Vascular Ehlers-Danlos syndrome (vEDS) is a rare condition characterized by connective tissue fragility. Direct spontaneous carotid-cavernous fistula (sCCF) is reportedly pathognomonic of vEDS. We conducted this study to understand the possible mechanisms of occurrence of sCCF in this subset of patients. We conducted a retrospective analysis of a monocentric vEDS cohort along with a literature review regarding sCCF in this condition. Of 133 patients regularly followed in our centre between 2000 and 2017, 13 (9.8%) had a diagnosis of direct sCCF (92.3% female, median age 33.0 years, interquartile range (IQR) [26.0–39.5]). There were 7 Glycine missense and 6 splice-site variants but no variant leading to haploinsufficiency. The literature search identified 97 vEDS patients with direct sCCF (79.4% female, 7.2% sex not reported, median age 31.0 years, IQR [24.0–39.0]). Increased carotid circumferential wall stress, higher carotid distensibility and lower carotid intima-media thickness could contribute to a higher risk for direct sCCF in vEDS. There is no predictive factor for the occurrence of sCCF apart from female sex in vEDS. In vEDS, anatomical and pathophysiological features of the intra-cavernous internal carotid artery make it prone to shunting in the cavernous sinus, due either to a spontaneous rupture or to a spontaneous dissection with pseudoaneurysm formation. Direct sCCF in seemingly healthy young individuals should be highly suggestive of vEDS and prompt further investigation.

Background and Purpose: Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disorder because of pathogenic variants in the COL3A1 gene. Arterial complications can affect all anatomic areas and about 25% involve supra-aortic trunks (SATs) but no systematic assessment of cervical artery lesions has been made. The primary objective was to determine an accurate prevalence of spontaneous SAT lesions in a large series of patients with vascular Ehlers-Danlos syndrome at diagnosis and during follow-up. Secondary objectives were to study their neurological consequences (transient ischemic attack or stroke) and the possible relationships with sex, genotype, ascertainment status. Methods: A retrospective review of a monocentric cohort of patients with molecularly proven vascular Ehlers-Danlos syndrome followed in a tertiary referral center from 2000 to 2017. Results: One hundred forty-four patients were analyzed, 56.9% (n=82) had SAT lesions: 64.6% females, 74.4% index-case patients. Most lesions were identified in early arterial assessment (48% at first work-up, mean age of 35.7±13.0 years). Cumulative incidence of a first identification of a SAT lesion was 41.7% at 40 years old. On the complete period of survey, 183 SAT lesions (with 132 dissections and 33 aneurysms) were identified, mainly in internal carotid arteries (56.3%) and vertebral arteries (28.9%), more rarely in patients with COL3A1 null mutations ( P =0.008). Transient ischemic attack or stroke were reported in n=16 (19.5%) of the 82 patients with SAT lesions without relation with age, sex, treatment, or hypertension. Conclusions: Cervical artery lesions are frequent and mostly asymptomatic in patients with vascular Ehlers-Danlos syndrome. Local dissections and aneurysms are the most frequent type of lesions, but transient ischemic attack or stroke seem rare.

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.