Urologic and gastrointestinal symptoms in the dystroglycanopathies

Abstract

Objective: To determine the frequency of urologic and gastrointestinal (GI) symptoms in a cohort of individuals with dystroglycanopathy compared with healthy household controls.Methods: Participants in a North American dystroglycanopathy natural history study (NCT00313677) and other members of their households completed a questionnaire modified from validated instruments and clinical criteria. Urologic and GI symptom frequency, effect on patient life, and medications taken for these symptoms were assessed. Those younger than 4 years or not toilet trained were excluded. Healthy human bladder, esophagus, and duodenum from surgical specimens were immunostained for glycosylated a-dystroglycan.Results: Thirty of 58 potential participants with dystroglycanopathy (51.7%) and 16 household controls participated. Subjects were aged 6 to 51 years (mean 26.7); 60.0% were female. Controls were aged 7 to 55 years (mean 34.6); 56.3% were female. The dystroglycanopathy cohort had higher frequency of urinary voiding symptoms (p 5 0.02), higher urologic symptom scores (p 5 0.05), and higher dysphagia symptom scores (p 5 0.04). A correlation existed between urologic symptom score and effect on life (r 5 0.71; 95% confidence interval 0.46, 0.85; p , 0.0001) and between dysphagia symptom score and effect on life (r 5 0.72; 95% confidence interval 0.48, 0.86; p , 0.0001). Glycosylated a-dystroglycan was present in visceral smooth muscle of all normal tissues analyzed.Conclusions: Urologic symptoms and dysphagia are reported more frequently by individuals with dystroglycanopathies than by household controls. These symptoms can cause a perceived negative effect on patient life. Our results suggest urologic and GI dysfunction may be part of the dystroglycanopathy phenotype, and that questions about these symptoms should be incorporated into routine care because they may influence medical management. The a-and b-dystroglycan proteins are encoded by the dystroglycan gene (DAG1) and constitute key components of the dystrophin-glycoprotein complex.1 After extensive glycosylation, a-dystroglycan serves as a link between the transmembrane b-dystroglycan protein and a number of ligands within the extracellular matrix.

Dystrophin is expressed in smooth muscle and afferent nerve fibers in the rat urinary bladder

“…The expression of dystrophin in smooth muscle cells of human and rat bladder tissue observed here is in line with previous research showing dystrophin expression in smooth muscle cells of healthy human bladder tissue. 9 The prostate pathology in the human tissue sample used could result in morphological changes of the bladder (decreased neuronal density, increased epithelial turnover, increased fibrosis in the submucosal layer). 19 This is why we chose not to quantitate dystrophin expression in these samples but only to verify whether dystrophin was present.…”

“…Dystrophin is not expressed exclusively in striated muscle but also in other tissues (i.e., brain, retina, kidney) . Recently, dystrophin was found in smooth muscle cells of normal human bladder tissue …”

“…8 Recently, dystrophin was found in smooth muscle cells of normal human bladder tissue. 9 The expression of dystrophin in multiple organs possibly determines the occurrence and severity of comorbidities in DMD. The DMD gene produces a range of different transcripts encoding various dystrophin isoforms ranging in size with molecular weights of 71, 116, 140, 260, and 427 kDa.…”

Neurogenic Bowel Dysfunction in Children and Adolescents

“…Affected individuals report symptoms of both bladder and bowel dysfunction. The most common bowel complaint is constipation, which in X-linked Duchenne Muscular Dystrophy (DMD) can become life-threatening, but generally the most disabling is fecal incontinence [30,31]. One series reported that in 47% of boys with DMD undergoing a colonic transit test, the radiopaque markers were retained in the recto-sigmoid, suggesting functional pelvic outlet obstruction [30].…”

“…Loss of the alpha-dystroglycan-laminin interaction, due to defective glycosylation of alpha-dystroglycan, underlies a group of congenital muscular dystrophies often associated with brain malformations, referred to as dystroglycanopathies, where NBD is reported [31]. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is frequently associated with chronic intestinal pseudo-obstruction.…”