Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and progressive optic atrophy. mtDNA deletions have been described, and a gene ...(WFS1) recently has been identified, on chromosome 4p16, encoding a predicted 890 amino acid transmembrane protein. Direct DNA sequencing was done to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome. DNA was also screened for structural rearrangements (deletions and duplications) and point mutations in mtDNA. No pathogenic mtDNA mutations were found in our cohort. We identified 24 mutations in the WFS1 gene: 8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations. Of these, 23 were novel mutations, and most occurred in exon 8. The majority of patients were compound heterozygotes for two mutations, and there was no common founder mutation. The data were also analyzed for genotype-phenotype relationships. Although some interesting cases were noted, consideration of the small sample size and frequency of each mutation indicated no clear-cut correlations between any of the observed mutations and disease severity. There were no obvious mutation hot spots or clusters. Hence, molecular screening for Wolfram syndrome in affected families and for Wolfram syndrome–carrier status in subjects with psychiatric disorders or diabetes mellitus will require complete analysis of exon 8 and upstream exons.
Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the
PLA2G6 gene. Direct gene sequencing detects ...∼85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel
PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of
PLA2G6 mutations. MLPA should thus be employed to detect CNVs of
PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencing.
Collaborative Care, an evidence-based model, has proven effective in treating depression and anxiety in healthcare settings. However, limited attention has been paid to exploring treatment outcome ...differences by clinical variables and diagnosis within this model. While previous research suggests that early and frequent contacts and swift treatment access lead to positive outcomes for depression and anxiety, these aspects have not been comprehensively examined in Collaborative Care. This study investigates the impact of clinical variables on treatment completion in patients primarily diagnosed with anxiety or depression who received collaborative care treatment as a treatment program. Analysis was completed as an observational study of patients (n =2018) with behavioral health diagnoses spanning from 2016 to 2023. Classification analysis offers insights into optimal practices for implementing Collaborative Care across diverse healthcare populations from pediatric to geriatric. Identifying clinical characteristics associated with successful treatment in Collaborative Care has far-reaching implications for model adoption and enhancing patient outcomes. Across all results, patients who received more clinical support and had shorter enrollment durations showed a strong association with successful treatment completion.Collaborative Care, an evidence-based model, has proven effective in treating depression and anxiety in healthcare settings. However, limited attention has been paid to exploring treatment outcome differences by clinical variables and diagnosis within this model. While previous research suggests that early and frequent contacts and swift treatment access lead to positive outcomes for depression and anxiety, these aspects have not been comprehensively examined in Collaborative Care. This study investigates the impact of clinical variables on treatment completion in patients primarily diagnosed with anxiety or depression who received collaborative care treatment as a treatment program. Analysis was completed as an observational study of patients (n =2018) with behavioral health diagnoses spanning from 2016 to 2023. Classification analysis offers insights into optimal practices for implementing Collaborative Care across diverse healthcare populations from pediatric to geriatric. Identifying clinical characteristics associated with successful treatment in Collaborative Care has far-reaching implications for model adoption and enhancing patient outcomes. Across all results, patients who received more clinical support and had shorter enrollment durations showed a strong association with successful treatment completion.
We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with ...628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% 93%–100%; specificity 78% 73%–82%). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.
Open access mutation database for monogenic diabetes syndromes.
ABSTRACT
Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal‐recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic ...germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One‐hundred and forty‐four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype–phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.
Warburg Micro syndrome (OMIM 60018) and Martsolf syndrome (OMIM 21270) are related autosomal recessive neurodevelopmental disorders. Micro syndrome is more severe and characterized by ocular (microphthalmos, microcornea, congenital cataracts and optic atrophy) and neurodevelopmental pathology (microcephaly, polymicrogyria, hypogenesis of the corpus callosum, severe learning disability and progressive limb spasticity) and hypothalamic hypogonadism. Causative germline mutations have been identified in RAB3GAP1 (41% of families), RAB3GAP2 (7% of families) and RAB18 (5% of families) and result in a strikingly consistent phenotype.
NATIONAL PARK SYSTEM: ESTABLISHING NEW UNITS Vincent, Carol Hardy
Current politics and economics of the United States, Canada and Mexico,
07/2013, Letnik:
15, Številka:
3
Journal Article
Units of the Park System generally are managed to preserve resources in their natural or historical conditions for the benefit of future generations. ...hunting, mining, and other consumptive ...resource uses generally are not allowed. ADDING UNITS BY PUBLIC LAW AND PRESIDENTIAL PROCLAMATION National Park System units are created by act of Congress, except that national monuments also may be added by presidential proclamation.2 The Antiquities Act of 1906 (16 U.S.C. 431 et seq.) authorizes the President to create national monuments, on land that is already federally owned or controlled, and that contains historic landmarks, historic and prehistoric structures, or other objects of historic or scientific interest.3 Presidents have designated 137 monuments since 1906.
About half of all children with a clinical diagnosis of Silver-Russell syndrome (SRS) have a detectable molecular genetic abnormality (maternal uniparental disomy of chromosome upd(7)mat or ...hypomethylation of H19 differentially methylated region (DMR). The selection of children for molecular genetic testing can be difficult for non-specialists because of the broad phenotypic spectrum of SRS and the tendency of the facial features to mitigate during late childhood. Several clinical scoring systems for SRS have been developed by specialist researchers, but the utility of these for guiding molecular genetic testing in routine clinical practice has not been established.
To evaluate the utility of four published clinical scoring systems for genetic testing in a cohort of patients referred to a clinical service laboratory.
Individuals with suspected SRS referred for molecular genetic testing of H19 DMR methylation status or upd(7)mat.
36 of 139 (25.9%) patients referred for testing had a genetic abnormality identified. Comparison of four published clinical scoring systems demonstrated that all included subjective criteria that could be difficult for the general clinician to assess. We developed a novel, simplified, scoring system utilising four objective, easily measured parameters that performed similarly to the most sensitive and specific published scoring system.
Effective utilisation of genetic testing by clinicians without specialist clinical genetics training will be facilitated by the development of targeted testing protocols that are based on robust objective clinical features and are designed for use in a busy clinical practice rather than a research setting.
Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the phospholipase A2 group 6 (Pla2G6) gene. Affected individuals usually present ...between the ages of 6 months and 2 years with rapid cognitive and motor regression and axial hypotonia. Gait disturbance, limb spasticity, cerebellar signs, and optic atrophy are other common features associated with INAD. Although magnetic resonance imaging (MRI) can sometimes contribute towards the diagnosis, the confirmation of INAD is by Pla2G6 gene analysis. In this case report, we describe the first individual (female) with INAD due to a combination of uniparental heterodisomy and isodisomy; we discuss the possible underlying mechanism and highlight the importance of parental carrier testing in accurately predicting the recurrence risk in these families. We also confirm the recent report of hypertrophy of the clava (also known as the ‘gracile tubercle’) as a useful MRI sign in INAD.
PDF
