Differences in MPS I and MPS II Disease Manifestations

Abstract

Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

“…This accumulation of GAGs contributes to the pathology of MPS II and MPS I. MPS II patients and MPS I patients share similar symptoms because of the accumulation of the same substrates. However, there are some differences between the pathologies of these MPSs [7].…”

“…Patients with MPS II exhibit mental retardation and systemic manifesta-tions including coarse facial features, hearing difficulty, skeletal deformities, rigid joints, a thick skin, hepatosplenomegaly, and valvular heart disease. MPS I patients present similar symptoms, but epidermal symptoms are infrequently observed [7]. MPS II is classified into two types based on the clinical phenotypes.…”

“…The "severe" early-onset form, which accounts for approximately 60% of patients with MPS II, exhibits cognitive impairment, behavioral difficulties, and frequent epileptic seizures [9]. Behavioral difficulties and seizures are frequently observed in MPS II patients with central nervous system (CNS) involvement, but they are rare in patients with MPS I [7]. The majority of patients die from obstructive airway disease or cardiac failure before the age of 20 [6,10,11].…”

Hunter Syndrome: The Phenotype of a Rare Storage Disease

“…The main distinction between the two types of manifestations is associated with central nervous system involvement, mainly represented by cognitive impairment and behavioral problems. Up to 2/3 of MPS type II affected patients have neurological impairment [3,7]. Individuals with mild disease have a minimal neurological deficit and can reach adulthood, but still show the disease's other characteristics [8].…”

“…Clinical signs and symptoms include coarse facial features, short neck, and large head with growth retardation (resulting in short stature of the disproportionate type characterized by a short trunk) associated with skeletal deformities (dysostosis multiplex), contractures, joint stiffness, and carpal tunnel syndrome [6,7,9,10]. Respiratory involvement presents as recurrent upper and lower respiratory tract infections and sleep apnoea [3,10] and cardiac impairment with cardiomyopathy, mitral or aortic stenosis, and regurgitation [6,11] are common.…”