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Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature.
Cleaver, R, Berg, J, Craft, E, Foster, A, Gibbons, RJ, Hobson, E, Lachlan, K, Naik, S, Sampson, JR, Sharif, S, et al
American journal of medical genetics. Part A. 2019;(3):344-349
Abstract
Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.
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MYT1L mutation in a patient causes intellectual disability and early onset of obesity: a case report and review of the literature.
Al Tuwaijri, A, Alfadhel, M
Journal of pediatric endocrinology & metabolism : JPEM. 2019;(4):409-413
Abstract
Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of monogenic and syndromic obesity. Case presentation Over the last decade, terminal and interstitial submicroscopic deletions of copy number variants (CNVs) in 2p25.3 and single nucleotide variants (SNVs) in myelin transcription factor 1 like (MYT1L) were detected by genome-wide array analysis and whole exome sequencing (WES) in patients with a nonspecific clinical phenotype that commonly includes intellectual disability (ID), early onset of obesity and speech delay. Here, we report the first Saudi female patient with mild to moderate ID, early onset of obesity and speech delay associated with a de novo pathogenic SNV in the MYT1L gene (c. 1585G>A [Gly529Arg]), which causes an amino acid change from Gly to Arg at position 529 that leads to mental retardation, autosomal dominant 39.
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The role of new adipokines in gestational diabetes mellitus pathogenesis.
Mierzyński, R, Poniedziałek-Czajkowska, E, Dłuski, D, Leszczyńska-Gorzelak, B
Ginekologia polska. 2018;(4):221-26
Abstract
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition dur-ing pregnancy. Explanation of the GDM pathogenesis is important due to preventing gestational complications. During pregnancy there are significant changes in maternal metabolism. Many of these changes are influenced by different adi-pokines produced in the placenta and adipose tissue. The exact role of adipokines in the pathogenesis of GDM remains still unknown. Several adipokines have been analysed throughout gestation and their levels have been suggested as biomarkers of maternal-perinatal outcomes. Some of them have been postulated as significant in the pathogenesis of pregnancy complications like GDM. This report aims to review some of the recent topics of adipokine research that may be of particular importance in patho-physiology and diagnosis of gestational diabetes mellitus. Because of manuscript length limitations, after thorough literature review and in view of the recent evidence, we focus on the one of the most well-known adipokine: adiponectin, and not so well-studied: nesfatin-1, chemerin, ghrelin, and CTRP 1.
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Mini-review: Update on the genetics of schizophrenia.
Coelewij, L, Curtis, D
Annals of human genetics. 2018;(5):239-243
Abstract
A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene sets of interest and also demonstrate an overlap with other psychiatric and nonpsychiatric disorders. Imputation of variants of the gene for complement component 4 (C4) from GWAS data has shown that the predicted expression of the C4A product is associated with schizophrenia risk. Very rare variants disrupting SETD1A, RBM12 or NRXN1 have a large effect on risk. Other rare, damaging variants are enriched in genes that are loss of function intolerant and/or whose products localise to the synapse. These and particular copy number variants can result in increased risk of schizophrenia but also of other neurodevelopmental disorders. The findings for C4 and NRXN1 may be especially helpful for elucidating the biological mechanisms that can lead to disease.
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Novel transmitters in brain stem vagal neurocircuitry: new players on the pitch.
Bülbül, M, Travagli, RA
American journal of physiology. Gastrointestinal and liver physiology. 2018;(1):G20-G26
Abstract
The last few decades have seen a major increase in the number of neurotransmitters and neuropeptides recognized as playing a role in brain stem neurocircuits, including those involved in homeostatic functions such as stress responsiveness, gastrointestinal motility, feeding, and/or arousal/wakefulness. This minireview will focus on the known physiological role of three of these novel neuropeptides, i.e., apelin, nesfatin-1, and neuropeptide-S, with a special emphasis on their hypothetical roles in vagal signaling related to gastrointestinal motor functions.
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Arc - An endogenous neuronal retrovirus?
Shepherd, JD
Seminars in cell & developmental biology. 2018;:73-78
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Abstract
The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain and has been implicated in various neurological disorders. However, little is known about Arc's evolutionary origins. Recent studies suggest that mammalian Arc originated from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestral to retroviruses. In particular, Arc contains homology to the Gag polyprotein that forms the viral capsid and is essential for viral infectivity. This surprising connection raises the intriguing possibility that Arc may share molecular characteristics of retroviruses.
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LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes.
Binks, SNM, Klein, CJ, Waters, P, Pittock, SJ, Irani, SR
Journal of neurology, neurosurgery, and psychiatry. 2018;(5):526-534
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Abstract
Recent biochemical observations have helped redefine antigenic components within the voltage-gated potassium channel (VGKC) complex. The related autoantibodies may be now divided into likely pathogenic entities, which target the extracellular domains of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), and species that target intracellular neuronal components and are likely non-pathogenic. This distinction has enhanced clinical practice as direct determination of LGI1 and CASPR2 antibodies offers optimal sensitivity and specificity. In this review, we describe and compare the clinical features associated with pathogenic LGI1 and CASPR2 antibodies, illustrate emerging laboratory techniques for antibody determination and describe the immunological mechanisms that may mediate antibody-induced pathology. We highlight marked clinical overlaps between patients with either LGI1 or CASPR2 antibodies that include frequent focal seizures, prominent amnesia, dysautonomia, neuromyotonia and neuropathic pain. Although occurring at differing rates, these commonalities are striking and only faciobrachial dystonic seizures reliably differentiate these two conditions. Furthermore, the coexistence of both LGI1 and CASPR2 antibodies in an individual occurs surprisingly frequently. Patients with either antibody respond well to immunotherapies, although systematic studies are required to determine the magnitude of the effect beyond placebo. Finally, data have suggested that CASPR2 and LGI1 modulation via genetic or autoimmune mechanisms may share common intermediate molecules. Taken together, the biochemical distinction of antigenic targets has led to important clinical advances for patient care. However, the striking syndrome similarities, coexistence of two otherwise rare antibodies and molecular insights suggest the VGKC complex may yet be a common functional effector of antibody action. Hence, we argue for a molecular evolution alongside a clinical and phenotypic re-evaluation.
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Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene and a review of the literature.
Bessette, AP, DeBenedictis, MJ, Traboulsi, EI
Ophthalmic genetics. 2018;(1):51-55
Abstract
BACKGROUND The clinical phenotype of patients presenting with autosomal recessive CDHR1-related retinopathy has not been well described. MATERIALS AND METHODS This is a retrospective case series of patients presenting to a single institution. Clinical data, including age, visual acuity, dilated fundus exam, fundus photos, fundus autofluorescence (FAF), optical coherence tomography, full-field electroretinograms (ERGs), and results of genetic testing, were collected. RESULTS Four patients were identified to have biallelic mutations in the CDHR1 gene. All four patients were found to have at least one c.783G>A (p.Pro261 = ) mutation. A novel splice site mutation, c.152-2A>G, was identified in two patients. Patients became symptomatic between the fourth and sixth decades of life. Three patients presented initially with nyctalopia and peripheral visual field constriction, and one patient presented with simultaneous onset of photophobia and nyctalopia. The fundus appearance was characterized by macular atrophy with or without peripheral retinal pigment epithelium changes and arteriolar attenuation. FAF showed a hyperautofluorescent ring surrounding a central area of speckled hypoautofluorescence. Full-field electroretinography was available on three patients and showed decreased cone-and-rod responses. CONCLUSIONS CDHR1-related retinal dystrophy should be considered in adult patients with a retinal dystrophy who present with symptoms of cone-and-rod dysfunction and macular atrophy on ophthalmoscopic examination.
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Circulating Nesfatin-1 Levels and Type 2 Diabetes: A Systematic Review and Meta-Analysis.
Zhai, T, Li, SZ, Fan, XT, Tian, Z, Lu, XQ, Dong, J
Journal of diabetes research. 2017;:7687098
Abstract
The role of nesfatin-1 in glucose homeostasis has been investigated previously. However, although numerous studies have examined the relationships between circulating nesfatin-1 levels and type 2 diabetes, the conclusions are contradictory. We aimed to probe the relationship between circulating nesfatin-1 levels and type 2 diabetes by meta-analysis. Seven studies including 328 type 2 diabetes patients and 294 control subjects were included. Although there was no obvious difference in circulating nesfatin-1 levels between patients with type 2 diabetes and the control group (MD = -0.04; 95% CI = -0.32 to -0.23), subgroup analysis showed higher nesfatin-1 levels in newly diagnosed type 2 diabetes patients (MD = 0.59; 95% CI = 0.45 to 0.74) and significantly lower nesfatin-1 levels in type 2 diabetes patients receiving antidiabetic treatment (MD = -0.26; 95% CI = -0.33 to -0.20). In conclusion, the analysis supports a relationship between circulating nesfatin-1 levels and type 2 diabetes, where newly diagnosed type 2 diabetes was associated with an elevated Nesfatin-1 level, and type 2 diabetes patients receiving antidiabetic treatment showed lower circulating nesfatin-1 levels.
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Autoimmune encephalitis with anti-leucine-rich glioma-inactivated 1 or anti-contactin-associated protein-like 2 antibodies (formerly called voltage-gated potassium channel-complex antibodies).
Bastiaansen, AEM, van Sonderen, A, Titulaer, MJ
Current opinion in neurology. 2017;(3):302-309
Abstract
PURPOSE OF REVIEW Twenty years since the discovery of voltage-gated potassium channel (VGKC)-related autoimmunity; it is currently known that the antibodies are not directed at the VGKC itself but to two closely associated proteins, anti-leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (Caspr2). Antibodies to LGI1 and Caspr2 give well-described clinical phenotypes. Anti-LGI1 encephalitis patients mostly have limbic symptoms, and anti-Caspr2 patients have variable syndromes with both central and peripheral symptoms. A large group of patients with heterogeneous symptoms are VGKC positive but do not have antibodies against LGI1 or Caspr2. The clinical relevance of VGKC positivity in these 'double-negative' patients is questionable. This review focusses on these three essentially different subgroups. RECENT FINDINGS The clinical phenotypes of anti-LGI1 encephalitis and anti-Caspr2 encephalitis have been described in more detail including data on treatment and long-term follow-up. A specific human leukocyte antigen (HLA) association was found in nontumor anti-LGI1 encephalitis, but not clearly in those with tumors. There has been increasing interest in the VGKC patients without LGI1/Caspr2 antibodies questioning its relevance in clinical practice. SUMMARY Anti-LGI1 encephalitis and anti-Caspr2 encephalitis are separate clinical entities. Early recognition and treatment is necessary and rewarding. The term VGKC-complex antibodies, lumping patients with anti-LGI1, anti-Caspr2 antibodies or lacking both, should be considered obsolete.