Mucopolysaccharide Storage Disease Research Articles

Characterization of otorhinolaryngologic manifestations in children with mucopolysaccharide storage disease typeⅠand type Ⅱ

Objective:To analyze the characteristics of otorhinolaryngological clinical manifestations in children with Mucopolysaccharide（MPS） type Ⅰ and type II in order to improve the knowledge of otorhinolaryngologists about this disease. Methods:Clinical data related to 55 children with MPS type Ⅰ and type II were retrospectively analyzed to investigate the clinical manifestations of MPS in ENT. Results:All 40 patients（72.72%） with MPS had at least one ENT symptom during the course of the disease, with 95% of them having an ENT symptom prior to the diagnosis of MPS; upper airway obstruction was the most common ENT symptom（34, 85.00%）, followed by recurrent upper respiratory tract infections（23, 57.50%）, and lastly, hearing loss（11, 27.50%）; all 26 patients had undergone at least one surgical procedure, of which 15（57.69%） had undergone ENT surgery, and all of these patients underwent ENT surgery before diagnosis. The most common ENT surgery was adenoidectomy. Conclusion:Early clinical manifestations of MPS patients are atypical, but the early and prevalent appearance of otolaryngologic symptoms and increased awareness of the disease among otolaryngologists has a positive impact on the prognosis of MPS.

Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B.

Sanfilippo syndrome type B (MPS IIIB) is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of α-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC) and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau) detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3β. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican was found in MEC of MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal glypican that would be harmful to neurons, because its heparan sulfate branches could potentiate the formation of Ptau and beta amyloid aggregates, which would be toxic as well as difficult to degrade.

From Serendipity to Therapy

My postdoctoral training in the biosynthesis of plant polysaccharides at the University of California, Berkeley, led me, rather improbably, to study mucopolysaccharide storage disorders in the intramural program of the National Institutes of Health (NIH). I have traced the path from studies of mucopolysaccharide turnover in cultured cells to the development of therapy for patients. The key experiment started as an accident, i.e., the mixing of cells of different genotypes, resulting in correction of their biochemical defect. This serendipitous experiment led to identification of the enzyme deficiencies in the Hurler and Hunter syndromes, to an understanding of the biochemistry of lysosomal enzymes in general, and to the cell biology of receptor-mediated endocytosis and targeting to lysosomes. It paved the way for the development of enzyme replacement therapy with recombinant enzymes. I have also included studies performed after I moved to the University of California, Los Angeles (UCLA), including a recent unexpected finding in a neurodegenerative mucopolysaccharide storage disease, the Sanfilippo syndrome, with implications for therapy.

Scintigraphic features of Morquio's syndrome: a case report

IntroductionTo the best of our knowledge, we present for the first time the bone scintigraphy findings of a patient with Morquio's syndrome.Case presentationA 46-year-old Caucasian man with Morquio's syndrome presented with lower back pain six weeks after a left total hip replacement. A whole body bone scan demonstrated an anthropomorphic skeletal pattern consistent with a mucopolysaccharide storage disease, thereby showing the cause of the patient's pain.ConclusionsTo the best of our knowledge, the bone scintigraphy findings of a case of Morquio's syndrome have never before been published. We present our case report to add to the knowledge we have of this rare disease.

Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders--clinical and echocardiographic findings in 64 patients.

Cardiovascular abnormalities were evaluated in 64 children aged between 1 year 9 months and 25 years with mucopolysaccharidoses (MPS) and related disorders. A heart murmur was heard in 18 patients, but in only 6 was it characteristic for specific valvular lesions. Echocardiography was performed in 63 children. In one girl cardiac lesions were diagnosed on autopsy. In 46 patients (72%), valvular lesions and/or different types of cardiomyopathy were detected. There were no characteristic changes for different types of MPS. In the majority of children in whom dermatan sulphate accumulated, cardiac involvement was the most frequent (88%) and severe. The most common lesion, regardless of MPS type, was thickening of the mitral valve (66%), with regurgitation or stenosis in 28 (44%). Aortic valve thickening was detected in 17 patients (27%), asymmetric septal hypertrophy or hypertrophic cardiomyopathy in 18, congestive cardiomyopathy in 1 and endocardial thickening in 13 patients. Cardiac involvement was less frequent in children with Sanfilippo disease. Two or more echocardiographic examinations were performed in 23 patients. In 19 of them (83%) cardiac changes were more severe during the second examination. One 7-year-old boy with Hunter disease underwent successful mitral valve replacement. CONCLUSIONS; Cardiac involvement is present in most patients with MPS although there are few clinical signs and symptoms. The most common and severe changes are in Hurler, Hunter, Maroteaux-Lamy and I-cell disease, rarely in Sanfilippo disease. Mitral valve deformation is most frequent in all patients. The cardiac lesions are progressive.

Mechanisms of Obstructive Sleep Apneas in Infants

During sleep, infants with obstructive sleep apneas are characterised by snoring, laborious breathing, and profuse sweating. During wakefulness, they may have breath-holding spells, and during feeding, difficult breathing and swallowing coordination. Abnormal weight, difficult growth, and recurring ear infections may also develop. During sleep apneas, cinefluoroscopy shows approximation of tongue and hypopharyngeal tissues, with an obliteration of the air space. The obstructed breaths occur mainly in REM, and light NREM sleep, associated with total short sleep time, and frequent arousals. Preterm infants, and term neonates are more prone to obstructive apneas than older healthy infants. Apneas are more frequently seen in boys and in case of excess in body weight. Obstructive apneas are frequently associated with upper airway anatomic abnormalities: malformations, soft tissue infiltration, and neurologic lesions impairing muscle contractions. Alterations of the autonomic nervous control may induce airways obstructions. Contributing factors include mucopolysaccharide storage disease, hypothyroidism, or Down's syndrome. Superimposed factors may occur, such as nasal obstruction, secretions in the airways, or tissue edema. Pressure- and chemo-sensitive reflexes may also favor obstruction. Environmental factors also contribute to the development of sleep apneas: body position, neck flexion, sleep deprivation, or the effects of sedative drugs.

Echo-Doppler abnormalities in mucopolysaccharide storage diseases.

Echo-Doppler abnormalities in mucopolysaccharide storage diseases.

Management of Tracheal Lesions in Hurler Syndrome

Hurler syndrome is a rare mucopolysaccharide storage disease that becomes clinically apparent during early childhood as mucopolysaccharide deposits form in skeletal and soft tissues. Progressive mucopolysaccharide deposition in the oropharynx and tracheal connective tissues leads to airway obstruction if untreated. Tonsillectomy, adenoidectomy, and tracheostomy have been utilized to provide symptomatic relief of upper airway obstruction. Treatment of tracheal lesions by laser excision is a recent innovative method for the management of airway obstruction in children with Hurler syndrome. We describe two boys with Hurler syndrome whose mucopolysaccharide tracheal lesions were excised by utilization of the carbon dioxide laser.

Deposition of lipopigment — a new feature of human splenic sinus endothelium (SSE)

Lipopigment (LP) deposition was studied in a series of 36 control and 79 pathological spleens. In the control group the LP deposition in SSE was rudimentary and did not display age-dependence. A varying degree of lysosomal and cytoplasmic siderosis was a frequent finding in haemolytic anemia without any significant LP induction. In the acquired secondary storage syndrome and in some inherited lysosomal enzymopathies, the amount of LP in splenic sinus endothelium (SSE) was significantly increased and in some instances its deposition reached very high values. As deposition was not accompanied by any detectable lysosomal lipid storage phenomenon in pulpar histiocytes, the pigmentogenesis is thought to be by a process resembling that for lipofuscin. In ceroid-lipofuscinosis group the SSE affection was of low degree, as seen in other viscera. The LP deposition seems thus to be a prominent, albeit variable feature of human SSE lysosomal pathology and may represent a monotonous response to various stimuli connected with increased demands on the SSE lysosomal system. Only in some lysosomal enzymopathies, typically in sphingomyelinase deficiency was SSE LP deposited progressively and concurrently with the stored lipid. LP deposition was accompanied by an increase in lysosomal enzyme activities but lacked the alkaline phosphatase induction in SSE described in lipid and mucopolysaccharide storage diseases. This and several other features which are reviewed clearly distinguish SSE from the pulpar histiocytes with which they have been often identified.

Results of a Quality Assurance Exercise for Urinary Glycosaminoglycan Excretion

Urine samples collected from four patients with a mucopolysaccharide storage disease (MPS) and two non-MPS patients were distributed to up to 33 laboratories as a test of their ability to detect abnormal glycosaminoglycan excretion. Seven national reference laboratories made a correct diagnostic assignment to all samples analysed. Qualitative turbidity and spot tests were shown to be unreliable. Failure to identify the excretion pattern occurred when reliance was placed on one-dimensional electrophoresis or thin layer chromatography as the sole method for glycosaminoglycan identification. Two-dimensional electrophoresis appeared to be the method of choice provided that staff had adequate experience in interpretation. Clinically unacceptable delays in analysis were common, with 80% of laboratories taking longer than 10 days to issue a report.

Combined Aortic and Mitral Valve Replacement in an Adult with Scheie's Disease

Mitral, aortic, and coronary arterial disease have been described in the various mucopolysaccharidoses. We report the first successful combined aortic and mitral valve replacement in an adult female patient with severe aortic and mitral stenosis due to Scheie's syndrome, a mucopolysaccharide storage disease. Both annulae were of sufficient integrity for good prosthetic placement, and the patient had an uneventful postoperative recovery.

Echocardiographic Abnormalities in the Mucopolysaccharide Storage Diseases

Echocardiographic Abnormalities in the Mucopolysaccharide Storage Diseases

Echocardiographic abnormalities in the mucopolysaccharide storage diseases

The mucopolysaccharide storage diseases express themselves clinically with a wide variety of abnormalities, including growth and mental retardation, skeletal abnormalities, clouded corneas, nerve compression syndromes, upper airway obstruction and cardiovascular involvement, to name the most common. In most cases the cause of early death is cardiorespiratory failure secondary to cardiovascular involvement and upper airway obstruction. The findings of cardiac ultrasound examination in 29 children, adolescents and young adults are presented. In addition to the previously well-described abnormalities of the mitral and aortic valves in several types of mucopolysaccharide storage disease, we report patchy involvement in some cases, 3 instances of asymmetric septal hypertrophy not previously reported in mucopolysaccharide storage diseases, cardiac involvement in half of our patients with Sanfilippo syndrome and a lack of age-related severity of cardiac involvement even within the specific syndromes.

52] Acetyl-CoA : α-glucosaminide N-acetyltransferase from rat liver

Publisher Summary Acetyl-CoA: α-glucosaminide N-acetyltransferase (N-acetyltransferase) is a lysosomal enzyme deficient in the hereditary mucopolysaccharide storage disease known as Sanfilippo C syndrome. The enzyme catalyzes the acetylation of terminal glucosamine residues of heparan sulfate, using acetyl-CoA as the acetyl donor. Once acetylated, the glucosamine can be hydrolyzed off the polysaccharide by the next enzyme in the degradation pathway––a-N-acetylglucosaminidase. Enzyme activity is measured, using [14C]glucosamine as the acetyl acceptor, by a modification of the procedure of Hopwood. The charged substrate, [14C]glucosamine, is separated from the neutral product N-[14C]acetylglucosamine by passing the reaction mixture over a 1-ml Dowex column. The chapter discusses the assay procedure on the enzyme. The enzyme can be partially purified by isolating lysosomal membranes from rat liver, following the procedures of Ohsumi et al. The chapter also discusses the properties of α-glucosaminide N-acetyltransferase.

The mucopolysaccharidoses: a synergism between clinical and basic investigation.

The mucopolysaccharidoses are a family of genetic diseases involving faulty degradation of one or more type of mucopolysaccharide or glycosaminoglycan. These conditions are characterized by skeletal, connective tissue, and intellectual manifestations. Biochemical investigations over the past 10-20 yr have enhanced our understanding of the clinical conditions and advanced our knowledge of catabolic pathways for complex biological structures. Identification of stored and excreted materials as partially degraded glycosaminoglycans allowed classification of these conditions on clinical and chemical criteria. The development of a cell culture model for studying the mucopolysaccharidoses lead to the identification of a variety of lysosomal sulfatases and glycosidases as deficient enzymes. This stimulated the identification of several new conditions. Knowledge of primary biochemical defects improved genetic services by providing accurate diagnosis, facilitating carrier identification and improving prenatal diagnosis. Glycosaminoglycan excretion patterns associated with individual enzyme defects suggested sequential degradative pathways for GAGs and related macromolecules. Attempts at enzyme replacement revealed a complex system of recognition markers and membrane receptors for the uptake of extracellular proteins. Multiple enzyme deficiencies are providing information on lysosomal enzyme synthesis and processing. The mucopolysaccharide storage diseases offer an excellent example of a productive synergism between basic biology and clinical medicine.

The Mucopolysaccharidoses: A Synergism between Clinical and Basic Investigation

The mucopolysaccharidoses are a family of genetic diseases involving faulty degradation of one or more type of mucopolysaccharide or glycosaminoglycan. These conditions are characterized by skeletal, connective tissue, and intellectual manifestations. Biochemical investigations over the past 10-20 yr have enhanced our understanding of the clinical conditions and advanced our knowledge of catabolic pathways for complex biological structures. Identification of stored and excreted materials as partially degraded glycosaminoglycans allowed classification of these conditions on clinical and chemical criteria. The development of a cell culture model for studying the mucopolysaccharidoses lead to the identification of a variety of lysosomal sulfatases and glycosidases as deficient enzymes. This stimulated the identification of several new conditions. Knowledge of primary biochemical defects improved genetic services by providing accurate diagnosis, facilitating carrier identification and improving prenatal diagnosis. Glycosaminoglycan excretion patterns associated with individual enzyme defects suggested sequential degradative pathways for GAGs and related macromolecules. Attempts at enzyme replacement revealed a complex system of recognition markers and membrane receptors for the uptake of extracellular proteins. Multiple enzyme deficiencies are providing information on lysosomal enzyme synthesis and processing. The mucopolysaccharide storage diseases offer an excellent example of a productive synergism between basic biology and clinical medicine.

Sulphated acid mucopolysaccharides in SV40-transformed human cells from normal and mucopolysaccharidosis patients

Lines of fibroblasts have been established from normal individuals and from patients diagnosed as suffering from one of the mucopolysaccharidoses or mucopolysaccharide-storage diseases. Transformation of these lines with SV40 virus has been found to reduce their capacity to secrete sulphated mucopolysaccharides into the growth medium. No differences were detected between the individual cell types in their secretory capacity, either before or after viral transformation. A direct relationship was found to exist between the rate of acid mucopolysaccharide production and cell-doubling time. The level of sulphated mucopolysaccharide detected within the cell was also reduced for all cell types after transformation by SV40. Transformed fibroblasts from mucopolysaccharidosis patients, however, showed a relatively greater reduction in storage capacity than those derived from normal individuals.

Preponderance of lysosomal bodies in cultured fibroblasts from patients with recessive epidermolysis bullosa dystrophica. An electron microscopic study.

Fibroblasts of skin explants from three normal men and six patients with recessive epidermolysis bullosa dystrophica (EBD-R) were cultured in Dulbecco's medium, grown to confluence, sectioned and studied with the electron microscope. The normal control fibroblasts from the 6th to 13th passage (secretory phase) showed irregular or lobed nuclei with centrally scattered chromatin. They also had prominent RER, Golgi complexes, variously shaped mitochondria and cytoskeletal microfibrils. Their peripheral cytoplasm exhibited many vacuoles and a small number of these were autophagic lysosomes. In addition to the ultrastructural features described in the control fibroblasts, the EBD-R cells from the 6th passage contained remarkable numbers of strongly electron dense lysosomal bodies through their entire cytoplasm with very few empty vacuoles. It is speculated that the accumulation of these lysosomes may be connected with a primary metabolic cellular defect in the dermal fibroblasts of patients with EBD-R akin to that described in mucopolysaccharide storage diseases.

The Prevention of Genetic Disease and Mental Retardation

During the past two decades, progress in understanding some genetic defects responsible for many physical and mental debilities has been impressive. It is now recognized, for example, that mental retardation occurs in appreciable numbers of humans with numerical and structural chromosome disorders (Down syndrome, cri-du-chat syndrome, etc). In other individuals, a single gene abnormality such as phenolketonuria has been identified at birth, and treatment can now be initiated to preserve life and reduce the debility. With other diseases, such as mucopolysaccharide storage disease, a specific biochemical defect may be identified, but satisfactory treatment is not yet available. In still other abnormalities, the causes are understood poorly and no treatment exists. It is now even possible to identify several single gene diseases in the 16- to 20-week-old fetus by means of biochemical studies on cells obtained by amniocentesis; in addition, all gross chromosome disorders can be recognized prenatally. However, these

Biochemical genetics in neurology.

Remarkable advances in the past five years now permit the control of an important segment of hereditary disorders of metabolism that cause central nervous system (CNS) damage. The application of this knowledge has provided immense relief of human suffering and distress. It is therefore exigent that neurologists be aware of these developments and how they may be applied to patients. This article describes briefly how we learned the causes of ten inherited lipid storage diseases and indicates how this information is used to control the incidence of these disorders. It also provides a precis of the current status of research in mucopolysaccharide storage diseases, and concludes with a demonstration of a new concept in hereditary neurologic diseases caused by a defect in the synthesis of critical brain components. LIPID STORAGE DISEASES Clinical Descriptions Physicians have been aware of clinical manifestations of several of the lipidoses for nearly a century.