Clinical characterization of cardiovascular abnormalities associated with feline mucopolysaccharidosis I and VI

Sleeper, Meg M.; Kusiak, Catherine M.; Shofer, Frances S.; O’Donnell, Patricia; Bryan, Caroline; Ponder, Katherine P.; Haskins, Mark E.

doi:10.1007/s10545-008-0821-1

Cited by 21 publications

(26 citation statements)

References 23 publications

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“…Despite these observations, LV volumes, ejection fraction, and CO were not significantly different from IDUA ϩ/Ϫ mice at baseline (Table 1). These observations of reduced cardiac function in resting mice are consistent with previous reports using echocardiography and cardiac catheterization (20,26).…”

Section: Resultssupporting

confidence: 93%

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Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies

Palpant¹,

Bedada²,

Peacock

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac dysfunction is a common cause of death among pediatric patients with mutations in the lysosomal hydrolase α-l-iduronidase (IDUA) gene, which causes mucopolysaccharidosis type I (MPS-I). The purpose of this study was to analyze adrenergic regulation of cardiac hemodynamic function in MPS-I. An analysis of murine heart function was performed using conductance micromanometry to assess in vivo cardiac hemodynamics. Although MPS-I (IDUA(-/-)) mice were able to maintain normal cardiac output and ejection fraction at baseline, this cohort had significantly compromised systolic and diastolic function compared with IDUA(+/-) control mice. During dobutamine infusion MPS-I mice did not significantly increase cardiac output from baseline, indicative of blunted cardiac reserve. Autonomic tone, measured functionally by β-blockade, indicated that MPS-I mice required catecholaminergic stimulation to maintain baseline hemodynamics. Survival analysis showed mortality only among MPS-I mice. Linear regression analysis revealed that heightened end-systolic volume in the resting heart is significantly correlated with susceptibility to mortality in MPS-I hearts. This study reveals that cardiac remodeling in the pathology of MPS-I involves heightened adrenergic tone at the expense of cardiac reserve with cardiac decompensation predicted on the basis of increased baseline systolic volumes.

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Section: Resultssupporting

confidence: 93%

“…Numerous animal models have facilitated the study of pathologies and potential therapies for MPS-I, including the MPS-I cat (26), dog (24), and the mouse knockout model (IDUA Ϫ/Ϫ ) (8,15). However, to our knowledge, no cardiovascular studies have provided insight into catecholaminergic regulation of heart function in MPS-I animal models or patients.…”

mentioning

confidence: 99%

Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies

Palpant¹,

Bedada²,

Peacock

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Myocardial GAG storage and valve abnormalities similar to those of MPS I patients have previously been described in MPS I cats (19,21,27). We noted complete correction of storage lesions in myocardium and aorta of the three cats with stable serum IDUA activity, and moderate improvement in the animal with reduced serum IDUA activity (Fig.…”

Section: Resultsmentioning

confidence: 56%

“…MPS I cats carry a 3-bp in-frame deletion producing the omission of a single aspartate residue from the IDUA protein, resulting in a complete loss of catalytic activity (24). These animals exhibit GAG storage in most tissues and develop substantial orthopedic, corneal, and cardiac disease within the first 6 mo of life (19)(20)(21). We treated four MPS I cats between 3 and 5 mo of age (Table 1) with an i.v.…”

Section: Resultsmentioning

confidence: 99%

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Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

Hinderer

Bell

Gurda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Patients with mucopolysaccharidosis type I (MPS I), a genetic deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), exhibit accumulation of glycosaminoglycans in tissues, with resulting diverse clinical manifestations including neurological, ocular, skeletal, and cardiac disease. MPS I is currently treated with hematopoietic stem cell transplantation or weekly enzyme infusions, but these therapies have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical sequelae, such as life-threatening cardiac valve involvement. Using the naturally occurring feline model of MPS I, we tested liver-directed gene therapy as a means of achieving longterm systemic IDUA reconstitution. We treated four MPS I cats at 3-5 mo of age with an adeno-associated virus serotype 8 vector expressing feline IDUA from a liver-specific promoter. We observed sustained serum enzyme activity for 6 mo at ∼30% of normal levels in one animal, and in excess of normal levels in three animals. Remarkably, treated animals not only demonstrated reductions in glycosaminoglycan storage in most tissues, but most also exhibited complete resolution of aortic valve lesions, an effect that has not been previously observed in this animal model or in MPS I patients treated with current therapies. These data point to clinically meaningful benefits of the robust enzyme expression achieved with hepatic gene transfer that extend beyond the economic and quality of life advantages over lifelong enzyme infusions.

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Overview of the Musculoskeletal System

Cole

Hespel

2020

Feline Diagnostic Imaging

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Clinical characterization of cardiovascular abnormalities associated with feline mucopolysaccharidosis I and VI

Cited by 21 publications

References 23 publications

Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies

Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

Overview of the Musculoskeletal System

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