Edoardo Monfrini

Leucine-Rich Repeat Kinase ( LRRK2 ) Genetics and Parkinson’s Disease

The discovery of LRRK2 mutations as a cause of Parkinsons disease (PD), including the sporadic late-onset form, established the decisive role of genetics in the field of PD research. Among LRRK2 mutations, the G2019S, mostly lying in a haplotype originating from a common Middle Eastern ancestor, has been identified in different populations worldwide. The G2385R and R1628P variants represent validated risk factors for PD in Asian populations. Here, we describe in detail the origin, the present worldwide epidemiology, and the penetrance of LRRK2 mutations. Furthermore, this chapter aims to characterize other definitely/probably pathogenic mutations and risk variants of LRRK2. Finally, we provide some general guidelines for a LRRK2 genetic testing and counseling. In summary, LRRK2 discovery revolutionized the understanding of PD etiology and laid the foundation for a promising future of genetics in PD research.

Mutational analysis of COQ2 in patients with MSA in Italy

COQ2 mutations have been implicated in the etiology of multiple system atrophy (MSA) in Japan. However, several genetic screenings have not confirmed the role of its variants in the disease. We performed COQ2 sequence analysis in 87 probable MSA. A homozygous change p.A43G was found in an MSA-C patient. Cosegregation analysis and the evaluation of CoQ10 content in muscle and fibroblasts did not support the pathogenic role of this variant.

X-linked Parkinsonism with Intellectual Disability caused by novel mutations and somatic mosaicism in RAB39B gene

BACKGROUND RAB39B pathogenic variants cause X-linked Parkinsonism associated with Intellectual Disability, known as Waisman syndrome, a very rare disorder that has been mainly identified through exome sequencing in large Parkinsons disease cohorts. In this study we searched for pathogenic variants in RAB39B in two Italian families affected by X-linked early-onset Parkinsonism and Intellectual Disability. METHODS Three patients received neurological evaluation and underwent RAB39B sequencing. RESULTS Two novel RAB39B frameshift variants were found to result in the absence of RAB39B protein (family 1: c.137dupT; family 2: c.371delA). Patients showed unilateral rest tremor and bradykinesia; one of them also displayed an early-onset postural tremor. Paramagnetic substance deposition in the substantia nigra, globus pallidi, red nucleus, putamen and pulvinar was assessed by brain imaging. Two patients also showed moderate calcification of globus pallidi. CONCLUSION In this study we highlight the evidence that X-linked early-onset Parkinsonism associated with Intellectual Disability occurs as a pattern of clinical and neuroimaging features attributable to RAB39B pathogenic variants.

Genetics of Movement Disorders and the Practicing Clinician; Who and What to Test for?

Purpose of ReviewThis review aims to provide the basic knowledge on the genetics of hypokinetic and hyperkinetic movement disorders to guide clinicians in the decision of “who and what to test for?”Recent FindingsIn recent years, the identification of various genetic causes of hypokinetic and hyperkinetic movement disorders has had a great impact on a better definition of different clinical syndromes. Indeed, the advent of next-generation sequencing (NGS) techniques has provided an impressive step forward in the easy identification of genetic forms. However, this increased availability of genetic testing has challenges, including the ethical issue of genetic testing in unaffected family members, “commercially” available home testing kits and the increasing number and relevance of “variants of unknown significance.”SummaryThe emergent role of genetic factors has important implications on clinical practice and counseling. As a consequence, it is fundamental that practicing neurologists have a proper knowledge of the genetic background of the diseases and perform an accurate selection of who has to be tested and for which gene mutations.

Call for Nomination of Members of the International Standing Committee of Human Cytogenomic Nomenclature

The present Committee (Jaclyn Biegel, Myriam Chaabouni, Johan T. den Dunnen, Jin-Yeong Han, Nils Mandahl, Jean McGowan-Jordan, Kathleen W. Rao, Annet Simons) was elected in the fall of 2011, with Lisa Shaffer as Chair. The Committee elected a new Chair, Jean McGowan-Jordan, during their meeting in Seattle in 2012. Several new members of the Committee now need to be elected. To facilitate continuity and maintain geographic distribution, the Chair of the new Committee will remain, along with Nils Mandahl, Johan T. den Dunnen, and Jin-Yeong Han. New members from the Americas (2), Europe (1), Africa and Australia/New Zealand/Oceania (1) are therefore required. The nominations of potential new Committee members shall be by e-mail. Nominations for candidates including their name, affiliation, postal address and e-mail address should be e-mailed to the Chair at jordan@cheo.on.ca before February 15, 2018, after which the list of nominated candidates will be published with the call for voting. Ballots for voting can be requested from the Chair at jordan@cheo.on.ca after February 15, 2018, by including your name, affiliation, postal address, and e-mail. The election ballots with voting procedures will then be distributed after March 15, 2018, to the requested address. Instructions for returning the ballots will accompany the ballot requests. Published online: January 23, 2018

Familial Duplication/Deletion of 1q42.13q43 as Meiotic Consequence of an Intrachromosomal Insertion in Chromosome 1

Rearrangements of the region 1q42.13q43 are rare, with only 7 cases reported to date. The imbalances described are usually the result of inherited translocations with other chromosomes. Moreover, few cases of both inter- and intrachromosomal deletions/duplications detected cytogenetically have been described. We report the molecular cytogenetic characterization of an inverted insertion involving the region 1q42.13q43 and segregating in 2 generations of a family. The deletion and the duplication of the same segment were detected in 2 affected family members. SNP array analysis showed the familial origin of the deletion/duplication due to the occurrence of a crossing-over during meiosis. Our report underlines the importance of determining the correct origin of chromosomal aberrations using different molecular cytogenetic tests in order to provide a good estimation of the reproductive risk for the members of the family.