LRRK2: Genetic mechanisms vs genetic subtypes.

In 2004, the identification of pathogenic variants in the LRRK2 gene across several families with autosomal dominant late-onset Parkinson's disease (PD) revolutionized our understanding of the role of genetics in PD. Previous beliefs that genetics in PD was limited to rare early-onset or familial forms of the disease were quickly dispelled. Currently, we recognize LRRK2 p.G2019S as the most common genetic cause of both sporadic and familial PD, with more than 100,000 affected carriers across the globe. The frequency of LRRK2 p.G2019S is also highly variable across populations, with some regions of Asian or Latin America reporting close to 0%, contrasting to Ashkenazi Jews or North African Berbers reporting up to 13% and 40%, respectively. Patients with LRRK2 pathogenic variants are clinically and pathologically heterogeneous, highlighting the age-related variable penetrance that also characterizes LRRK2-related disease. Indeed, the majority of patients with LRRK2-related disease are characterized by a relatively mild Parkinsonism with less motor symptoms with variable presence of α-synuclein and/or tau aggregates, with pathologic pleomorphism widely described. At a functional cellular level, it is likely that pathogenic variants mediate a toxic gain-of-function of the LRRK2 protein resulting in increased kinase activity perhaps in a cell-specific manner; by contrast, some LRRK2 variants appear to be protective reducing PD risk by decreasing the kinase activity. Therefore, employing this information to define appropriate patient populations for clinical trials of targeted kinase LRRK2 inhibition strategies is very promising and demonstrates a potential future application for PD using precision medicine.

An Exploratory Survey on the Care for Ataxic Patients in the American Continents and the Caribbean.

Little is known about access of rare disease carriers to health care. To increase this knowledge, the Pan American Hereditary Ataxia Network (PAHAN) conducted an exploratory survey about care for hereditary ataxias in American continents and the Caribbean. A questionnaire was sent to health professionals about the hereditary ataxias identified; access to care; and local teaching and research. The number of ataxics under current care per 100,000 inhabitants was subtracted from the expected overall prevalence of 6/100,000, to estimate the prevalence of uncovered ataxic patients. Local Human Development Indexes (HDI) were used to measure socio-economic factors. Twenty-six sites participated. Twelve sites had very high, 13 had high, and one site had medium HDI. Participants reported on 2239 and 602 patients with spinocerebellar ataxias and recessive forms under current care. The number of patients under current care per inhabitants varied between 0.14 and 12/100,000. The estimated prevalence of uncovered ataxic patients was inversely proportional to HDIs (rho = 0.665, p = 0.003). Access to diagnosis, pre-symptomatic tests, and rehabilitation were associated with HDIs. More and better molecular diagnostic tools, protocols and guidelines, and professional training for ataxia care were the top priorities common to all respondents. Evidence of inequalities was confirmed. Lower HDIs were associated with high potential numbers of uncovered ataxic subjects, and with lack of molecular diagnosis, pre-symptomatic testing, and rehabilitation. More and better diagnostic tools, guidelines, and professional training were priorities to all sites. PAHAN consortium might help with the last two tasks.

Multiple myxomatous aneurysms with bypass and clipping in a 37-year-old man.

BACKGROUND: Cardiac myxoma is the most common cardiac tumor. Neurologic complications are seen in 20%-35%, most frequently embolic ischemic stroke, and rarely secondary to intracranial aneurysms. The mechanism of aneurysm formation in these patients is speculative. METHODS: We report, herein, a 37-year-old male with a cardiac myxoma who experienced repeated ischemic stroke and intracerebral hematoma despite resection of heart tumor, secondary to multiple cerebral aneurysm. RESULTS: We offered him surgery with a bypass and clipping, because growing of aneurysm was not suitable for endovascular treatment. CONCLUSION: Bypass and clipping are possible options in this type of disease. Aneurysm biopsy supports mycotic theory of aneurysm formation.