Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-L-iduronidase and attendant accumulation of the glycosaminoglycans dermatan and heparan sulfates. Current treatments are suboptimal and leave residual disease including corneal clouding, skeletal deformities, valvular heart disease and cognitive impairment. We treated neonatal mucopolysaccharidosis I dogs with intravenous recombinant α-L-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 65-81 weeks. In contrast to previous results in animals and patients treated at a later age, all animals failed to mount an antibody response to enzyme therapy, consistent with neonatal tolerization. The higher dose of enzyme led to complete normalization of lysosomal storage in liver, spleen, lung, kidney, synovium and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and Author contributions: NME and PID conceived and designed the study, analyzed data and wrote the manuscript. ADD performed experiments and data analysis and wrote the manuscript. MFM, CAV, and AF-W performed pathology. CHV, WG, and EAR performed radiology and MRIs. MP, SS, AHC and SL performed biochemistry. JKJ and EMS conducted animal work. KLK, JDP, and JAW conducted veterinary neurology procedures and support. WAW and LEM conducted veterinary cardiology procedures and support. RDW, DMB and AMB conducted veterinary ophthalmology procedures and support.Publisher's Disclaimer: 'This manuscript has been accepted for publication in Science Translational Medicine. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencetranslationalmedicine.org.The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS.' natural history study to measure intellectual function over time in these patients is ongoing. In the canine model, even a larger 2 mg/kg weekly dose of ERT was not sufficient to clear accumulated GAG from the heart valve in older animals, though it was able to improve histologic evidence of lysosomal storage efficacy(12,13). It is possible that some MPS I pathology, including valvular disease, may be difficult or impossible to reverse. NIH Public AccessWhile some MPS I disease is not readily reversed by IV ERT, prevention may be easier to achieve. In particular, we were intrigued by reports that early or high-dose IV ERT could treat lysosomal storage in the brain in mice (14-20). We therefore treated MPS I dogs shortly after birth to determine whether hard-to-treat disease including cardiac valvular disease, skeletal disease, and corneal clouding, would respond to early initiation of therapy, and whether treating them would require a higher dose. We also sought to compare early, high-dose IV ERT to ERT administered directly into spinal fluid (intrathecally, IT) (21,22) for treatment of lysosomal storage in ...
Abstract. An 8-month-old, female, mixed-breed dog presented to the Iowa State University Veterinary Teaching Hospital with a 1-month history of vomiting and diarrhea. An exploratory laparotomy was performed revealing markedly distended and fluid-filled small and large intestines that were not obstructed. The clinical condition of the dog did not improve subsequent to exploratory surgery, and it was euthanized. At necropsy, both the small and large intestines were distended (approximately 4 cm in diameter) and fluid-filled, and the wall was thin. The abdominal cavity contained approximately 500 ml of a brownish clear fluid. Microscopic lesions of the intestines were confined to the intestinal tunica muscularis and muscularis mucosae and consisted of locally extensive-to-diffuse replacement of the smooth muscle by fibrous tissue and multifocal infiltration by a moderately dense mononuclear inflammatory infiltrate. A unique finding was the presence of similar microscopic lesions in the tunica muscularis of the urinary bladder and stomach.
An 8-year-old, spayed female, domestic shorthair cat with a history of hyperthyroidism, anorexia, dehydration, cervical ventroflexion, and behavioral changes was referred to the Iowa State University College of Veterinary Medicine. The cat was obtunded, with severe dehydration (15%) and hypothermia (86 degrees F), and severe muscle atrophy and fasciculations. Serum biochemical abnormalities included severe hypernatremia (195 mmol/L, reference interval 155-165 mmol/L), hyperchloridemia (161 mmol/L, reference interval 123-131 mmol/L), and hypokalemia (3.6 mmol/L, reference interval 4.0-5.7 mmol/L). Calculated osmolality was 418 mOsm/kg (reference interval 280-305 mOsm/kg), attributable to the hypernatremia. The cat was kept warm and given fluid and glucocorticoid therapy and supportive measures but remained unresponsive. Hypernatremia and hyperosmolality improved through day 3, when the cat died suddenly. At necropsy, a 1.25-cm mass was found in the area of the thalamus and interthalamic adhesion that extended to the ventral aspect of the cerebrum. The histologic and immunohistochemical diagnosis was B-cell lymphoma. Hypernatremia and hyperosmolality in this cat were attributed to primary adipsia and hypothalamic dysfunction secondary to effacement of central nervous system tissue by neoplastic lymphocytes. To the authors' knowledge, this is the first reported case of central nervous system lymphoma, confirmed by use of immunohistochemical analysis as a B-cell phenotype, associated with hypernatremia. It also is the first reported case of lymphoma in animals limited to the thalamus, hypothalamus, and cerebrum, with no involvement of the spinal cord.
Objective: To describe the neurologic deficits associated with profound hyponatremia in 2 critically ill foals. Series summary: A 4‐month‐old Thoroughbred colt and an 11‐day‐old Paint filly presented for acute diarrhea and depression. Severe neurologic deficits including blindness and head pressing were noted upon initial examination along with marked hyponatremia observed on biochemistry profile. Aggressive intravenous sodium replacement increased the serum sodium concentration to subnormal values with concurrent resolution of neurologic deficits. Intensive monitoring and fluid therapy were continued; the Thoroughbred colt was euthanized due to lack of response to the primary disease while the Paint filly was discharged clinically healthy without further complications. New or unique information provided: Mild hyponatremia (122–132 mEq/L) is a common clinicopathologic finding in equine medicine associated with a variety of diseases. The vast majority of horses with mild hyponatremia do not demonstrate direct clinical manifestations as a result of low serum sodium concentration. However, when severe acute hyponatremia occurs (<122 mEq/L), such as with acute enterocolitis, subtle to profound neurologic deficits may be observed and immediate and rapid treatment as well as serial evaluations of serum sodium concentration are warranted. Significant, and potentially permanent, neurologic deficits can occur if water balance and tonicity are not properly addressed. The cases presented here describe additional cases of a previously published disease in foals, acute hyponatremia and associated neurologic deficits, and describe the microscopic examination of the central nervous system in one foal that did not survive.
Abstract. A 6-year-old, gelded, Paint horse displayed clinical signs of muscle wasting and limb stiffness for a 6-month period. The horse's clinical signs abated with corticosteroid therapy, but returned upon cessation of treatment. Upon necropsy, severe lesions of aortic thickening and aortic valve rigidity were observed. Histologically, the tunica media of the aorta, coronary arteries, and pulmonary arteries were expanded by foci of elastin fiber calcification and extracellular matrix with lacunae formation. The vascular lesions are comparative to what has been described as medial arterial calcification, seen in humans suffering from chronic renal failure or diabetes mellitus. No exposure to vitamin D-containing plants or feedstuff could be documented at the time of onset or during the period of clinical signs. The current case describes dramatic lesions of arterial medial calcification of the aorta, coronary, and pulmonary arteries of undetermined cause.
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