Hereditary cerebral small vessel disease: Assessment of a HTRA1 variant using protein stability predictors and 3D modelling.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive vascular disorder caused by biallellic variants in HTRA1. Recently, it has been reported that several heterozygous mutations in HTRA1 are responsible for a milder late-onset cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. The majority of them are missense that affects the Htr1A protease activity due to a dominant-negative effect caused by defective trimerization or monomer activation. The molecular mechanism related to the structural destabilization of the protein supports the practical utility of integrating computational stability predictors to prioritize candidate variants in this gene. In this work, we report a family with several members diagnosed with subcortical ischemic events and progressive cognitive impairment caused by the novel c.820C > G, p.(Arg274Gly) heterozygous variant in HTRA1 segregating in an autosomal dominant manner and propose its molecular mechanism by a three-dimensional model of the protein's structure.

Persistent hyperglycemia >155 mg/dL in acute ischemic stroke patients: how well are we correcting it?: implications for outcome.

BACKGROUND AND PURPOSE: We aimed to analyze the frequency of persistent hyperglycemia (PH), its implications for outcome, and to document the inpatient management of hyperglycemia. METHODS: Post hoc analysis of the GLIAS (Glycemia in Acute Stroke) study, a multicenter, prospective, and observational cohort study of 476 acute ischemic stroke patients. Capillary finger-prick glucose was determined on admission and during the first 48 hours. We defined PH was defined as at least 2 values ≥155 mg/dL. Outcome (modified Rankin Scale) was evaluated at 3 months. RESULTS: PH developed in 117 patients (24.7%). PH was associated with poorer outcome (modified Rankin Scale score >2: 56.2% vs 28.1%; P<0.01) and higher mortality (26.7% vs 5.9%; P<0.01) than those with glycemia <155 mg/dL. PH ≥155 mg/dL was associated with a 4-fold increase in the odds of poor outcome at 3 months (odds ratio, 4.7; 95% confidence interval, 2.2-10.2) after adjustment for age, gender, hypertension, diabetes, stroke severity, admission glycemia, and infarct volume. Only 20% of patients with hyperglycemia ≥155 mg/dL received insulin on admission, with a progressive increase in the use of insulin during the following 48 hours. However, 114 (39.1%) out of 291 patients who received corrective treatment for hyperglycemia still had levels ≥155 mg/dL. CONCLUSIONS: PH ≥155 mg/dL is a common observation in acute ischemic stroke patients that is associated with poorer outcome and higher mortality. Almost 40% of patients maintained levels ≥155 mg/dL despite corrective treatment.

[Migraine and interatrial septal abnormalities in patients under 55 with cryptogenic stroke]. / Migraña y alteraciones del septo auricular en pacientes menores de 55 años con infarto cerebral criptogenético.

BACKGROUND AND OBJECTIVE: Patent foramen ovale (PFO) is more frequent in migraine patients and is a cause of brain infarct among patients under 55 years old. Our goal was to study the association between PFO and migraine in ischemic stroke patients under 55 years old. PATIENTS AND METHOD: Observational study with inclusion of consecutive stroke patients admitted to a stroke unit (1995--2005). We selected patients under 55 years of age with first-ever acute cerebral infarction of cryptogenic origin. Demographic data, vascular risk factors, stroke vascular territory, stroke severity, the presence of PFO and/or atrial septal aneurysm (ASA) in echocardiography and functional status at discharge by the modified Rankin Scale score were analysed according to previous migraine. RESULTS: From a total of 130 patients, 76 were males. The 13.8% had previous migraine, 3.9% among male and 27.8% among female (p < 0.001). Migraine patients were younger than non migraine ones (p = 0.041) and had a higher frequency of vascular risk factors (not significant [NS]). Stroke severity and functional status at discharge were similar in both groups. Previous history of migraine was associated with FOP (38.9% vs. 26.8%; NS) and FOP plus ASA (odds ratio = 5; 95% confidence interval, 1.422-17.580). The latter association was higher in female (33.3% vs. 0%; NS). CONCLUSIONS: Previous migraine is more frequently associated with double interatrial septal abnormality (PFO plus ASA) in cerebral infarct patients under 55 years of age. This association could be higher in women.