Discovery of a new biomarker for the mucopolysaccharidoses (MPS), dipeptidyl peptidase IV (DPP-IV; CD26), by SELDI-TOF mass spectrometry

Surface enhanced laser desorption/ionisation time of flight (SELDI-TOF) mass spectrometry has been used to search for new protein biomarkers in the plasma of patients with mucopolysacharidoses (MPS). Differences in the levels of some plasma proteins, particularly the apolipoprotein ApoCI, were observed between MPS patients and normal controls, using the different chromatographic surfaces (ProteinChips^®). ApoCI was identified by both its mass and by immunological techniques. In plasma, it exists in two forms, ApoCI and a truncated form which lacks two N-terminal amino acids, ApoCI′. In controls, the ratio of ApoCI′:ApoCI observed using the cation-exchange surface (CM10) was approximately 1:2 whereas in most MPS patients it varied from 1:1 to 1:0.8. The ratio of ApoCI′:ApoCI in plasma is determined by the activity of dipeptidyl peptidase IV, DPP-IV (also known as the leucocyte antigen CD26), which was found to be elevated up to 3-fold in MPS patients. The DPP-IV activity decreased in MPS I patients undergoing enzyme replacement therapy, indicating that it could be a useful biomarker for monitoring the efficacy of treatment in MPS disease. As DPP-IV has an important regulatory role in metabolism, it is possible that its elevation could cause some of the secondary pathology in MPS, and inhibition of DPP-IV might have a role in MPS therapy.     

Hypertrophic cardiomyopathy in mucopolysaccharidoses: Regression after bone marrow transplantation

Summary Mucopolysaccharide storage disease (MPS) presents clinically with a broad spectrum of abnormalities, among which cardiovascular involvement has been described.The echocardiographic findings have recently been reported for the various types of MPS. Among these, asymmetric septal hypertrophy (ASH) has been documented.We present a case of a 9-year-old girl suffering from type I MPS, atypical variant, with echocardiographic signs of ASH. She was given a bone marrow transplant after which the hypertrophic cardiomyopathy regressed.     

Mitral and aortic regurgitation in 84 patients with mucopolysaccharidoses

In echocardiographic and necropsy studies nodular thickening of the mitral valve and, less frequently, of the aortic valve has been found in 60%–90% of patients with mucopolysaccharidoses (MPS). Little is known about the haemodynamic consequences of these morphological changes. In this study 84 unselected patients with different enzymatically proven MPS and 84 age and sex matched, healthy persons were studied prospectively by colour Doppler flow mapping. The patients' age ranged from 1 to 47 years (median 8.1 years). Mitral and aortic regurgitation were defined as a holosystolic or holodiastolic jet originating from the valve into the left atrium or the left ventricular outflow tract, respectively, with peak velocities exceeding 2.5 m/s. Of the 84 patients with satisfactory studies, mitral regurgitation was detected in 64.3% and aortic regurgitation in 40.5%, respectively. Regurgitation was severe in 4.8% of mitral valves and 8.3% of aortic valves. The frequency of aortic and/or mitral regurgitation was 75% in all patients, 89% in MPS I, 94% in MPS II, 66% in MPS III, 33% in MPS IV, and 100% in MPS VI. Combined mitral and aortic regurgitation was present in 29% of our patients. None of the control persons showed mitral or aortic regurgitation.     

Mucopolysaccharidoses in Calcutta

Seven hundred children referred to the clinic for mental retardation were screened for various inborn errors of metabolism. Eighteen were found to have mucopolysaccharidoses (MPS). Ten of these children were followed for a period of five years. Three of them died. Two of them had type 1 MPS, based on physical findings, biochemical investigations and deficient iduronidase activities of leucocytes. There were seven patients with MPS type II in this series. Two pairs were siblings. Skin cultures carried out in Dr Neufeld's Laboratory showed iduronate sulphatase deficiency. Three patients had type IV mucopolysaccharidoses. Two were siblings. In one patient leucocyte beta-galactosidase activity was about 1/8th of normal control. One patient had MPS type VI; her leucocytes had no detectable aryl sulfatase B. One patient had unclassifiable MPS. They had some clinical improvement as a result of parental care but the progression of the disease has remained unaffected.     

Outcome of Displacement Bone Marrow Transplantation for Inborn Errors of Metabolism

The concept of displacement bone marrow transplantation arose from our work at Westminster 1970–1973, by which time we had extended the donors from matched siblings to other family and unrelated donors. DBMT is not a panacea, but can be applied to about 7% of understood inborn errors, where it is possible to devise in vitro tests to predict in vivo donor effects. Its use to install donor bone marrow as a component factory for the life of the recipient, and the importance of immunoprophylaxis are summarised. Worthwhile correction has been achieved for 48 previously fatal genetic diseases, partial correction for another five, but there has been failure for three diseases. Some 80% of our patients were not found in known families and could not have been prevented.     

Severe mitral insufficiency in mucopolysaccharidosis type III-B (Sanfilippo syndrome)

Summary A 6-year-old girl with mucopolysaccharidosis (MPS) III-B (Sanfilippo syndrome) who developed severe mitral regurgitation and congestive heart failure requiring surgery (valvuloplasty) is reported. One year after surgery the patient remains well, with marked improvement in her physical activity, and without signs of heart failure. This is only the second report of severe mitral regurgitation in MPS III, and is the first report of a successful repair (valvuloplasty) of a dysplastic mitral valve in the MPS. Mitral valvuloplasty should be considered instead of valve replacement in any MPS patient with mitral valve regurgitation requiring surgery.     

Characterization of a C57BL/6 congenic mouse strain of mucopolysaccharidosis type IIIA

The original mucopolysaccharidosis type IIIA (MPS IIIA) mice were identified in a mixed background with contributions from four different strains. To ensure long-term stability and genetic homogeneity of this lysosomal storage disease (LSD) model, the aim of this study was to develop and characterize a C57BL/6 congenic strain. The B6.Cg-Sgsh(mps3a) strain compares favorably with the original mixed donor strain, exhibiting low liver sulfamidase activity and significant brain heparan sulfate-derived disaccharide elevation from birth. A rapid increase in brain disaccharide levels occurred after birth, with a plateau reached by 13 weeks of age at 110x the levels observed in brains of age-matched unaffected mice. Typical lysosomal inclusions were observed in cerebral cortical and cerebellar neurons and in liver hepatocytes and Kupffer cells. Ubiquitin-positive spheroids and GM(2)-ganglioside were also detected in brain. Using the Morris water maze in male mice, impaired memory and spatial learning was evident at 20 weeks of age in B6.Cg-Sgsh(mps3a) MPS IIIA mice. Other behavioral changes include motor, cognitive and sensory deficits, and aggression. Male B6.Cg-Sgsh(mps3a) MPS IIIA mice exhibited more behavioral abnormalities than B6.Cg-Sgsh(mps3a) MPS IIIA females, as observed previously in the original mixed background strain. Affected mice generally survive to 9 to 12 months of age, before death or euthanasia for humane reasons. Overall, minor differences were apparent between the new congenic and previously described mixed MPS IIIA strains. Availability of an in-bred strain will ensure more reproducible experimental outcomes thereby assisting in our goal of developing effective therapies for LSD with central nervous system disease.     

HUNTER'S SYNDROME. An Ultrastructural Study of an Autopsy Case

An autopsy case of a 10-year, 8-month-old boy with Hunter's syndrome Is reported with emphasis on the ultrastructural findings of almost all the organs, except the brain. Intracytoplasmic inclusion bodies were observed in various organs as follows: nerve cells and glia in the spinal cord, hepatocytes and Kupffer cells in the liver, sinusoidal endothelium of the spleen, proximal tubules, podocytes and epithelium of Bowman's capsule of the kidney, interstitial fibroblast-like cells among cardiac muscle bundles, cardiac valves and aorta, exocrine and endocrine cells of the pancreas, adrenocortical cells, follicular epithelial cells of the thyroid, Leydig cells of the testis, chondrocytes, fibroblasts and endothelium of capillaries throughout the body. Three types of inclusion bodies were morphologically distinguishable. Type 1: clear vacuole, Type 2: zebra body, Type 3 : clear vacuole with a lipid-like lamellar structure. The clear vacuole (Type 1) was thought to represent an accumulation of glycosaminoglycans, and the zebra body (Type 2), probably ganglioside. The type 3 inclusion body might be an intermediate and mixed form of the type 1 and type 2 inclusions. Histochemical study also suggested that the type 3 inclusion body contained glycosaminoglycan and a type of lipid. ACTA PATHOL JPN 38: 1175 ∼ 1190, 1988.     

Abnormalities in the hair morphology of patients with some but not all types of mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of inherited, progressive, metabolic diseases, caused by the deficiency of one of the enzymes involved in the degradation of glycosaminoglycans (GAGs). The disease is usually fatal, with the life span of most untreated MPS patients being between one and two decades. In this report, on the basis of scanning electron microscopy (SEM) studies, we demonstrate that, besides the many other symptoms of MPS, there are characteristic abnormalities in the hair morphology of patients suffering from some types of this disease (MPS I, MPS II, MPS IIIA, MPS IIIB), but not from other types (MPS IVA, MPS IVB, MPS VI), where the changes are minor, if any. Different GAGs accumulate in the tissues of patients suffering from the various MPS types, and analysis of the disease types in which severe hair abnormalities occur or not could suggest that the accumulation of heparan sulfate, rather than dermatan sulfate or keratan sufate, may be responsible for the major changes in hair morphology. Considerable abnormalities in hair morphology occur in patients suffering from MPS I, MPS II, MPS IIIA, and MPS IIIB, but not in patients suffering from MPS IVA, MPS IVB, and MPS VI; this feature might potentially be used as an additional test for the assessment of the efficacy of treatments for MPS patients (types I, II, IIIA, and IIIB).     

Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence

Aim: The aim of this study was to estimate the incidence and prevalence of mucopolysaccharidoses (MPS disorders) in Scandinavia. Methods: The retrospective period used for the incidence study covered the period from 1975 to 2004 in Sweden and Denmark and from 1979 to 2004 in Norway. Prevalence was derived from the number of MPS patients alive as of December 31, 2007. Results: The incidence of all MPS disorders was 1.75 cases in Sweden, 3.08 cases in Norway and 1.77 cases in Denmark per 100 000 newborns. The incidence of MPS I was the most common in all three countries, with 0.67, 1.85 and 0.54 cases per 100 000 newborns, respectively; for MPS II, numbers were 0.27, 0.13 and 0.27, respectively. For patients with other MPS disorders the incidence varied widely. The prevalence for all MPS disorders was 4.24, 7.06 and 6.03 per 1 000 000 inhabitants in Sweden, Norway and Denmark, respectively. Conclusion: From three Scandinavian countries the incidence of MPS disorders is retrospectively evaluated for 25 years in Norway and 30 years in Sweden and Denmark. Incidence and prevalence studies of lysosomal disorders are prerequisites for cost benefit calculations in the face of newly developed and expensive therapies in the future.