Differences in MPS I and MPS II Disease Manifestations.

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.

Nuevas recomendaciones para el cuidado de los pacientes con mucopolisacaridosis tipo I / New recommendations for the care of patients with mucopolysaccharidosis type I

Dados los avances sobre mucopolisacaridosis Icon posterioridad al consenso publicado en la Argentina por un grupo de expertos en 2008, se revisan recomendaciones respecto a estudios genéticos, seguimiento cardiológico, cuidado de la vía aérea, alertas sobre aspectos auditivos, de la patología espinal y neurológica. Se hace revisión de la terapéutica actual y se enfatiza en la necesidad de un diagnóstico y tratamiento precoces, así como de un seguimiento interdisciplinario

Considering the advances made on mucopolysaccharidosis type I after the consensus study published by a group of experts in Argentina in 2008, recommendations about genetic testing, cardiological follow-up, airway care, hearing impairment detection, spinal and neurological conditions, as well as current treatments, were reviewed. Emphasis was placed on the need for early diagnosis and treatment, as well as an interdisciplinary follow-up

Morphologic description of male reproductive accessory glands in a mouse model of mucopolysaccharidosis type I (MPS I).

Mucopolysaccharidosis type I (MPS I) is a genetic disease caused by a deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA). IDUA degrades two types of glycosaminoglycans (GAGs): heparan and dermatan sulfates, important components of extracellular matrix, with signaling and structural functions. The accumulation of GAGs results in progressive physiological impairments in a variety of tissues, making MPS I a complex and multisystemic disease. Due the advent of therapeutic strategies which have increased patients' life expectancy, our group have been investigating the effect of IDUA deficiency on the reproductive system. In the present study, we aimed to characterize some of the accessory glands of the male reproductive tract in an MPS I mouse model. We used 6-month-old Idua+/+ and Idua-/- male mice to evaluate the histology of the seminal vesicles and prostate. Interstitial deposits of GAGs and collagen fibers were also observed. Seminal vesicles were smaller in the Idua-/- group, regardless of the normal staining pattern of the epithelial cells, marked with antiandrogen receptor. The prostate of Idua-/- mice presented necrotic acini and increased deposition of collagen fibers in the interstitium. All glands presented evident deposits of GAGs in the extracellular matrix, especially inside vacuolated interstitial cells. We concluded that, at this stage of the disease, the prostate is the most damaged accessory gland and may therefore, be the first to manifest functional impairments during disease progression.

Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells.

In mucopolysaccharidosis-I (MPS-I), alpha-L-iduronidase deficiency leads to progressive heparan sulfate (HS) and dermatan sulfate (DS) glycosaminoglycan (GAG) accumulation. The functional consequences of these accumulated molecules are unknown. HS critically influences tissue morphogenesis by binding to and modulating the activity of several cytokines (eg, fibroblast growth factors [FGFs]) involved in developmental patterning. We recently isolated a multipotent progenitor cell from postnatal human bone marrow, which differentiates into cells of all 3 embryonic lineages. The availability of multipotent progenitor cells from healthy volunteers and patients with MPS-I (Hurler syndrome) provides a unique opportunity to directly examine the functional effects of abnormal HS on cytokine-mediated stem-cell proliferation and survival. We demonstrate here that abnormally sulfated HS in Hurler multipotent progenitor cells perturb critical FGF-2-FGFR1-HS interactions, resulting in defective FGF-2-induced proliferation and survival of Hurler multipotent progenitor cells. Both the mitogenic and survival-promoting activities of FGF-2 were restored by substitution of Hurler HS by normal HS. This perturbation of critical HS-cytokine receptor interactions may represent a mechanism by which accumulated HS contributes to the developmental pathophysiology of Hurler syndrome. Similar mechanisms may operate in the pathogenesis of other diseases where structurally abnormal GAGs accumulate.

Impaired elastogenesis in Hurler disease: dermatan sulfate accumulation linked to deficiency in elastin-binding protein and elastic fiber assembly.

Hurler disease resulting from a deficiency in alpha-L-iduronidase, which causes an accumulation of dermatan sulfate and heparan sulfate glycosaminoglycans, is characterized by connective tissue and skeletal deformations, cardiomyopathy, cardiac valve defects, and progressive coronary artery stenosis. In this report, we present evidence that accumulation of dermatan sulfate but not heparan sulfate moieties is linked to impaired elastic fiber assembly that, in turn, contributes substantially to the development of the clinical phenotype in Hurler disease. Our data suggest that dermatan sulfate-bearing moieties bind to and cause functional inactivation of the 67-kd elastin-binding protein, a molecular chaperone for tropoelastin, which normally facilitates its secretion and assembly into elastic fibers. We demonstrate that, in contrast to normal skin fibroblasts and cells from Sanfilippo disease, which accumulate heparan sulfate, Hurler fibroblasts show reduced expression of elastin-binding protein and do not assemble elastic fibers, despite an adequate synthesis of tropoelastin and sufficient production of a microfibrillar scaffold of elastic fibers. Because cultured Hurler fibroblasts proliferate more quickly than their normal counterparts and the addition of exogenous insoluble elastin reduces their proliferation, we suggest that cell contacts with insoluble elastin play an important role in controlling their proliferation.

Murine MPS I: insights into the pathogenesis of Hurler syndrome.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme alpha-L-iduronidase. A murine model which shows complete deficiency in alpha-L-iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long-term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM2 and GM3 gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.

The mucopolysaccharidoses and mucolipidoses.

The mucopolysaccharidoses and mucolipidoses are recessively inherited lysosomal storage diseases. Each of the disorders can now be specifically identified in cultured fibroblasts. As a group these disorders clinically present with a Hurler-like phenotype. Genetic heterogeneity and variable expression of the same enzyme deficiency require a combined clinical and laboratory approach to the diagnosis of these disorders. This feature is demonstrated by mucopolysaccharidosis I. This diagnosis refers to a specific deficiency of the lysosomal enzyme alpha-L-iduronidase. Further characterization requires clinical assessment to determine whether the final diagnosis is the Hurler syndrome, the Scheie syndrome or the Hurler-Scheie compound. Clinically each of these three disorders may be difficult to distinguish from other mucopolysaccharidoses or mucolipidoses. There is no specific treatment currently available for any of these disorders. However, a specific diagnosis should be established in each case to insure an accurate prognosis (some of these disorders are compatible with near normal life expectancy and normal intelligence), appropriate genetic counseling for the family and timely use of prenatal diagnosis by amniocentesis which is available for each of these disorders.