Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

The influence of empathizing and systemizing on humor processing: Theory of Mind and humor

This paper investigates the influence of empathizing and systemizing on cognitive and affective humor processing in two studies. Three cartoon types differing in their logical mechanisms (LMs) and cognitive requirements were presented to participants with high scores on one scale and low scores on the other (empathizers and systemizers): visual puns, semantic cartoons and Theory of Mind cartoons. Empathizers and systemizers were expected to process these cartoon types differently. While empathizers and systemizers did not differ in recognition time and comprehensibility in study one (N = 33), empathizers did portray higher funniness scores in study two (N = 55). Furthermore, empathizers more often gave emotional/motivational explanations as well as more mentalistic explanations as to why they think a cartoon is funny. In addition, Theory of Mind cartoons provoked the highest number of mentalistic explanations. This shows that stimulus characteristics (such as LMs) as well as inter-individual differences influence whether mentalizing is required and applied to processing humor, and that empathizing and systemizing influence humor appreciation

Humor as character strength and its relation to life satisfaction and happiness in Autism Spectrum Disorders

The goal of this study was to examine the importance of humor as character strength in individuals with Asperger's syndrome/High Functioning Autism (AS/HFA) and how it relates to life satisfaction and orientation to happiness. Thirty-three individuals with AS/HFA and 33 gender-, age- and education-matched typically developing (TD) participants filled out scales assessing character strengths (VIA-IS), life satisfaction (SWLS) and orientation to happiness (OTH). Profile analyses of the character strengths and character strengths factors revealed significant differences between the two groups. Humor was found to be the 8th highest out of 24 character strengths in TD, but was only at the 16th position in individuals with AS/HFA when the strengths are rank-ordered. In TD participants, humor is related to life of pleasure, life of engagement, life of meaning and life satisfaction. In individuals with AS/HFA, humor is only related to life of pleasure. This shows that 1) individuals with AS/HFA seem not to consider humor as one of their important strengths, which is in line with humor difficulties reported earlier and 2) humor does not seem to contribute to life satisfaction to the same degree as in TD controls