An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease.

Importance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes. Objective: To identify novel genes and mechanisms associated with familial CSVD. Design, Setting, and Participants: This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset

Effect of COVID-19 Lockdowns on Physical Activity, Eating Behavior, Body Weight and Psychological Outcomes in a Post-Bariatric Cohort.

PURPOSE: Little is known about the consequences of COVID-19 lockdowns on physical activity (PA), eating behavior, and mental health in post-bariatric surgery (BS) patients. We aimed to analyze the relations between changes in PA during COVID-19 lockdowns and changes in body weight and a comprehensive set of lifestyle and psychological outcomes in patients who have undergone BS. MATERIAL AND METHODS: In April-May 2020 (lockdown#1), we performed an online survey in a cohort of 937 adults who underwent BS and were followed-up at our university medical center for at least one year. We assessed changes in PA, eating behavior, body weight, fatigue, and depression (PHQ-9). In November-December 2020 (lockdown#2), we recorded body weight in 280 patients who had reported decreased PA during lockdown #1. RESULTS: During lockdown #1 (N = 420 patients included, 44% response rate), decreased PA was reported by 67% patients. Compared to those who reported increased or unchanged PA, patients with decreased PA were more likely to report a ≥ 5% weight gain (OR (95% CI): 3.15 (1.46-7.65), increased fatigue (2.08 (1.36-3.23)), a worsening of eating behavior (2.29 (1.47-3.58)), and moderate-to-severe depressive symptoms (4.74 (2.14-11.76)). During lockdown #2 (N = 225 patients, 80% response rate), significant weight gain since before lockdown #1 was reported (+ 2.8 (95% CI: 1.7-3.8) kg, p < 0.001), with 36% patients reporting a ≥ 5% weight gain. CONCLUSIONS: PA may counteract detrimental effects of COVID-19 lockdown on post-BS weight trajectories and mental health outcomes. Follow-up measures are needed in this setting to assess the long-term impact of lockdown.

COVID-19 and its Severity in Bariatric Surgery-Operated Patients.

OBJECTIVE: Obesity is a major risk factor for severe forms of coronavirus disease (COVID-19), but little is known about the post-bariatric surgery (BS) setting. The prevalence of likely COVID-19 and its risk factors in patients followed up after BS was assessed. METHODS: A total of 738 patients who underwent BS and were followed up at a university medical center were surveyed. A retrospective comparison of characteristics at baseline, 1 year after BS, and at the time of lockdown was performed between patients with COVID-19-likely events (CL) based on a combination of reported symptoms and those for whom COVID-19 was unlikely. RESULTS: CL occurred in 62 (8.4%) patients, among whom 4 (6.4%) had a severe form requiring hospitalization and 1 (1.6%) died. The CL group had a higher proportion of persistent type 2 diabetes (T2D) at last follow-up (36.2% vs. 20.3%, P = 0.01). BMI at the time of lockdown was lower in the CL group (30.2 ± 5.1 vs. 32.8 ± 6.5 kg/m2 ; P < 0.01) with higher percent weight loss since BS in the CL group. Severe forms of COVID-19 requiring hospitalization were associated with persistent T2D at the last follow-up visit. CONCLUSIONS: In BS patients, CL were associated with persistent T2D and lower BMI.

Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.

OBJECTIVE: Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. METHODS: We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants. RESULTS: In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls. CONCLUSIONS: Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

Genotype-phenotype correlations in cerebral cavernous malformations patients.

OBJECTIVE: To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers. METHODS: A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed. RESULTS: A deleterious mutation was detected in 128 probands. Three hundred thirty-three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety-four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2-weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient-echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient-echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05). INTERPRETATION: Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient-echo sequence lesions with age differs between CCM1 and CCM2 patients.

ATP1A2 mutations in 11 families with familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is an autosomal dominant form of migraine with aura. The disease is caused by mutations of at least three genes among which two have been identified, CACNA1A and ATP1A2. Very few mutations have been identified so far in ATP1A2. We screened the coding sequence of ATP1A2 in 26 unrelated FHM probands in whom CACNA1A screening was negative. A total of eight different mutations were identified in 11 of the probands (41%), including six missense mutations, one small deletion leading to a frameshift, and one in frame deletion. All were novel mutations. Two mutations were recurrent, in three and two families, respectively. Genotyping of 94 relatives of these 11 probands identified 47 mutation carriers, among whom 36 were clinically affected. Sequencing of all 23 exons in an ethnically matched panel detected only one exonic coding polymorphism.

Clinical features of cerebral cavernous malformations patients with KRIT1 mutations.

Cerebral Cavernous Malformations (CCM/OMIM 604214) are vascular malformations causing seizures and cerebral hemorrhages. They occur as a sporadic and autosomal dominant condition, the latter being characterized by the presence of multiple CCM lesions. Stereotyped truncating mutations of KRIT1, the sole CCM gene identified so far, have been identified in CCM1 linked families but the clinical features associated with KRIT1 mutations have not yet been assessed in a large series of patients. We conducted a detailed clinical, neuroradiological and molecular analysis of 64 consecutively recruited CCM families segregating a KRIT1 mutation. Those families included 202 KRIT1 mutation carriers. Among the 202 KRIT1 mutation carriers, 126 individuals were symptomatic and 76 symptom-free. Mean age at clinical onset was 29.7 years (range, 2-72); initial clinical manifestations were seizures in 55% of the cases and cerebral hemorrhages in 32%. Average number of lesions on T2 weighted MRI was 4.9 (+/-7.2) and on gradient echo sequences 19.8 (+/-33.2). Twenty-six mutation carriers harbored only one lesion on T2-weighted MRI, including 4 mutation carriers, aged from 18 to 55 yr-old, who presented only one CCM lesion both on T2-weighted and on highly sensitive gradient echo MRI sequences. Five symptom free mutation carriers, aged from 27 to 48 yr-old, did not have any detectable lesion both on T2WI and gradient echo MRI sequences. Within KRIT1/CCM1 families, both clinical and radiological penetrance are incomplete and age dependent. Importantly for genetic counseling, nearly half of the KRIT1 mutation carriers aged 50 or more are symptom-free. The presence of only one lesion, even when using gradient echo MRI sequences, can be observed in some patients with an hereditary form of the disease. Incomplete neuroradiological penetrance precludes the use of cerebral MRI to firmly establish a non carrier status, even at an adult age and even when using highly sensitive gradient echo MRI. Altogether these data suggest that the hereditary nature of the disorder may be overlooked in some mutation carriers presenting as sporadic cases with a unique lesion.