Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis

Introduction DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures. Materials and methods Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome. Results Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family. Conclusion To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.

646 A Review of The Urodynamic Referral Pathway and The Accuracy of Urodynamic Study Requests

Aim Urodynamic studies (UDS) are physiological measurements of voiding and storage function of the lower urinary tract that are commonly performed in clinical practice to investigate bothersome lower urinary tract symptoms. Despite considerable efforts to improve UDS, standardisation of the practice remains to be challenging. This audit thus, presents a review the current UDS referral process and analysis of the clinical details included on urodynamic requests. Method This audit included retrospective data from 112 patients between March and Oct 2020, 98 of which had UDS performed. Patient electronic records, referral forms and clinic letters were all used for data collection. Results Data shows that 47% of patients were females with average age of 56 years, range (16-86) years. The reason of UDS was clearly stated in 8 referrals only and the clinical examination findings were clearly mentioned in 31% only. More than three quarters of patients (i.e., 77%) had assessment of post void residual prior to UDS, but half of the proportion had no history of relevant medications. In 98 patients who had UDS done, the main findings showed that 4 patients had normal studies, 3 with dysfunctional voiding, 7 had bladder outflow obstruction, 32 patients were diagnosed with detrusor overactivity, 12 had stress incontinence and 7 showed detrusor underactivity. Conclusions Finding of this audit clearly suggest a level of unclarity in the great majority of referrals. Evidently, key history of relevant medication is overlooked in half of the referrals. Improvements to the current pathway to UDS is therefore pivotal.

Rehabilitation Protocols for Children with Dysfunctional Voiding

Dysfunctional voiding is a functional voiding disorder characterized by an intermittent uroflow rate due to involuntary intermittent contractions of the striated muscle of the external urethral sphincter or pelvic floor muscles (PFMs) during voiding in neurologically normal children. Symptoms include voiding difficulties as well as urgency, voiding frequency and, in some instances, urinary incontinence and/or nocturnal enuresis. Recurrent urinary tract infections, chronic constipation and/or fecal incontinence and vesicoureteral reflux (VUR) contribute to this condition. Urotherapy is the mainstay of the treatment. It starts with education and demystification and simple behavioral modifications. Specific measures include PFM exercises with various forms of biofeedback concentrating at the recognition of PFM function and their relaxation. However, the PFMs are part of the abdominal capsule and they act in coordination with lower abdominal muscles. These muscles need to be relaxed during voiding. Diaphragmatic breathing exercises were introduced to teach children abdominal muscle relaxation. Easy to learn exercises do not require any specific equipment and can be performed at all health care levels. Children from five years of age could benefit from these exercises. In children resistant to standard treatment, botulinum toxin type A application, intermittent catheterization and surgery in children with VUR are recommended.

Therapeutic Effects of Urethral Sphincter Botulinum Toxin A Injection on Dysfunctional Voiding with Different Videourodynamic Characteristics in Non-Neurogenic Women

Although female dysfunctional voiding (DV) is common in urological practice, it is difficult to treat. This study evaluated the therapeutic efficacy of urethral botulinum toxin A (BoNT-A) on non-neurogenic female DV. Based on the videourodynamic study (VUDS), the DV was classified into three subgroups according to the obstructive site. A successful treatment outcome was defined as an improvement of voiding efficiency by 10% and reported global response assessment by ≥1. The study compared therapeutic efficacy, baseline urodynamic parameters, and changes in urodynamic parameters between the treatment success and failure groups and among three DV subgroups. Predictive factors for successful treatment were also investigated. A total of 81 women with DV were categorized into three groups: 55 (67.9%) had mid-urethral DV, 19 (23.5%) had distal urethral DV, and 7 (8.6%) had combined BN dysfunction and mid-urethral DV after BN transurethral incision. The treatment outcome was successful for 55 (67.9%) patients and failed for 26 (32.1%). Successfully treated patients had a significant decrease of detrusor pressure, post-void residual volume, and bladder outlet obstruction index, as well as an increase in voiding efficiency at follow-up versus the treatment failure group. The logistic regression of urodynamic parameters and clinical variables revealed that a greater volume of first sensation of filling predicts a successful BoNT-A treatment outcome (p = 0.047). The urethral BoNT-A injection is effective in treating non-neurogenic women with DV, with a success rate of 67.9%. The videourodynamic characteristics of DV may differ among patients but does not affect the treatment outcome.