors and nonspecific leukoencephalopathy in the patient. It confirms the large phenotypic spectrum and incomplete clinical penetrance of a COL4A1 mutation. Therefore, systematic research of family history should be carried out in all (even elderly) patients with vascular leukopathy. Furthermore, detecting a COL4A1 mutation in this asymptomatic patient enabled us to diagnose this disease in other relatives of his family. They were then offered appropriate medical care with genetic counseling, prenatal screening, and prevention of aggravating factors (vascular risk factors, avoiding head traumatism, and violent effort inducing hypertension).
Weng et al. [8] reported a sporadic intracerebral hematoma in a 73-year-old patient with a COL4A1 mutation. Our case report describes a late-onset disease related to a hereditary COL4A1 mutation possibly triggered by anticoagulant treatment. In addition to intracerebral hematoma, renal dysfunction and hematuria occurred, suggestive of some characteristics of HANAC syndrome.
In our patient, the diagnosis of the COL4A1 mutation raised questions about anticoagulant treatment in this pathology. Atrial fibrillation was a formal indication of anticoagulation because of a high risk of ischemia (dilated left atrium). The balance of benefit and harm was discussed in this paucisymptomatic COL4A1 patient. Anticoagulant treatment was favored because of the high risk of ischemia linked to atrial fibrillation with a dilated left atrium. The rapid accumulation of microbleeds, occurring in the leukoencephalopathy of the brainstem and in the striatum, under anticoagulant treatment signaled vascular fragility [9].
Cerebral hemorrhage illustrates the difficulties in counterbalancing the ischemic risk caused by the arrhythmia with the risk of hemorrhage due to a COL4A1 mutation in presymptomatic patients. The mechanisms of this rapid evolution after a long asymptomatic period remain unknown, but cardiovascular risk factors associated with the introduction of anticoagulant treatment may have increased the vascular fragility induced by the COL4A1 mutation. Management of aggravating factors, especially vascular risk factors, requires further study in order to determine the best treatment in elderly patients with a COL4A1 mutation.
Disclosure Statement
The authors have nothing to disclose.
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