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Urofacial syndrome (UFS; MIM# 236730) is a rare autosomal recessive condition characterised by urinary bladder and bowel voiding dysfunction with a pathognomonic abnormality of facial movement with expression. UFS can be caused by biallelic putative loss-of-function mutations in HPSE2, which encodes heparanase 2. Failure to discover HPSE2 mutations in all cases of UFS suggests genetic heterogeneity. The urinary tract features of UFS overlap those seen in the spectrum of non-syndromic non-neurogenic voiding dysfunction and vesicoureteric reflux (VUR). This overlap suggests there may be some aspects of pathogenesis in common. The project aimed to define the genotypic and phenotypic spectrum associated with mutations in HPSE2 by Sanger sequencing and multiplex ligation-dependent probe amplification (MPLA) in newly referred cases of UFS and making comparison to a review of mutations and phenotypes seen in the literature. This work discovered five further families with HPSE2 associated UFS increasing known mutations whilst, reinforced that this is an under-recognised condition and emphasised the previously under-reported feature of facial weakness. The failure to discover HPSE2 mutations in all cases referred provided further evidence of genetic heterogeneity. The project also aimed to discover further genes associated with UFS. Autozygosity mapping and whole exome sequencing was carried out in cases of UFS without mutations in HPSE2. This led to the recognition that UFS is also caused by biallelic putative loss-of-function mutations in LRIG2 encoding the leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) protein in three families. Failure to identify LRIG2 mutations in all HPSE2 negative families suggests further genetic heterogeneity. To address the question of whether the pathogenesis of UFS overlaps more common conditions with a similar spectrum of urinary tract abnormalities I aimed to examine whether pathogenic variants in HPSE2 and LRIG2 were seen in these phenotypes. Unexpectedly this led to the discovering of further families affected by UFS but failed to show an association of variants in UFS genes with non-syndromic urinary tract abnormalities. However, variants of potential interest were discovered. As part of work toward understanding the pathogenesis of UFS and designing a model to test the pathogenesis of sequence variants expression studies in a Xenopus tropicalis hpse2 knock-down model of UFS were carried out. The knock-down model provided valuable insight in to the likely pathogenesis of UFS with evidence pointing towards a congenital peripheral neuropathy with failure of correct nerve path finding. Understanding the pathogenesis of UFS has the potential to direct further research in to therapeutic intervention.

Abstract: Purpose: The relationship between severity of voiding dysfunction and quality of life in children with daytime wetting was analyzed. Materials and Methods: The relationship between age, gender, severity of voiding dysfunction (measured by DVSS) and quality of life (measured by PinQ) in the child with daytime wetting was analyzed. Twenty-four children (4 males, 20 females) aged 5-10 years (xˉ 8.17 years, SD 1.37) and their parents completed the DVSS and PinQ. Results: Parent and child total DVSS and total PinQ Scores had similar results with only a significant mean difference between the parent total DVSS scores based on gender. Only Gender with Parental Total DVSS Score (r = 0.462, p = 0.023) and Child Total DVSS Score with Parent Total DVSS Scores (r = 0.472, p = 0.020) were significant correlations. Conclusions: Results illustrate the importance of early recognition and intervention to minimize the impact daytime wetting has on the child.

Individuals with bladder voiding dysfunction who do not respond to standard treatments have limited options. Activation of reflex micturition through sensory pudendal nerve stimulation provides a means to empty the bladder. Little is known about the mechanisms behind this pathway, and afferent-mediated voiding is less than results obtained by direct sacral root drive. This project investigated the neurophysiology of reflex bladder activation and evaluated new stimulus patterns and locations to improve afferent excitation of spinal circuits that produce bladder excitation and voiding.The use of novel physiologically based burst-patterned pudendal nerve stimuli significantly increased bladder contractions over currently used continuous stimulation (52.0 ± 44.5%, p < 0.004). Bladder excitation was effective at lower frequencies (1–10 pulses at 100–200 Hz repeated at 0.5–1 Hz) and higher frequencies (1–2 pulses at 200 Hz repeated at 20–33 Hz).Stimulating with lower and higher frequencies at different urethral locations before and after spinalization suggested two neural pathways for exciting reflex bladder contractions: a supra-sacral circuit initiated in the proximal urethra that responds to both frequency ranges and a sacral circuit initiated in the distal urethra that only responds to higher frequency stimuli. Subject pathology will dictate which circuit is the neuroprosthetic target.Stimulation with fine wire electrodes in the urethral wall excited the proximal urethra initiated circuit with minimal sphincter recruitment and evoked greater voiding efficiencies for the use of lower frequency burst-patterned stimuli (72.7 ± 27.6%) than other stimulus patterns on the same electrodes (p > 0.08) or any stimulus patterns on electrodes with urethral closure (p < 0.01). This pre-clinical translational study extended the functional proxy of bladder excitation to an effective functional voiding output.This work increases the knowledge-base of lower urinary tract neurophysiology, indicating more effective stimulation strategies and locations. This research will advance peripheral nerve-based neuroprostheses for bladder excitation, improving functional outputs and matching interventions to the patient population.