Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia

Abstract

We present our experience with the diagnosis of 26 patients (19 families) with congenital disorders of glycosylation classified as type Ia due to PMM 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 and T237M) 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 detected in other patients. R123X is the only stop codon mutation so far described in 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 points to the necessity of widening the criteria for CDG in the routine screening for inborn metabolic diseases.

Conformational Response to Ligand Binding in Phosphomannomutase2

“…3 and 4 ). This effect was reported for K51R, R123G, R123Q, G175R, and G176V ( 5 , 33 – 35 ). We can expect that a mutation affecting these residues reduces functionality to such an extent that when combined with a second hypomorphic mutation will result in less than 50% residual activity.…”

Congenital disorder of glycosylation type Ia: Heterogeneity in the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency

“…p.R141H was more prevalent among patients from Western European countries, whilst the frequency of p.F119L was highest among Scandinavian patients, and it gradually decreased moving southward in Europe (Kjaergaard 2004;Matthijs et al 2000). Our first patient had two previously reported pathogenic mutations in the PMM2 gene, p.I132T (De Lonlay et al 2001) and p.F207S (Briones et al 2002). The ethnic bias of mixed parentage with part Asian ancestry may explain the conspicuous absence of the two commoner mutations in this patient.…”

Recognizable phenotypes in CDG

“…Inverted nipples were seen in 183 of 343 patients (53%). In the available case series of 10 or more patients, the frequency of inverted nipples has been variably reported as 5 of 20 patients, or 25 % (Barone et al 2015), 3 of 11 adult patients, or 27 % (Monin et al 2014), 9 of 26, or 35 % (Briones et al 2002), 36 % out of 66 patients (Pérez et al 2011), 10 of 26, or 38 % (Grünewald et al 2001), 7 of 10 patients (Thompson et al 2013), 10 of 13, or 77 % (Imtiaz et al 2000), 16 of 17 patients, or 94 % (Honzík et al 2012)–although it disappeared over time in 6 of those 16 patients–and in 23 of 23 patients (Kjaergaard et al 2001), although it disappeared over time in 2 of them. It can sometimes be unilateral (van de Kamp et al 2007; Léticée et al 2010).…”