First trimester prenatal diagnosis of Sanfilippo disease (MPSIII) type B

Minelli, Antonella; Danesino, Cesare; Curto, Francesco Lo; Tenti, P.; Zampatti, C; Simoni, Giuseppe; Rossella, F.; Fois, Alberto

doi:10.1002/pd.1970080106

Cited by 14 publications

(5 citation statements)

References 7 publications

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“…Whereas cell defects identified in patient iPSc could impinge on their differentiation capacity, assays performed in several paradigms indicated that they behave like control iPSc, giving rise to differentiated cell progeny with similar efficiency, kinetics and pattern. These results appear consistent with the absence of clinical manifestations of the disease during fetal life and at birth in affected children (51,52) and animal models (19,53). However, these observations are not sufficient to conclude that stem cells behave normally in MPSIIIB.…”

supporting

confidence: 84%

Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells

Lemonnier

Blanchard

Toli

et al. 2011

Human Molecular Genetics

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By providing access to affected neurons, human induced pluripotent stem cells (iPSc) offer a unique opportunity to model human neurodegenerative diseases. We generated human iPSc from the skin fibroblasts of children with mucopolysaccharidosis type IIIB. In this fatal lysosomal storage disease, defective α-N-acetylglucosaminidase interrupts the degradation of heparan sulfate (HS) proteoglycans and induces cell disorders predominating in the central nervous system, causing relentless progression toward severe mental retardation. Partially digested proteoglycans, which affect fibroblast growth factor signaling, accumulated in patient cells. They impaired isolation of emerging iPSc unless exogenous supply of the missing enzyme cleared storage and restored cell proliferation. After several passages, patient iPSc starved of an exogenous enzyme continued to proliferate in the presence of fibroblast growth factor despite HS accumulation. Survival and neural differentiation of patient iPSc were comparable with unaffected controls. Whereas cell pathology was modest in floating neurosphere cultures, undifferentiated patient iPSc and their neuronal progeny expressed cell disorders consisting of storage vesicles and severe disorganization of Golgi ribbons associated with modified expression of the Golgi matrix protein GM130. Gene expression profiling in neural stem cells pointed to alterations of extracellular matrix constituents and cell-matrix interactions, whereas genes associated with lysosome or Golgi apparatus functions were downregulated. Taken together, these results suggest defective responses of patient undifferentiated stem cells and neurons to environmental cues, which possibly affect Golgi organization, cell migration and neuritogenesis. This could have potential consequences on post-natal neurological development, once HS proteoglycan accumulation becomes prominent in the affected child brain.

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supporting

confidence: 84%

Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells

Lemonnier

Blanchard

Toli

et al. 2011

Human Molecular Genetics

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“…Two-dimensional electrophoresis of urinary GAGs was carried out as described previously (Whiteman and Young 1977). The enzyme assay for NAGLU was performed on plasma and/or leukocytes as described previously (Marsh and Fensom 1985) or on chorionic villi for the prenatal test (Minelli et al 1988).…”

Section: Methodsmentioning

confidence: 99%

Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB)

Beesley

Jackson

Young

et al. 2005

J of Inher Metab Disea

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Sanfilippo syndrome type B (mucopolysaccharidosis IIIB) is an autosomal recessive disease that is caused by the deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). NAGLU is involved in the degradation of the glycosaminoglycan (GAG) heparan sulphate, and a deficiency results in the accumulation of partially degraded GAGs inside lysosomes. Early clinical symptoms include hyperactivity, aggressiveness and delayed development, followed by progressive mental deterioration, although there are a small number of late-onset attenuated cases. The gene for NAGLU has been fully characterized and we report the molecular analysis of 18 Sanfilippo B families. In total, 34 of the 36 mutant alleles were characterized in this study and 20 different mutations were identified including 8 novel changes (R38W, V77G, 407-410del4, 703delT, A246P, Y335C, 1487delT, E639X). The four novel missense mutations were transiently expressed in Chinese hamster ovary cells and all were shown to decrease the NAGLU activity markedly, although A246P did produce 12.7% residual enzyme activity.

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“…The low frequency of individual mutations makes it unlikely that mutation screening will improve the accuracy of the initial diagnostic procedures based on the analysis of metabolites and the determination of enzyme activity, the latter being sensitive enough for prenatal diagnosis. 25,26 However, mutation analysis will allow carrier-testing for siblings, especially if a partner is consanguineous, and will enable a more accurate prognosis for families of newly diagnosed patients, thereby improving genetic counselling. Mutation analysis is also of great importance for the selection of patients for trials of enzyme or gene replacement therapies and the evaluation of the efficacy of the protocols.…”

Section: Discussionmentioning

confidence: 99%

Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes

et al. 1999

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Sanfilippo B syndrome (mucopolysaccharidosis IIIB, MPS IIIB) is caused by a deficiency ofα-N-acetylglucosaminidase, a lysosomal enzyme involved in the degradation of heparan sulphate. Accumulation of the substrate in lysosomes leads to degeneration of the central nervous system with progressive dementia often combined with hyperactivity and aggressive behaviour. Age of onset and rate of progression vary considerably, whilst diagnosis is often delayed due to the absence of the pronounced skeletal changes observed in other mucopolysaccharidoses. Cloning of the gene and cDNA encoding α-N-acetylglucosaminidase enabled a study of the molecular basis of this syndrome. We were able to identify 31 mutations, 25 of them novel, and two polymorphisms in the 40 patients mostly of Australasian and Dutch origin included in this study. The observed allellic heterogeneity reflects the wide spectrum of clinical phenotypes reported for MPS IIIB patients. The majority of changes are missense mutations; also four nonsense and nine frameshift mutations caused by insertions or deletions were identified. Only five mutations were found in more than one patient and the observed frequencies are well below those observed for the common mutations in MPS IIIA. R643C and R297X each account for around 20% of MPS IIIB alleles in the Dutch patient group, whilst R297X, P521L, R565W and R626X each have a frequency of about 6% in Australasian patients. R643C seems to be a Dutch MPS IIIB allele and clearly confers the attenuated phenotype. One region of the gene shows a higher concentration of mutations, probably reflecting the instability of this area which contains a direct repeat. Several arginine residues seem to be 'hot-spots' for mutations, being affected by two or three individual base pair exchanges.

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First trimester prenatal diagnosis of Sanfilippo disease (MPSIII) type B

Cited by 14 publications

References 7 publications

Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells

Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells

Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB)

Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes

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