Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease

Christiane Auray-Blais; Denis Cyr; Aimé Ntwari; Michael L. West; Josanne Cox-Brinkman; Daniel G. Bichet; Dominique P. Germain; Rachel Laframboise; Serge B. Melançon; Tracy Stockley; Joe T.R. Clarke; Régen Drouin

doi:10.1016/j.ymgme.2007.10.001

Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease

Christiane Auray-Blais, Denis Cyr, Aimé Ntwari, Michael L. West, Josanne Cox-Brinkman, Daniel G. Bichet, Dominique P. Germain, Rachel Laframboise, Serge B. Melançon, Tracy Stockley, Joe T.R. Clarke, Régen Drouin

Medicine

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

90 Citas (Scopus)

Resumen

Fabry disease is a complex, multisystemic and clinically heterogeneous disease, in which the urinary excretion of globotriaosylceramide (Gb₃), the principal substrate of the deficient enzyme, α-galactosidase A, is more prominent than the increased concentrations of the lipid in the plasma of affected hemizygotes and heterozygotes. We have developed and validated a simultaneous analysis of Gb₃ and creatinine in a 2.6-min run using filter paper discs saturated with urine and analyzed by LC-MS/MS. Using this method, we studied the relationship between urinary levels of total Gb₃/creatinine excretion and four types of mutations in the GLA gene (missense, nonsense, frameshift, and splice-site defects) in 32 children and 78 adult patients with Fabry disease. Forty-one patients were treated by enzyme replacement therapy and 69 were untreated. Our results show that the mean recoveries of Gb₃ and creatinine from the urine filter paper standards were 91% and 97%, respectively, with precision, reproducibility, and linearity within acceptable ranges. Statistical analysis using the independent variables of sex, age, types of mutations and treatment showed that the mutation factor has a statistically significant impact on urinary Gb₃ excretion (p = 0.0007). This means that the levels of urinary excretion of Gb₃/creatinine in children and adults with Fabry disease are directly related to the types of mutations. The same correlation was found for the sex (p < 0.0001) and treatment (p = 0.0011). In conclusion, we studied 35 mutations in 110 children and adults with Fabry disease and found a significant correlation between the types of mutations and total Gb₃ excretion in Fabry patients.

Idioma original	English
Páginas (desde-hasta)	331-340
Número de páginas	10
Publicación	Molecular Genetics and Metabolism
Volumen	93
N.º	3
DOI	https://doi.org/10.1016/j.ymgme.2007.10.001
Estado	Published - mar. 2008

Nota bibliográfica

Funding Information:
The authors thank the nurse-coordinators, geneticists and genetic counsellors at each collaborating centre: Carolina Azcona, (Toronto), Kaye Lemoine (Halifax), Carole Fortier (Montreal), Nicole Labbé (Quebec), and Dr. Karelle Benistan (Paris) and Dr. John James Mitchell (Montreal) for their collaboration in providing urine samples from Fabry patients. We acknowledge the assistance of Claude Alie and Dr. René Gagnon for their keen expertise. We are particularly grateful to the patients with Fabry disease for their cooperation. Without them this study would not have been possible. This research was funded in part by a grant-in-aid of research from Genzyme Canada Inc. We are grateful to Waters for their continued scientific support. R.D. holds the Canada Research Chair in “Genetics, Mutagenesis and Cancer”.

ASJC Scopus Subject Areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Molecular Biology
Genetics
Endocrinology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

ODS de las Naciones Unidas

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10.1016/j.ymgme.2007.10.001

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Auray-Blais, C., Cyr, D., Ntwari, A., West, M. L., Cox-Brinkman, J., Bichet, D. G., Germain, D. P., Laframboise, R., Melançon, S. B., Stockley, T., Clarke, J. T. R., & Drouin, R. (2008). Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease. Molecular Genetics and Metabolism, 93(3), 331-340. https://doi.org/10.1016/j.ymgme.2007.10.001

Auray-Blais, C, Cyr, D, Ntwari, A, West, ML, Cox-Brinkman, J, Bichet, DG, Germain, DP, Laframboise, R, Melançon, SB, Stockley, T, Clarke, JTR & Drouin, R 2008, 'Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease', Molecular Genetics and Metabolism, vol. 93, n.º 3, pp. 331-340. https://doi.org/10.1016/j.ymgme.2007.10.001

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title = "Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease",

abstract = "Fabry disease is a complex, multisystemic and clinically heterogeneous disease, in which the urinary excretion of globotriaosylceramide (Gb3), the principal substrate of the deficient enzyme, α-galactosidase A, is more prominent than the increased concentrations of the lipid in the plasma of affected hemizygotes and heterozygotes. We have developed and validated a simultaneous analysis of Gb3 and creatinine in a 2.6-min run using filter paper discs saturated with urine and analyzed by LC-MS/MS. Using this method, we studied the relationship between urinary levels of total Gb3/creatinine excretion and four types of mutations in the GLA gene (missense, nonsense, frameshift, and splice-site defects) in 32 children and 78 adult patients with Fabry disease. Forty-one patients were treated by enzyme replacement therapy and 69 were untreated. Our results show that the mean recoveries of Gb3 and creatinine from the urine filter paper standards were 91% and 97%, respectively, with precision, reproducibility, and linearity within acceptable ranges. Statistical analysis using the independent variables of sex, age, types of mutations and treatment showed that the mutation factor has a statistically significant impact on urinary Gb3 excretion (p = 0.0007). This means that the levels of urinary excretion of Gb3/creatinine in children and adults with Fabry disease are directly related to the types of mutations. The same correlation was found for the sex (p < 0.0001) and treatment (p = 0.0011). In conclusion, we studied 35 mutations in 110 children and adults with Fabry disease and found a significant correlation between the types of mutations and total Gb3 excretion in Fabry patients.",

author = "Christiane Auray-Blais and Denis Cyr and Aim{\'e} Ntwari and West, {Michael L.} and Josanne Cox-Brinkman and Bichet, {Daniel G.} and Germain, {Dominique P.} and Rachel Laframboise and Melan{\c c}on, {Serge B.} and Tracy Stockley and Clarke, {Joe T.R.} and R{\'e}gen Drouin",

note = "Funding Information: The authors thank the nurse-coordinators, geneticists and genetic counsellors at each collaborating centre: Carolina Azcona, (Toronto), Kaye Lemoine (Halifax), Carole Fortier (Montreal), Nicole Labb{\'e} (Quebec), and Dr. Karelle Benistan (Paris) and Dr. John James Mitchell (Montreal) for their collaboration in providing urine samples from Fabry patients. We acknowledge the assistance of Claude Alie and Dr. Ren{\'e} Gagnon for their keen expertise. We are particularly grateful to the patients with Fabry disease for their cooperation. Without them this study would not have been possible. This research was funded in part by a grant-in-aid of research from Genzyme Canada Inc. We are grateful to Waters for their continued scientific support. R.D. holds the Canada Research Chair in “Genetics, Mutagenesis and Cancer”.",

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AU - Auray-Blais, Christiane

AU - Cyr, Denis

AU - Ntwari, Aimé

AU - West, Michael L.

AU - Cox-Brinkman, Josanne

AU - Bichet, Daniel G.

AU - Germain, Dominique P.

AU - Laframboise, Rachel

AU - Melançon, Serge B.

AU - Stockley, Tracy

AU - Clarke, Joe T.R.

AU - Drouin, Régen

N1 - Funding Information: The authors thank the nurse-coordinators, geneticists and genetic counsellors at each collaborating centre: Carolina Azcona, (Toronto), Kaye Lemoine (Halifax), Carole Fortier (Montreal), Nicole Labbé (Quebec), and Dr. Karelle Benistan (Paris) and Dr. John James Mitchell (Montreal) for their collaboration in providing urine samples from Fabry patients. We acknowledge the assistance of Claude Alie and Dr. René Gagnon for their keen expertise. We are particularly grateful to the patients with Fabry disease for their cooperation. Without them this study would not have been possible. This research was funded in part by a grant-in-aid of research from Genzyme Canada Inc. We are grateful to Waters for their continued scientific support. R.D. holds the Canada Research Chair in “Genetics, Mutagenesis and Cancer”.

PY - 2008/3

Y1 - 2008/3

N2 - Fabry disease is a complex, multisystemic and clinically heterogeneous disease, in which the urinary excretion of globotriaosylceramide (Gb3), the principal substrate of the deficient enzyme, α-galactosidase A, is more prominent than the increased concentrations of the lipid in the plasma of affected hemizygotes and heterozygotes. We have developed and validated a simultaneous analysis of Gb3 and creatinine in a 2.6-min run using filter paper discs saturated with urine and analyzed by LC-MS/MS. Using this method, we studied the relationship between urinary levels of total Gb3/creatinine excretion and four types of mutations in the GLA gene (missense, nonsense, frameshift, and splice-site defects) in 32 children and 78 adult patients with Fabry disease. Forty-one patients were treated by enzyme replacement therapy and 69 were untreated. Our results show that the mean recoveries of Gb3 and creatinine from the urine filter paper standards were 91% and 97%, respectively, with precision, reproducibility, and linearity within acceptable ranges. Statistical analysis using the independent variables of sex, age, types of mutations and treatment showed that the mutation factor has a statistically significant impact on urinary Gb3 excretion (p = 0.0007). This means that the levels of urinary excretion of Gb3/creatinine in children and adults with Fabry disease are directly related to the types of mutations. The same correlation was found for the sex (p < 0.0001) and treatment (p = 0.0011). In conclusion, we studied 35 mutations in 110 children and adults with Fabry disease and found a significant correlation between the types of mutations and total Gb3 excretion in Fabry patients.

AB - Fabry disease is a complex, multisystemic and clinically heterogeneous disease, in which the urinary excretion of globotriaosylceramide (Gb3), the principal substrate of the deficient enzyme, α-galactosidase A, is more prominent than the increased concentrations of the lipid in the plasma of affected hemizygotes and heterozygotes. We have developed and validated a simultaneous analysis of Gb3 and creatinine in a 2.6-min run using filter paper discs saturated with urine and analyzed by LC-MS/MS. Using this method, we studied the relationship between urinary levels of total Gb3/creatinine excretion and four types of mutations in the GLA gene (missense, nonsense, frameshift, and splice-site defects) in 32 children and 78 adult patients with Fabry disease. Forty-one patients were treated by enzyme replacement therapy and 69 were untreated. Our results show that the mean recoveries of Gb3 and creatinine from the urine filter paper standards were 91% and 97%, respectively, with precision, reproducibility, and linearity within acceptable ranges. Statistical analysis using the independent variables of sex, age, types of mutations and treatment showed that the mutation factor has a statistically significant impact on urinary Gb3 excretion (p = 0.0007). This means that the levels of urinary excretion of Gb3/creatinine in children and adults with Fabry disease are directly related to the types of mutations. The same correlation was found for the sex (p < 0.0001) and treatment (p = 0.0011). In conclusion, we studied 35 mutations in 110 children and adults with Fabry disease and found a significant correlation between the types of mutations and total Gb3 excretion in Fabry patients.

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Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODS de las Naciones Unidas

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