Abstract
Summary: We present our experience with the diagnosis of 26 patients (19 families) with congenital disorders of glycosylation classified as type Ia due toPMM deficiency. In all but one of these CDG Ia families the patients are compound heterozygous for mutations in PMM2. Eighteen different mutations were detected. In contrast to other series in which R141H represents 43–50% of the alleles, only 9/36 (25%) alleles have this mutation. Two mutations (R123Q andT237M) have been found on three disease chromosomes, four (V44A, Y64C, P113L and F207S) on two disease chromosomes and 12 mutations (D65Y, Y76C, IVS3+2C>T, E93A, R123X, V129M, I153T, F157S, E197A, N216I, T226S, C241S) only on one disease chromosome. V44A and D65Y probably originated in the Iberian peninsula, as they have only been reported in Portuguese and Latin-American patients; Y64C, Y76C, R123X and F207S have not been detectedin other patients. R123X is the only stop codon mutation so far describedin PMM2. The common European F119L mutation has not been found in our patients, although it is very frequent in other populations (43% allele frequency in Danish patients). Probably because of this genetic heterogeneity, Spanish patients show very diverse phenotypes that are, in general, milder than in other series. This pointsto the necessity of widening the criteria for CDG in the routine screening for inborn metabolic diseases.
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REFERENCES
Artigas J, Cardo E, Pineda M, Nosas R, Jaeken J (1998) Phosphomannomutase defiency and normal pubertal development. J Inherit Metab Dis 21: 78–79.
Briones P, Vilaseca MA, GarcÃa-Silva MT, et al (2001) Congenital disorders of glycosylation (CDG) may be underdiagnosed when mimicking mitochondrial disease. Eur J Paediatr Neurol 5: 127–131.
Cardo E, Montero R, Castanyer B, Ruiz-Gómez MA, Taboada D, Pérez-Ferrón J (1999) SÃndrome de proteÃnas deficientes en carbohidratos tipo I. Caso familiar. Rev Neurol 29: 545.
Carratalá F, Juste M, Moya M (1999) SÃndrome de glicoproteinas deficientes en carbohidratos. Descripción clÃnica de un caso. Rev Neurol 29: 567.
Chabás A, Girós ML, Guardiola A (1991) Low β-glucuronidase activity in a healthy member of a family with mucopolysaccharidosis VII. J Inherit Metab Dis 14: 908–914.
Colomé C, Ferrer I, Artuch R, Vilaseca A, Pineda M, Briones P (2000) Personal experience with the application of CDT assays to the detection of congenital disorders of glycosylation. Clin Chem Lab Med 38: 965–969.
de Lonlay P, Seta N, Barrot S, et al (2001) A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet 38: 14–19.
di Rocco M, Barone R, Adami A, et al (2000) Carbohydrate-deficient glycoprotein syndromes: the Italian experience. J Inherit Metab Dis 23: 391–395.
Erlandson A, Bjursell C, Stibler H, Kristiansson B, Wahlstrom J, Martinsson T (2001) Scandinavian CDG-Ia patients: genotype/phenotype correlation and geographic origin of founder mutations. Hum Genet 108: 359–367.
Freeze HH (1998) Disorders in protein glycosylation and potential therapy: tip of an iceberg? J Pediatr 133: 593–600.
GarcÃa Silva MT, de Castro J, Stibler H, et al (1996) Prenatal hypertrophic cardiomyopathy and pericardial effusion in carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 19: 257–259.
Grünewald S, Schollen E, Van Schaftingen E, Jaeken J, Matthijs G (2001) High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase defiency). Am J Hum Genet 68: 347–354.
Imtiaz F, Worthington V, Champion M, et al (2000) Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1. J Inherit Metab Dis 23: 162–174.
Jaeken J, Carchon H (2000) What's new in congenital disorders of glycosylation? Eur J Paediatr Neurol 4: 163–167.
Jaeken J, Matthijs G (2001) Congenital disorders of glycosylation. Annu Rev Genomics Hum Genet 2: 129–151.
Jaeken J, Artigas J, Barone R, et al (1997) Phosphomannomutase defiency is the main cause of carbohydrate-deficient glycoprotein syndrome with type I isoelectrofocusing pattern of serum sialotransferrins. J Inherit Metab Dis 20: 447–449.
Keir G, Winchester BG, Clayton P (1999) Carbohydrate-deficient syndromes: inborn errors of proteinglycosylation. Ann Clin Biochem 36: 20–36.
Kjaergaard S, Skovby F, Schwartz M (1998) Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1. Eur J Hum Genet 6: 331–336
Matthijs G, Schollen E, Pardon E, et al (1997) Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaekensyn drome). Nature Genetics 16: 88–92.
Matthijs G, Schollen E, Van Schaftingen E, Cassiman JJ, Jaeken J (1998) Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1a. Am J Hum Genet 62: 542–550.
Matthijs G, Schollen E, Bjursell C, et al (2000) Mutationupdate: mutations inPMM2 cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat 16: 386–394.
Pineda M, PavÃa C, Vilaseca MA, et al (1996) Normal pubertal development in a female with carbohydrate deficient glycoprotein syndrome. Arch Dis Child 74: 242–243.
Pirard M, Matthijs G, Heykants L, et al (1999) Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. FEBS Lett 452: 319–322.
Poo P, Escofet C, Pineda M, Vilaseca MA, Ferrer I (1999) SÃndrome de glicoproteÃnas deficientes en carbohidratos tipo I con hemorragia cerebral neonatal. Rev Neurol 28: 197.
Schollen E, Pardon E, Heykants L, et al (1998) Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene. Hum Mol Genet 7: 157–164.
Schollen E, Martens K, Geuzens E, Matthijs G (2002) D-HPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG). Eur J Hum Genet 10: 643–648.
Seta N, Barnier A, Hochedez F, Besnard MA, Durand G (1996) Diagnostic value of western blotting in carbohydrate-deficient glycoprotein syndrome. Clin Chim Acta 254: 131–140.
Stibler H, Jaeken J (1990) Carbohydrate deficient serum transferrin in a new systematic hereditary syndrome. Arch Dis Child 65: 107–111.
Van Ommen CH, Peters M, Barth PG, Vreken P, Wanders RJ, Jaeken J (2000) Carbohydrate-deficient glycoprotein syndrome type 1a: a variant phenotype with borderline cognitive dysfunction, cerebellar hypoplasia, and coagulation disturbances. J Pediatr 136: 400–403.
Van Schaftingen E, Jaeken J (1995) Phosphomannomutase defiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 377: 318–320.
Westphal V, Petterson S, Patterson M, et al (2001) Functional signifiance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia. Genet Med 3: 385–386.
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Briones, P., Vilaseca, M.A., Schollen, E. et al. Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia. J Inherit Metab Dis 25, 635–646 (2003). https://doi.org/10.1023/A:1022825113506
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DOI: https://doi.org/10.1023/A:1022825113506