Search

Dystroglycan is an essential component of the dystrophin-glycoprotein complex that links the actin-associated cytoskeleton to the extracellular matrix (ECM). Dystroglycan, encoded by the DAG1 gene, is proteolytically cleaved into α-Dystroglycan, a highly glycosylated protein that binds to ECM ligands, and β-Dystroglycan, a transmembrane protein non-covalently linked to α-Dystroglycan. Biallelic variants in DAG1 cause primary dystroglycanopathies with a wide phenotypic variability. Through exome sequencing we identified heterozygous truncating DAG1 variants in 18 individuals from 10 unrelated families. Five variants were stop gains and five were frameshift; with the majority localized in α-Dystroglycan (90%). Segregation analysis was available for seven families, with one variant being de novo, three dominantly inherited and three inherited from an asymptomatic parent. WGS performed in six patients excluded the presence of additional deep intronic DAG1 variants. The most common clinical features were the presence of high CK levels (18/18), myalgia (9/18) and muscle hypertrophy (3/18). Mild levels of learning or social difficulties were also observed in some patients (4/18). Histological analysis was performed in eight patients and showed the presence of mild dystrophic or myopathic changes. Dystroglycan immunostaining, either β-Dystroglycan or α-Dystroglycan, was reduced in four out of five patients. RNAseq data from muscle biopsies from two unrelated patients showed the expression of both wild-type and truncated alleles, indicating that nonsense-mediated decay is not triggered by these alleles. To date, few studies have reported the presence of heterozygous truncating DAG1 variants in asymptomatic or pauci-symptomatic individuals. Here, we describe 18 additional individuals with AD DAG1 hyperCKemia with mild muscular manifestations. Expression of both the truncated and wild-type alleles argues against haploinsufficiency as the underlying pathomechanisms in DAG1 -AD individuals. [ABSTRACT FROM AUTHOR]

Non-purging compensatory behaviors (NPCB; e.g. driven exercise, fasting, other extreme behaviors) are a subcategory of compensatory behaviors typically characterized as infrequent and less severe. Limited prior research has studied NPCB despite their increasing prevalence among adults with binge-spectrum eating disorders (B-ED). More research is needed to understand the types of NPCB present among B-ED and the association between NPCB, clinical severity, and treatment outcomes. Secondary analyses were conducted among 155 adults with B-ED in cognitive-behavioral (CBT)-based clinical trials. At baseline and post-treatment, clinical interviews of eating pathology assessed binge eating frequency, purging compensatory behavior frequency, and global eating pathology. The following NPCB were also assessed: driven exercise, 24-h fasting, 8+ waking hours of compensatory fasting, chewing and spitting, and other extreme weight control behaviors. Participants engaging in NPCB reported higher global eating pathology than those not engaging in NPCB. Frequency of chewing and spitting and 24-h fasting significantly decreased over treatment. Engagement in NPCB at baseline did not predict CBT outcomes. The current study highlights the prevalence and clinical severity of NPCB in B-ED but offers promising results regarding the potential for CBT to improve these behaviors. More research is needed on other extreme weight control behaviors reported qualitatively in our sample and on the maintenance of improvements in non-purging behaviors after CBT. [ABSTRACT FROM AUTHOR]