Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome

Abstract

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urologic dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized.

Presentation and Management Patterns of Lower Urinary Tract Symptoms in Adults Due to Rare Inherited Neuromuscular Diseases

“…Our study corroborates prior studies that have described these various conditions. [13][14][15][16] It was previously believed that bladder function was not affected by DMD, however, over half of 88 boys interviewed in one study reported urinary problems. 16 Urinary complaints varied, but the most common complaints were daytime incontinence, nocturia, nocturnal enuresis, urinary frequency, and urinary urgency.…”

Rett syndrome: a neurological disorder with metabolic components

“…Given the association between MeCP2 and HDAC3, non-specific HDAC inhibitors, commonly prescribed for seizure maintenance, should be approached cautiously as a treatment in RTT. Additionally, both RTT patients and Mecp2 mutant mice present with metabolic syndrome [ 15 , 180 ], oxidative stress [ 27 , 29 ], cardiac defects [ 211 , 212 ], decreased bone density [ 174 , 213 ] and urological dysfunction [ 214 , 215 ]. As CNS-targeted gene therapy becomes a more realistic therapeutic approach, peripheral deficiency of MeCP2 must be considered more than ever as these symptoms are likely to persist following targeted genetic treatment to the brain.…”

Treating Rett syndrome: from mouse models to human therapies

“…Independent of disease stage, subsets of patients also experience gastrointestinal problems (Motil et al 2012), abnormal cardiorespiratory coupling (Kumar et al 2017), decreased bone density (Shapiro et al 2010), early-onset osteoporosis (Haas et al 1997), bruxism (Alpoz et al 1999), dyslipidaemia (Justice et al 2013; Segatto et al 2014), inflammation of the gallbladder (Anderson et al 2014), scoliosis (Anderson et al 2014), urological dysfunction (Ward et al 2016), and sleep disturbances (Young et al 2007). Additionally, RTT patients have an increased incidence of unexpected death, and often die due to respiratory infection, cardiac instability, and respiratory failure (Laurvick et al 2006; Anderson et al 2014).…”