Novel Pathologic Findings Associated with Urinary Retention in a Mouse Model of Mucopolysaccharidosis Type IIIB

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome type B) is a metabolic disorder with devastating clinical characteristics starting in early childhood and leading to premature death. A knockout mouse strain was developed that models this disease. Mice of the strain B6.129S6- Naglu^tm1Efn/J are invaluable for investigating pathogenesis and possible treatment modalities. However, the mouse strain also exhibits some objectionable phenotypic features. One such feature, urinary retention, not only is atypical of human MPS IIIB but often leads to early termination of experiments due to animal welfare concerns. The aim of this study was to investigate abnormalities associated with the urinary retention. Necropsies were performed on 9-mo-old mice; urinalysis, hematology and blood chemistry parameters were evaluated, and urogenital specimens were microscopically examined. Histopathologic examinations of urinary tract specimens proved illuminating regarding pathology in the urinary tract. A large mononuclear cell infiltrate was discovered in mutant mice of both sexes, more pronounced in females compared with male mice. The infiltrate comprises of large rounded or polygonal cells with generous variably vacuolated, granular eosinophilic cytoplasm and small round vesicular nuclei. These cells were present throughout and expand the interstitium of the lower urinary tract. Either this results in extrinsic compression of the lumen of the urethra, eventually leading to obstructive uropathy, bladder hyperdistension, and urinary retention or possibly interferes with the neurogenic component of micturition needs to be further investigated. The novel finding of an unexpected mononuclear cell infiltrate in the urinary tract in the knockout mice B6.129S6- Naglu^tm1Efn/J is reported.Abbreviations: BSA, bovine serum albumin; BUN, blood urea nitrogen; MPS III B, mucopolysaccharidosis type III BMucopolysaccharidosis type IIIB, also called Sanfilippo syndrome type B, is a metabolic disorder with devastating clinical characteristics in humans. The onset of the disease is usually between 2 and 4 y of age; clinical symptoms, including hyperactivity, aggressive behavior, hearing and vision defects, mental retardation, and mild somatic changes progress rapidly and are followed by premature death, generally in the second decade of life.^3,24 The pathogenesis of MPS IIIB can be described as a lysosomal storage disorder resulting from failure to degrade the lysosomal glycosaminoglycan heparan sulfate due to absence of the enzyme α-N-acetylglucosaminidase (Naglu). This inherited disorder is elicited by mutations in the Naglu gene, which is located on chromosome 17q21.³ More than 85 mutations have been identified so far.The B6.129S6- Naglu^tm1Efn/J mouse strain was developed through targeted mutation by disruption of exon 6 of the Naglu gene.²⁰ These mice are invaluable to continued investigations of pathogenesis of MPS IIIB, possible clinical interventions, and an eventual cure for this devastating disease. However, in addition to a number of desirable characteristics, B6.129S6- Naglu^tm1Efn/J mice exhibit several objectionable phenotypic features.¹² One such adverse feature is urinary retention, leading to a grossly enlarged urinary bladder, potential hydronephrosis, and uremia. This specific abnormality of the genetically engineered mice not only is atypical of human MPS IIIB but due to its effect on animal welfare may lead to early termination of experiments.Urinary retention leading to overdistension of the urinary bladder is a consequence of altered micturition due to urinary incontinence, dysuria, or a combination of both. Micturition is normally a conscious, voluntary act, whereas urinary incontinence is distinguished by the loss of the voluntary management of urination. Dysuria, however, relates to difficult and painful voiding of urine.¹⁹ Both disorders of micturition can cause moderate to severe distension of the bladder either as an acute or chronic condition. Dysuria may be elicited by any obstructive uropathy, and urinary incontinence can be classified as neurogenic or nonneurogenic.¹Bladder distension in multiple strains of mice has been described as a sequela of the toxicity of various substances,^17,25,32 in studies of urinary tract malformations,²⁶ after infection,⁶ and a characteristic of various transgenic mouse strains with various pathogenic pathways, such as mice with a mutated preprotachykinin gene, hypersensitive serotonin 3A receptor mutant mice, and mice lacking the muscarinic receptors M2 and M3.^4,16,23 In addition, urinary retention with bladder enlargement comprises a part of the mouse urologic syndrome, which develops spontaneously in aged mice^15,28 and has only been reported to occur in male mice. The pathogenesis of mouse urologic syndrome is unclear.In our study colony of B6.129S6- Naglu^tm1Efn/J mice, most exhibited moderate to severe enlargement of the urinary bladder in a sex-independent fashion, whereas control (wildtype) mice had a normal or, in a few cases only, slightly enlarged bladder.¹² As mentioned previously, bladder enlargement was the most common cause of euthanasia for animal-welfare reasons, thereby decreasing the data collection time.The aim of the present study was to investigate the clinical and pathologic correlations underlying anomalous bladder enlargement in a mouse model of MPS IIIB. In addition, we attempted to determine whether the observed urinary retention was dependent on the genetic mutation or background strain used, to facilitate interpretation of results from treatment development studies, interpretation which might otherwise be difficult or impossible.