Intrafamilial variability in Hurler syndrome and Sanfilippo syndrome type A: Implications for evaluation of new therapies

McDowell, Geraldine; Cowan, Tina M.; Blitzer, Miriam G.; Greene, Carol L.

doi:10.1002/ajmg.1320470732

Cited by 8 publications

(5 citation statements)

References 10 publications

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“…Indeed, an accumulation of normally nonpathogenic sequence variants may be responsible for some of the mild MPS-I alleles in combination with a severe allele. It is accepted that differences in environmental and genetic backgrounds may, in part, explain differences in the clinical phenotypes of patients with the same disease genotype (reviewed in Neufeld, 1991; see sib variation in McDowell et al, 1993;Scott et al, 1993a). Four of the mutations for MPS-I that have been observed more than once are associated with more than one haplotype (W402X, P533R, A75T, and R89Q); i.e., different genetic backgrounds (Scott et al, 1992b,d;.…”

Section: Polymorphisms and Nonpathogenic Sequence Variantsmentioning

confidence: 99%

“…For more detailed clinical descriptions, see McKusick andNeufeld, 1983, andNeufeld andMuenzer, 1989. ) Even when looking at sibs or patients with the same genotype, caution must be taken as shown by the differences in phenotypes seen in sibs (e.g., McDowell et al, 1993;Scott et al, 1993a). As described for other genetic diseases, mild alleles may allow some enzymatic function, and this residual enzyme activity may be modulated by other factors.…”

Section: Genotype Phenotype Correlationsmentioning

confidence: 99%

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Molecular genetics of muccpolysaccharidosis type I: Diagnostic, clinical, and biological implications

et al. 1995

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Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive disease caused by mutations in the alpha-L-iduronidase (IDUA) gene. These mutations lead to a deficiency of the glycosidase alpha-L-iduronidase (IDUA), which is required for the degradation of heparan sulphate and dermatan sulphate and thus the storage of these glycosaminoglycans in the lysosome. There is a wide range of clinical phenotypes in MPS-I (eponyms: Hurler syndrome, severe; Hurler/Scheie syndrome, intermediate; Scheie syndrome, mild), which makes prediction of disease severity and genetic counselling difficult. However, since cloning of the IDUA gene, mutation analysis has provided some molecular explanations for the range of MPS-I phenotypes, in turn facilitating the selection and evaluation of patients undergoing experimental treatment protocols such as bone marrow transplantation. A total of 46 mutations now have been defined for MPS-I consisting of 8 nonsense mutations, 21 missense mutations, 3 splice site mutations, and 14 minor deletions and/or insertions. Furthermore, 30 polymorphisms or nonpathogenic sequence variants have been defined, including 7 amino acid substitutions. Among patients of European origin, there are two major MPS-I mutations and a number of less frequent mutations. It is possible to follow mutation analysis of 292 patients, which can be divided into eight main patient groups of different ethnic and/or geographic origin with significant variation in mutant allele frequencies. A complex picture of molecular heterogeneity is emerging, building a valuable database for genotype/phenotype correlation. Mutation analysis is also providing some of the first clues into the structure and function of IDUA.

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Section: Polymorphisms and Nonpathogenic Sequence Variantsmentioning

confidence: 99%

Section: Genotype Phenotype Correlationsmentioning

confidence: 99%

Molecular genetics of muccpolysaccharidosis type I: Diagnostic, clinical, and biological implications

et al. 1995

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“…A small number of more slowly progressive forms with later onset have been described in Sanfilippo A and B (Lindor et al 1994;Van de Kamp et al 1981). Phenotypic variations within Sanfilippo A and B kinships have also been reported (Di Natale 1991;McDowell et al 1993). All four subtypes are autosomal recessive disorders and the genes have been identified in types A, B and D. A gene for Sanfilippo type C has recently been localized to the pericentromeric region of chromosome 8 (Ausseil et al 2004).…”

mentioning

confidence: 97%

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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“…Intrafamilial variability has been recognised in LSD in humans. 17 , 18 Therefore, it may be considered that phenotypic variability exists in Japanese domestic cats with the same pathogenic genetic variant.…”

Section: Discussionmentioning

confidence: 99%

Skeletal radiographic manifestations of GM2 gangliosidosis variant 0 (Sandhoff disease) in two Japanese domestic cats

Hasegawa

Hamamoto

et al. 2022

Journal of Feline Medicine and Surgery Open Reports

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Case series summary Two Japanese domestic cats with GM2 gangliosidosis variant 0, diagnosed at different times, are included in this case series. Both cats were diagnosed by genetic analysis and had the HEXB:c.667C>T pathogenic genetic variant, which have been previously reported in Japanese domestic cats with GM2 gangliosidosis variant 0. Clinical signs and the identification of vacuolation in circulating lymphocytes were consistent with those in previous reports of feline GM2 gangliosidosis variant 0. Radiography showed that both cases had similar skeletal radiographic manifestations, which has not been previously reported in Japanese domestic cats with GM2 gangliosidosis variant 0. Radiographic findings included abnormally shaped vertebral bodies, obscure or irregular endplates (both of which were seen especially in the cervical and thoracic vertebrae), generalised osteopenia and new bone proliferation around articular facets. Relevance and novel information To the best of our knowledge, this is the first report to present the skeletal radiographic abnormalities of Japanese domestic cats with GM2 gangliosidosis variant 0 caused by the HEXB:c.667C>T pathogenic genetic variant. Furthermore, together with a report published in 2015 on the radiographic findings of feline GM2 gangliosidosis variant 0 caused by another pathogenic genetic variant, this report suggests that these findings may be indicators of feline GM2 gangliosidosis variant 0. The easily obtained radiographic findings described in this report may be useful as a finding suggestive of feline GM2 gangliosidosis variant 0, in addition to the cytological finding of the vacuolated cells. The report emphasises the utility of radiography for diagnosis of cases with suspected progressive neurodegenerative diseases.

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Intrafamilial variability in Hurler syndrome and Sanfilippo syndrome type A: Implications for evaluation of new therapies

Cited by 8 publications

References 10 publications

Molecular genetics of muccpolysaccharidosis type I: Diagnostic, clinical, and biological implications

Molecular genetics of muccpolysaccharidosis type I: Diagnostic, clinical, and biological implications

Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB)

Skeletal radiographic manifestations of GM2 gangliosidosis variant 0 (Sandhoff disease) in two Japanese domestic cats

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