1. Hwang YT, Dudding T, Aliaga SM, Arpone M, Francis D, Li X, Slater HR, Rogers C, Bretherton L, du Sart D, Heard R, Godler DE. {{Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia}}. {Genes (Basel)};2016;7(9)
Mosaicism for FMR1 premutation (PM: 55-199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)-a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.
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2. Khalfallah O, Jarjat M, Davidovic L, Nottet N, Cestele S, Mantegazza M, Bardoni B. {{Depletion of the fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis}}. {Stem Cells};2016 (Sep 24)
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs). Repressing FMRP in ESCs increased the expression of amyloid precursor protein (APP) and Ascl1. When inducing neuronal differentiation, betaIII-tubulin, p27kip1 , NeuN and NeuroD1 were up-regulated, leading to an accelerated neuronal differentiation, that was partially compensated at later stages. Interestingly, we observed that neurogenesis is also accelerated in the embryonic brain of Fmr1-knockout (KO) mice, indicating that our cellular model recapitulates the molecular alterations present in vivo. Importantly, we rescued the main phenotype of the Fmr1 knockdown cell line, not only by reintroducing FMRP but also by pharmacologically targeting APP processing, showing the role of this protein in the pathophysiology of FXS during the earliest steps of neurogenesis. Our work allows to define an early therapeutic window but also to identify more effective molecules for treating this disorder. This article is protected by copyright. All rights reserved.
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3. Novo-Filho GM, Montenegro MM, Zanardo EA, Dutra RL, Dias AT, Piazzon FB, Costa TV, Nascimento AM, Honjo RS, Kim CA, Kulikowski LD. {{Subtelomeric Copy Number Variations: The Importance of 4p/4q Deletions in Patients with Congenital Anomalies and Developmental Disability}}. {Cytogenet Genome Res};2016 (Sep 24)
The most prevalent structural variations in the human genome are copy number variations (CNVs), which appear predominantly in the subtelomeric regions. Variable sizes of 4p/4q CNVs have been associated with several different psychiatric findings and developmental disability (DD). We analyzed 105 patients with congenital anomalies (CA) and developmental and/or intellectual disabilities (DD/ID) using MLPA subtelomeric specific kits (P036 /P070) and 4 of them using microarrays. We found abnormal subtelomeric CNVs in 15 patients (14.3%), including 8 patients with subtelomeric deletions at 4p/4q (53.3%). Additional genomic changes were observed at 1p36, 2q37.3, 5p15.3, 5q35.3, 8p23.3, 13q11, 14q32.3, 15q11.2, and Xq28/Yq12. This indicates the prevalence of independent deletions at 4p/4q, involving PIGG, TRIML2, and FRG1. Furthermore, we identified 15 genes with changes in copy number that contribute to neurological development and/or function, among them CRMP1, SORCS2, SLC25A4, and HELT. Our results highlight the association of genes with changes in copy number at 4p and 4q subtelomeric regions and the DD phenotype. Cytogenomic characterization of additional cases with distal deletions should help clarifying the role of subtelomeric CNVs in neurological diseases.
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4. Parihar R, Ganesh S. {{Autism genes: the continuum that connects us all}}. {J Genet};2016 (Sep);95(3):481-483.
5. Waldman A, Arndt KA, Avram MM, Brown MR, Dover JS, Fabi SG, Friedmann DP, Geronemus RG, Goldberg DJ, Goldman MP, Green JB, Ibrahimi OA, Jones DH, Kilmer SL, McDaniel DH, Obagi S, Ortiz AE, Rohrer TE, Taylor MB, Torres A, Weinkle SH, Weiss MA, Weiss ET, Weiss RA, Poon E, Alam M. {{ASDS Cosmetic Dermatologic Surgery Fellowship Milestones}}. {Dermatol Surg};2016 (Oct);42(10):1164-1173.
BACKGROUND: The American Council of Graduate Medical Education, which oversees much of postgraduate medical education in the United States, has championed the concept of « milestones, » standard levels of achievement keyed to particular time points, to assess trainee performance during residency. OBJECTIVE: To develop a milestones document for the American Society for Dermatologic Surgery (ASDS) Cosmetic Dermatologic Surgery (CDS) fellowship program. METHODS: An ad hoc milestone drafting committee was convened that included members of the ASDS Accreditation Work Group and program directors of ASDS-approved Cosmetic Dermatologic Surgery (CDC) fellowship training programs. Draft milestones were circulated through email in multiple rounds until consensus was achieved. RESULTS: Thirteen milestones were developed in the 6 Accreditation Council for Graduate Medical Education (ACGME) competency areas, with 8 of these being patient-care milestones. Additional instructions for milestone administration more specific to the CDS fellowship than general ACGME instructions were also approved. Implementation of semiannual milestones was scheduled for the fellowship class entering in July 2018. CONCLUSION: Milestones are now available for CDS fellowship directors to implement in combination with other tools for fellow evaluation.
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6. Zhao XN, Usdin K. {{Ups and Downs: Mechanisms of Repeat Instability in the Fragile X-Related Disorders}}. {Genes (Basel)};2016;7(9)
The Fragile X-related disorders (FXDs) are a group of clinical conditions resulting from the expansion of a CGG/CCG-repeat tract in exon 1 of the Fragile X mental retardation 1 (FMR1) gene. While expansions of the repeat tract predominate, contractions are also seen with the net result being that individuals can show extensive repeat length heterogeneity in different tissues. The mechanisms responsible for expansion and contraction are still not well understood. This review will discuss what is known about these processes and current evidence that supports a model in which expansion arises from the interaction of components of the base excision repair, mismatch repair and transcription coupled repair pathways.
