Monogenic cerebral small‐vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology

Abstract

Background and purpose Guidelines on monogenic cerebral small‐vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin‐A‐related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS) and type IV collagen (COL4)A1/2. Methods We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. Results We have proposed ‘red‐flag’ features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus. Conclusions The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.

TREX1‐associated retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

“…Symptoms normally start in early to middle adulthood and without any established treatment patients invariably deteriorate and suffer premature death largely from neurological decline. 1 Fewer than 25 families with RVCL-S have been identified to date. 2 The condition is caused by a frameshift or nonsense mutation of the C-terminal region in the TREX1 gene (3p21) which encodes three prime repair exonuclease 1 (TREX1) protein.…”

“…6 The majority of patients with RVCL-S experience an inexorable neurological decline and die from the consequences of progressive cognitive impairment within 10 years of diagnosis. 1,6 Although this disorder is only occasionally reported in the ophthalmic literature, it may be under recognized. It is essential to consider the diagnosis of RVCL-S in patients with a retinal vasculopathy in the absence of a pre-disposing systemic medical condition and without serological evidence of an undiagnosed autoimmune condition.…”

“…6 RVCL-S is characterized by a progressive, visionimpairing occlusive retinopathy and white-matter brain lesions. 1,6 In early stages, the occlusive retinal vasculopathy predominantly affects capillaries and manifests by CWS, aneurysms and telangiectasia. 7 FFA findings demonstrate peri-foveal capillary non-perfusion, vascular remodelling, enlarged foveal avascular zone and neovascularization in advanced cases.…”

“…With the presentation of occlusive retinopathy and neurological symptoms or signs, neuroimaging should be considered as there are typical features which may aid in the diagnosis of RVCL-S. 6 Furthermore, systemic manifestations of RVCL-S often lead to the misdiagnosis of brain tumours, multiple sclerosis or vasculitis and may result in unnecessary invasive procedures such as biopsies of the brain, liver or kidney. 6 Misdiagnosis, can also lead to inappropriate treatments including immunosuppression or antiplatelet therapy, for which there is no role in RVCL-S. 1 In the majority of cases, the onset of retinopathy occurs prior to cerebral disease, often in combination with other systemic features. 2,6,8 The ophthalmologist is uniquely able to identify patients with RVCL-S and establish a diagnosis, via referral for appropriate genetic testing.…”

A Case of Atypical Multiple Sclerosis Mimicking Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Syndrome

“…Brain lesions can mimic tumors or tumefactive inflammation. We thought that our patient was not compatible with CARASIL, MELAS and CARASAL in terms of both lesions in brain and clinically [13]. For these reasons, we did not consider the CARASIL, CARASAL and MELAS syndromes in our patient.…”