Craniofacial Abnormalities in a Murine Knock-Out Model of Mucopolysaccharidosis I H: A Computed Tomography and Anatomic Study

Abstract

The genetic mucopolysaccharidoses are a group of lysosomal storage diseases in which mucopolysaccharides (glycosaminoglycans) accumulate as the result of a malfunction or lack of a lysosomal degradation enzyme. There are currently seven known forms of mucopolysaccharidoses. Type I results from an enzymatic deficiency of alpha-L-iduronidase. There are three subtypes of mucopolysaccharidoses I that are commonly recognized: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome. Of the three subtypes, Hurler syndrome has the most severe clinical picture. Craniofacial anomalies and cognitive impairment are some of the more pronounced features of Hurler syndrome. Hurler syndrome has been described in cats, dogs, mice, and human beings and is inherited as an autosomal recessive trait. The biochemical nature of the disease is preserved across species lines. Clinically, the disease has similar effects in human beings and animals. It has been difficult to reverse the phenotype of the disease even with replacement of the defective alpha-L-iduronidase enzyme. The purpose of this study is to characterize the cranio-facial differences in the murine knock-out model of Hurler syndrome objectively. Twenty-three measurements were taken from computed tomographic scans in a coronal and sagittal plane on 24 black C57/B6 knock-out Hurler syndrome mice. The seven statistically significant measurements are width of the cervical canal, height of the foramen magnum, width between the external auditory canals, width of the skull base at the mandibular condyles, midocular distance, spread of the mandibular condyles, and width of the zygoma at the maxilla. This information now provides researchers with objective data from living Hurler syndrome-affected mice that will allow them to follow therapies directed at improving craniofacial outcomes for any therapy over time.

Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation

“…In addition, two MPS I-H mouse models have been generated using knockout strategies that disrupt the Idua gene using an insertion cassette [10, 11]. The MPS I-H animal models have phenotypes that are generally consistent with the disease manifestations of MPS I-H patients, including deficiency of α-L-iduronidase activity [11, 12], accumulation of GAGs in most tissues [6, 10, 11, 13, 14], increased urine GAG excretion [11, 15], accumulation of GM 2 and GM 3 gangliosides in the brain [16, 17], abnormal facial appearance [16, 18], bone deformities [11, 19], neuropathology [20, 21], and cardiac manifestations [22, 23]. …”

Liver-Directed Human Amniotic Epithelial Cell Transplantation Improves Systemic Disease Phenotype in Hurler Syndrome Mouse Model

“…In humans, the constellation of skeletal dysplasia and spinal abnormalities (the latter not seen in the mouse model) are known as the dysostosis multiplex. In the mouse model, widening of the zygomatic arches, foreshortening of the premaxillary bones, and enlargement of the cranium have been especially well‐documented 31, 34, 38, 39. The increasing zygomatic bone volume and density in fact, is a signature phenotype of Idua –/– MPS1 mice 31 and was thus selected as a point of comparison for our study.…”

“…Homozygous knockout (MPS1) mice start to develop disease phenotype including flattened facial profile, broadened head, thickened digits at 3 weeks of age. Severe phenotypes such as defective bone formation and broadening of the zygomatic bone have established by 8 weeks [34] (Supporting Information Fig. S2A).…”

“…Abbreviations: BD, bile duct; CV, central vein; GAG, glycosaminoglycan; IDUA, a-L-iduronidase; PV, portal vein; WT, wild type. [31,34,38,39]. The increasing zygomatic bone volume and density in fact, is a signature phenotype of Idua -/-MPS1 mice [31] and was thus selected as a point of comparison for our study.…”

The Study of Kissing Molars in Patients Admıtted to Uşak University Faculty of Dentistry

“…8,12,18 Kalıtsal metabolik bozukluk ve enzim anormalliği ile karakterize bir rahatsızlık olan MPS; kornea, kalp, karaciğer, santral sinir sistemi, kemik ve diğer bölgelerde anormal mukopolisakkarit birikimine yol açar. 19 MPS'nin en yaygın klinik özellikleri, kısa boy, makrosefali, kaba yüz, anormal saçlar, belirgin frontal çıkıntılar, kornea bulanıklaşması, geniş burun ucuyla deprese burun köprüsü, dolu yanaklar, genişlemiş dudaklar, uzun düzleşmiş bir filtrum ile sertleşmiş torasik kafes ve J-şekilli sella tursikadır. 20 kemik kavitesi ile ilişkilidir.…”