Neurochemistry of the mucopolysaccharidoses: brain glycosaminoglycans in normals and four types of mucopolysaccharidoses.
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Adolescent↗
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The mucopolysaccharidoses: inborn errors of glycosaminoglycan catabolism.
The mucopolysaccharidoses are genetic disorders of glycosaminoglycan metabolism. Patients with these diseases accumulate within the lysosomes of most tissues excessive amounts of dermatan and/or heparan sulfates, or of keratan sulfate. The clinical consequences of such glycosaminoglycan storage range from skeletal abnormalities to cardiovascular problems, and to motor and mental retardation. In all mucopolysaccharidoses, except Morquio disease, an excessive accumulation of sulfate-labeled glycosaminoglycans has been demonstrated in fibroblasts cultured from the patient's skin. It was subsequently shown that this was due to the deficiency of specific proteins which were named "corrective factors", because their addition to the culture medium effected a normalization of the impaired glycosaminoglycan catabolism in the respective mucopolysaccharidosis fibroblasts. The investigation of the function of the corrective factors, and other studies, led to the identification of the enzymatic defect in each of the mucopolysaccharidoses. Seven lysosomal enzyme deficiencies are now recognized among this group of disorders. A classification of the diseases, according to the mutant gene products, reveals that there is considerable phenotypic variation not only between diseases, but also within several disease types. With the availability of the appropriate enzyme assays, the previous difficulties in diagnosing these disorders have now been overcome. Methods are also available for the prenatal diagnosis, and the detection of heterozygous individuals, in most of the mucopolysaccharidoses. Although correction of the metabolic defect through enzyme replacement has been achieved in tissue culture, many problems remain to be solved before such therapy may become applicable in the patients themselves.
Glycosaminoglycans↗
An improved determination of total glycosaminoglycans in body fluids by formation of complexes with quinacrine: changes in amniotic fluid total glycosaminoglycans during normal pregnancies and in pregnancies at risk for mucopolysaccharidoses.
Acidic glycosaminoglycans form insoluble complexes with quinacrine and this has been exploited for their analysis in blood, urine and amniotic fluid. The method is specific for glycosaminoglycans including keratan sulphate and the samples do not have to be deproteinized. Values for normal urine, serum and amniotic fluid are presented. Urinary total glycosaminoglycans excreted by patients with mucopolysaccharidoses were also determined. The normal changes in amniotic fluid total glycosaminoglycans have been measured between 14 weeks' gestation and term, and values are given for amniotic fluid total glycosaminoglycans in several pregnancies at risk for mucopolysaccharidoses. It is suggested that this method is a potentially valuable analytical tool in the pre-natal diagnosis of mucopolysaccharidoses.
Amniotic Fluid↗
A review and selection of simple laboratory methods used for the study of glycosaminoglycan excretion and the diagnosis of the mucopolysaccharidoses.
The current state of knowledge on the biochemical abnormalities in the mucopolysaccharidoses is reviewed. Methods for the estimation and identification of glycoasminoglycans excreted in the mucopolysaccharidoses are discussed and a selection of simple and reliable methods of value in a small hospital laboratory have been given in detail in an appendix.
Arylsulfatases↗
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.
Aspartylglucosaminuria↗
Acridine orange particles in cultured fibroblasts. A comparative study of macular corneal dystrophy, systemic mucopolysaccharidoses types I-H and II, and normal controls.
Vital staining with the fluorescent dye, acridine orange, was evaluated as a means of detecting abnormalities of lysosomes in cultivated fibroblasts of patients with macular corneal dystrophy and mucopolysaccharidoses types I-H (Hurler's syndrome) and type II (Hunter's syndrome). Multiple cultures were compared with normal fibroblasts using a "double-masked" design to exclude observer bias. Cells of patients with the mucopolysaccharidoses were easily and accurately separated from other fibroblasts. Contrary to a recent report, corneal fibroblasts of patients with macular corneal dystrophy were indistinguishable from control cells.
Acridine Orange↗
Prolonged methanol fixation of soluble mucosubstances in mucopolysaccharidoses.
A simple and efficient method for the demonstration of highly water soluble acid mucosubstances in cold microtone sections is described. It consists of prolonged treatment of cold microtome sections with methanol (for at least 1 h) and subsequent staining with 0.1% azure A in distilled water or in 30% methanol. The procedure is recommended particularly for the bioptical examination of mucopolysaccharidoses.
Azure Stains↗
Fine structural and ultracytochemical studies on the lymphocytes in three types of genetic mucopolysaccharidoses.
Lymphocytes from 6 patients with 3 types of genetic mucopolysaccharidoses (Hurler's syndrome, Hunter's syndrome and Morquio's syndrome) contained numberous vacuoles in their cytoplasm. The size of the vacuoles ranged from approximately 300 nm to 750 nm. The percentage of the lymphocytes with vacuoles varied from 10% to 38%. The vacuoles showed acid phosphatase activity, which indicated their lysosommal nature. Staining with dialyzed iron solution usually localized acid mucosubstance in the peripheral region of these vacuoles after glutaraldehyde fixation. Ferritin and horseradish peroxidase were observed in the vacuoles after incubation of the patient's lymphocytes with these tracers. This finding indicates the participation of endocytosis in the formation of these vacuoles.
Acid Phosphatase↗
Molecular size difference of urinary heparan sulfates from normal individuals and genetic mucopolysaccharidoses.
Heparan sulfates were isolated from the urine of normal individuals and patients with genetic mucopolysaccharidoses after exhaustive digestion with chondroitinase ABC. Electrophoresis of these preparations on cellulose acetate membrane revealed one spot corresponding in mobility to reference heparan sulphate in barium acetate buffer, while electrophoresis in 0.1 M HCl resulted in two distinct spots for each case; one corresponded in migration rate to reference heparan sulfate, and the other was faster in mobility than reference heparan sulfate but slightly retarded when compared with reference heparin. On thin-layer gel filtration on Sephadex G-200 (superfine) heparan sulfate from normal urine was polydispersed in character and its molecular size was larger than those of other preparations. Heparan sulfates from Hunter's and Sanfilippo's urine were monodispersed and small in molecular size. The molecular size of heparan sulfate from Sanfilippo's urine was the smallest of all. Heparin sulfate from Hurler's urine appeared to be composed of two populations; one corresponded in molecular size to heparan sulfate from normal urine, and the other corresponded to that of Hunter's urine.
Adolescent↗
Differentiation of mucopolysaccharidoses by analyses of the excreted sulfated mucopolysaccharides.
Analyses of sulfated mucopolysaccharides excreted by patients with Hunter, Hurler, Scheie, Sanfilippo A and Sanfilippo B syndromes are reported. Three distinct methods, namely agarose gel electrophoresis, enzymatic degradation and molecular weight determination, were used in an attempt to differentiate the mucopolysaccharidoses by analysis of the urinary mucopolysaccharides. It is shown that by the combination of these methods it is possible to differentiate most of the syndromes and also to demonstrated that some patients with the same syndrome excrete different types of sulfated mucopolysaccharides.
Diagnosis, Differential↗
beta-Galactosidase in mucopolysaccharidoses and mucolipidoses. Deficiency of GM1 beta-galactosidase in liver and leukocytes.
beta-Galactosidase activities were studied in livers and leukocytes of mucopolysaccharidoses and mucolipidoses (I-cell disease and adult "beta-galactosidase deficiency" with macular cherry-red spots). Marked deficiency of hepatic 4-methylumbelliferyl (4MU) and GM1 beta-galactosidases was demonstrated in these diseases. Leukocyte GM1 beta-galactosidase was also deficient in mucolipidoses. The parents of the patients with I-cell disease and "beta-galactosidase deficiency" had normal beta-galactosidase activity in plasma and leukocytes, compared to the low enzyme activity in heterozygous carriers of GM1-gangliosidosis. The cause of this enzyme deficiency in these diseases is not clear at present. It seems to be affected seondarily by exgenous factors such as unknown stored materials in the cells. Mucopolysaccharides were not increased in the livers of two cases of I-cell disease and a case of "beta-galactosidase deficiency".
Adolescent↗
The mucopolysaccharidoses (a review).
The mucopolysaccharidoses are a group of genetic diseases characterized by storage of incompletely degraded glycosaminoglycans. Such storage causes marked distortion of many tissues with consequent severe somatic changes and mental retardation. Storage of glycosaminoglycans results from markedly diminished activity of specific hydrolases requisite for the normal degradation of glycosaminoglycans. The specific enzymic defects have been identified in nine different diseases. In some cases evidence has been obtained indicating the existence of additional allelic diseases based on the same enzyme. The knowledge obtained from these studies has made prenatal diagnosis possible and has led to the possibility that therapy may be undertaken utilizing enzyme replacement.
Acetylglucosaminidase↗
Cardiac manifestations of the mucopolysaccharidoses.
The cardiovascular manifestations of the mucopolysaccharidoses (MPS) have not been well characterized. We studied nine children with various forms of MPS, using noninvasive cardiac diagnostic techniques. The echocardiograms of two brothers with Type I H/S MPS showed slow mitral valve early diastolic closure velocities (MVEDC) (18, 29 mm/sec) consistent with mitral stenosis. Each had a soft opening snap, low frequency presystolic murmurs and X-ray evidence of calcific mitral stenosis. Three patients with Type II A MPS had echocardiographic evidence of impaired left ventricular function, suggesting the presence of myocardial damage. One of these had an abnormal electrocardiogram; non had murmurs. No cardiac abnormalities were discovered in two patients with Type III A and IV MPS. One patient with Type VI A MPS had presystolic, holostolic and early diastolic murmurs. A soft opening snap was recorded. The echocardiogram showed a slow MVEDC (18 mm/sec) and a slightly enlarged left atrial dimension (2.2 cm/m2). In summary, noninvasive studies are useful in evaluating patients with MPS. Type I H/S and Type VI A patients may show evidence of valvular deformity, the former associated with mitral valvular calcification and the latter with both aortic and mitral valve involvement. Type II A patients have muscle function abnormalities and Type III A and IV are shown by noninvasive methods to be free of cardiovascular abnormalities.
Adolescent↗
Carpal tunnel syndrome in pediatric mucopolysaccharidoses. Report of four cases.
Four pediatric patients with mucopolysaccharidoses and an associated carpal tunnel syndrome are presented. Findings in these cases were typical of the adult form of median nerve compression at the wrist, but the patients had minimal symptoms in view of these findings. The importance of careful clinical eximination and early surgical decompression is emphasized.
Carpal Tunnel Syndrome↗
Corneal manifestations of the systemic mucopolysaccharidoses.
Newer biochemical understanding of the mucopolysaccharidoses now allows a better classification of these diseases. The dermatan and keratan sulfate-storing diseases have corneal clouding. The heparan sulfate-storing diseases have retinal changes and usually central nervous system manifestations.
Child↗
Median nerve compression and trigger finger in the mucopolysaccharidoses and related diseases.
Patients with Hurler's syndrome (MPS-1H), I-cell disease (ML-II) and pseudo-Hurler's syndrome (ML-III) had median nerve compression and triggering of the fingers which limited finger extension. To our knowledge, this combination has not been reported previously in patients with mucopolysaccharidoses and related disorders. In all of our 3 cases the median nerve was compressed by thickened flexor tenosynovium. Synovectomy and resection of the volar carpal ligament improved the hand function in all, including the mentally retarded patient with Hurler's syndrome. Release of the fibroosseous tunnel in two patients was followed by an increased range of motion (but not full extension). A fourth patient, without a mucopolysaccharide storage disorder, also had the combination of trigger finger and carpal tunnel syndrome.
Carpal Tunnel Syndrome↗
Syndrome of the defective lysosome--the genetic mucopolysaccharidoses.
The genetic mucopolysaccharidoses represent the group of disorders recognized in the early 1900's. In half a century, it was recognized that these were disorders of polyanionic macromolecules known as glycosaminoglycans. Within the past five years, these disorders have been identified as prototypes of lysosomal diseases, are a genetically heterogeneous group and this heterogeneity is recognizable in in vitro systems. Finally, these disorders represent prototypes for the development of methods of enzyme replacement therapy.
Glycosaminoglycans↗
The iduronidase-deficient mucopolysaccharidoses: clinical and roentgenorgraphic features.
Hurler and Scheie syndromes, two of the six clinically distinct mucopolysaccharidoses, are deficient in the same lysosomal enzyme, alpha-L-iduronidase. A third group of iduronidase-deficient patients can now be identified during the pediatric years using clinical and radiographic criteria. Based on inferential evidence for allelism between the Hurler and Scheie genes, the occurrence of genetic compounds which simultaneously carry both mutant alleles may be predicted to occur. This can be considered analogous to the structural gene mutations leading to hemoglobin SC disease. Four patients with phenotypes intermediate between Hurler and Scheie syndromes are flet to represent genetic compounds of this type. Both clinical and roentgenographic features are helpful in distinguishing these patients from those with Hurler syndrome or Scheie syndrome. Fibroblast correction characteristics identical to those of Hurler syndrome and Scheie syndrome and absence of consanguinity are additional features which favor classification as genetic compounds. The possibility of a third mutant allele at the Hurler-Scheie locus or of extreme phenotype variation are not considered likely alternative explantations. Depending on the frequency of the Scheie syndrome and the Hurler syndrome, genetic compounds may occur with an intermediate frequency or may be more common than either homozygous condition.
Adolescent↗