BackgroundDistal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ.MethodsWe used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ.ResultsA homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed.ConclusionIn conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.
The prevalence of Type II Diabetes (T2D) has been increasing and has become a disease of significant public health burden in Jordan. None of the previous genome-wide association studies (GWAS) have specifically investigated the Middle East populations. The Circassian and Chechen communities in Jordan represent unique populations that are genetically distinct from the Arab population and other populations in the Caucasus. Prevalence of T2D is very high in both the Circassian and Chechen communities in Jordan despite low obesity prevalence. We conducted GWAS on T2D in these two populations and further performed meta-analysis of the results. We identified a novel T2D locus at chr20p12.2 at genome-wide significance (rs6134031, P = 1.12 × 10−8) and we replicated the results in the Wellcome Trust Case Control Consortium (WTCCC) dataset. Another locus at chr12q24.31 is associated with T2D at suggestive significance level (top SNP rs4758690, P = 4.20 × 10−5) and it is a robust eQTL for the gene, MLXIP (P = 1.10 × 10−14), and is significantly associated with methylation level in MLXIP, the functions of which involves cellular glucose response. Therefore, in this first GWAS of T2D in Jordan subpopulations, we identified novel and unique susceptibility loci which may help inform the genetic underpinnings of T2D in other populations.
Methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism is a major inherited risk factor of venous thromboembolism. We sought to determine its prevalence in genetically isolated populations of Chechens and Circassians in Jordan. The MTHFR C677T mutation was analyzed from blood samples taken from 120 random unrelated Chechens and 72 Circassians. The prevalence of the MTHFR mutation in the Chechen population was 27.5% (allele frequency 15%); the prevalence among the Circassians was 50% (allele frequency 29.2%). The prevalence in the Chechen population is similar to that in Jordan and other world populations, but it is higher in the Circassian population. This study will contribute to understanding the interaction between genetic and environmental risk factors underlying thrombosis and will be useful in deciding which genetic variants should be tested in a clinical genetic testing service.
In low- and middle-income countries (LMIC) it is vital to understand acceptable, comprehensive, and culturally appropriate ways of communicating about mental distress. Diagnostic terminology is rarely used, may be stigmatizing, and is subject to misinterpretation. Local terms, such as idioms of distress, can improve mental health literacy and service delivery. Our objective was to examine lived experience and coping connected to distress and depression in an under-researched population: young men from LMIC urban slums. We conducted 60 qualitative interviews with men (ages 18–29) in Bhashantek slum, Bangladesh. Themes were generated using thematic analysis and grounded theory techniques. The heart-mind (mon), mentality (manoshikota), mood (mejaj), head (matha or “brain”), and body (shorir) comprised the self-concept, and were related to sadness, hopelessness, anger, worry, and mental illness. The English word “tension” was the central idiom of distress. “Tension” existed on a continuum, from mild distress or motivational anxiety, to moderate distress including rumination and somatic complaints, to severe psychopathology including anhedonia and suicidality. Respondents connected “tension” to burnout experiences and mental illness which was summarized in an ethnopsychological model. These findings can inform culturally sensitive measurement tools and interventions that are acceptable to the community, potentially increasing engagement and enhancing therapeutic outcomes.
Background Binary categorical approaches to diagnosing depression have been widely criticized due to clinical limitations and potential negative consequences. In place of such categorical models of depression, a ‘staged model’ has recently been proposed to classify populations into four tiers according to severity of symptoms: ‘Wellness;’ ‘Distress;’ ‘Disorder;’ and ‘Refractory.’ However, empirical approaches to deriving this model are limited, especially with populations in low- and middle-income countries. Methods A mixed-methods study using latent class analysis (LCA) was conducted to empirically test non-binary models to determine the application of LCA to derive the ‘staged model’ of depression. The study population was 18 to 29-year-old men (n = 824) from an urban slum of Bangladesh, a low resource country in South Asia. Subsequently, qualitative interviews (n = 60) were conducted with members of each latent class to understand experiential differences among class members. Results The LCA derived 3 latent classes: (1) Severely distressed (n = 211), (2) Distressed (n = 329), and (3) Wellness (n = 284). Across the classes, some symptoms followed a continuum of severity: ‘levels of strain’, ‘difficulty making decisions’, and ‘inability to overcome difficulties.’ However, more severe symptoms such as ‘anhedonia’, ‘concentration issues’, and ‘inability to face problems’ only emerged in the severely distressed class. Qualitatively, groups were distinguished by severity of tension, a local idiom of distress. Conclusions The results indicate that LCA can be a useful empirical tool to inform the ‘staged model’ of depression. In the findings, a subset of distress symptoms was continuously distributed, but other acute symptoms were only present in the class with the highest distress severity. This suggests a distress-continuum, disorder-threshold model of depression, wherein a constellation of impairing symptoms emerge together after exceeding a high level of distress, i.e., a tipping point of tension heralds a host of depression symptoms.
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