Late‐Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo A syndrome

Hove, Johan L.K. Van; Wevers, Ron A.; Cleemput, Johan Van; Moerman, Philippe; Sciot, Raf; Matthijs, Gert; Schollen, E; Jong, J.G.N. de; Carey, W.F.; Muller, Viv; Nicholls, C.D.; Perkins, Kelly; Hopwood, John J.

doi:10.1002/ajmg.a.20068

Cited by 32 publications

(29 citation statements)

References 22 publications

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“…Less severe SGSH alleles that result in extended lifespan have been reported (19, 20, 30 -32), although onset is during childhood; thus these cases are not diagnosed as ANCL. (There is one previous report of adult onset MPSIIIA, but neurodegeneration was not a feature in this case (33).) Therefore, SGSH deficiencies have not previously been associated with ANCL.…”

Section: Discussionmentioning

confidence: 47%

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

Sleat¹,

Ding

Wang

et al. 2009

Molecular & Cellular Proteomics

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Diagnosis of lysosomal storage diseases (LSDs) can be problematic in atypical cases where clinical phenotype may overlap with other genetically distinct disorders. In addition, LSDs may result from mutations in genes not yet implicated in disease. Thus, there are individuals that are diagnosed with apparent LSD based upon clinical criteria where the gene defect remains elusive. The objective of this study was to determine whether comparative proteomics approaches could provide useful insights into such cases. Most LSDs arise from mutations in genes encoding lysosomal proteins that contain mannose 6-phosphate, a carbohydrate modification that acts as a signal for intracellular targeting to the lysosome. We purified mannose 6-phosphorylated proteins by affinity chromatography and estimated relative abundance of individual proteins in the mixture by spectral counting of peptides detected by tandem mass spectrometry. Our rationale was that proteins that are decreased or absent in patients compared with controls could represent candidates for the primary defect, directing biochemical or genetics studies. On a survey of brain autopsy specimens from 23 patients with either confirmed or possible lysosomal disease, this approach identified or validated the genetic basis for disease in eight cases. These results indicate that this protein expression approach is useful for identifying defects in cases of undiagnosed lysosomal disease, and we demonstrated that it can be used with more accessible patient samples, e.g. cultured cells. Furthermore this approach was instrumental in the identification or validation of mutations in two lysosomal proteins, CLN5 and sulfamidase, in the adult form of neuronal ceroid lipofuscinosis.

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Section: Discussionmentioning

confidence: 47%

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

Sleat¹,

Ding

Wang

et al. 2009

Molecular & Cellular Proteomics

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“…Among the 10 cases reported as ''mild'' forms, the genetic analysis has been made only for three cases: the one described by Miyazaki et al [2002], which showed S347F and D444G mutations, the other one reported by Di Natale et al [2003] which showed a heterozygous genotype E369K/P128L, and the third one reported by Van Hove et al [2003], in which no mutation was found.…”

Section: Discussionmentioning

confidence: 99%

“…However, among the hundreds of patients affected by mucopolysaccharidosis III, only few cases of adults have been reported with clinical signs of Sanfilippo type A syndrome moderately involved from the neurological and physical point of view: three brothers reported by Wisniewski et al [1985], two sibs described by Lindor et al [1994], two more by Date et al [1998], and another one recently reported by Miyazaki et al [2002]. Di Natale et al [2003] described two second cousins, one affected by the classical severe form of the disease and the other affected by a mild form of the illness; in the same year, Van Hove et al [2003] reported an additional adult patient whose main clinical feature was the presence of severe cardiomyopathy in the absence of any neurological involvement.…”

Section: Introductionmentioning

confidence: 99%

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An adult Sanfilippo type A patient with homozygous mutation R206P in the sulfamidase gene

et al. 2005

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The Sanfilippo type A syndrome, one of the most frequent forms of mucopolysaccharidosis III, is characterized by severe mental retardation, progressive neurological degeneration, and mild somatic changes. It is due to a deficiency of heparan-N-sulfatase (sulfamidase) activity and consequent excretion of heparan sulfate in the urine. The disease is transmitted through an autosomal recessive mechanism, and more than 60 gene mutations have been identified. Up to now, only 10 cases of attenuated form of Sanfilippo type A syndrome have been described, and the specific mutation has been identified only in two of them. We report here on a female patient, 20 years old, with Sanfilippo type A syndrome presenting with a mild clinical phenotype characterized essentially by a moderate nonevolving mental retardation. The genetic analysis demonstrated that the patient is homozygous for mutation R206P; presence of polymorphism R456H was also found. This study places R206P as a mild mutation underlying Sanfilippo type A disease.

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“…R89Q) that are known to lead to milder phenotypes (12). Furthermore, a patient whose MPS IIIA was diagnosed in the fourth decade of life, with very mild symptoms (13), was shown to have very low levels of the heparan sulphate-derived disaccharide. Notwithstanding these initial observations, creatinine is derived from muscle metabolism and levels increase with age; therefore, for phenotype predictions using this ap- Relative levels of GAG-derived oligosaccharides in urine from MPS-affected individuals before and after bone marrow transplant.…”

Section: Markers For the Mucopolysaccharidosesmentioning

confidence: 99%

Disease-Specific Markers for the Mucopolysaccharidoses

et al. 2004

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Unprecedented demands are now placed on clinicians for early diagnosis as we enter into an era of advancing treatment opportunities for the mucopolysaccharidoses (MPS). Biochemical monitoring of any therapeutic avenue will also be prerequisite. To this end, we aimed to identify a range of urinary oligosaccharides that could be used to identify and characterize patients with MPS. We analyzed 94 urine samples from 68 patients with MPS and 26 control individuals for oligosaccharides derived from glycosaminoglycans using electrospray ionization-tandem mass spectrometry. The oligosaccharide profile for each patient group was compared with that of the control group. The Mann-Whitney U test was used to measure the difference between each patient group and the controls for each analyte. Urine samples from patients before and at successive times after bone marrow transplantation were also evaluated. A number of oligosaccharides were identified in the urine of each MPS subtype, and for each of these, specific oligosaccharide profiles were formulated. These profiles enabled the identification of all 68 patients and their subtypes with the exception of MPS IIIB and IIIC. Selected oligosaccharides were used to assess three individuals after a bone marrow transplant, and, in each case, a substantial reduction in the level of diagnostic oligosaccharides, posttransplantation, was observed. The identification and measurement of glycosaminoglycan-derived oligosaccharides in urine provides a sensitive and specific screen for the early identification of individuals with MPS. The resulting oligosaccharide profiles not only characterize subtype but also provide a disease-specific fingerprint for the biochemical monitoring of current and proposed therapies. The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders characterized by a deficiency in one of the lysosomal enzymes required to degrade glycosaminoglycans (GAG). There are 11 known enzyme deficiencies that give rise to seven distinct types of MPS, with a combined incidence of~1 in 16,000 (1). In all MPS subtypes, partially degraded GAG accumulate in the lysosomes of affected cells and/or are excreted in the urine. The lysosomal storage of GAG leads to the chronic and progressive deterioration of cells, tissues, and organs (2). The MPS share many clinical manifestations, including organomegaly, abnormal facial features, and dysostosis multiplex. Impaired hearing, vision, and joint mobility, as well as abnormal airway and cardiovascular function, are common, although there is wide clinical heterogeneity within each enzyme deficiency. Profound mental retardation is characteristic of the severe forms of MPS I, II, and VII and all subtypes of MPS III. Similar and severe skeletal and joint abnormalities are present in MPS I, II, VI, and VII, whereas MPS IV develops different skeletal pathology.The clinical management for MPS is changing, as new treatment options, such as enzyme replacement therapy, that will complement and replace bone marrow transplantatio...

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Late‐Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo A syndrome

Cited by 32 publications

References 22 publications

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

An adult Sanfilippo type A patient with homozygous mutation R206P in the sulfamidase gene

Disease-Specific Markers for the Mucopolysaccharidoses

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