A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation

Abstract

PMM2-CDG (PMM2 gene mutations) is the most common congenital disorder of N-glycosylation. We conducted a nationwide survey to characterize the frequency, clinical features, glycosylation and genetic correlates in Italian patients with PMM2-CDG. Clinical information was obtained through a questionnaire filled in by the referral physicians including demographics, neurological and systemic features, neuroimaging data and genotype. Glycosylation analyses of serum transferrin were complemented by MALDI-Mass Spectrometry (MALDI-MS). Between 1996 and 2012, data on 37 Italian patients with PMM2-CDG were collected. All the patients with a severe phenotype were unable to walk unaided, 84 % had severe intellectual disability and 81 % microcephaly. Conversely, among 17 mildly affected patients 82 % had independent ambulation, 64 % had borderline to mild intellectual disability and 35 % microcephaly. Epilepsy and stroke-like events did not occur among patients with the mild phenotype. The rate and extent of systemic involvement were more pronounced in severely affected patients. The L32R misfolding mutation of the PMM2 gene occurred in 70 % of the patients with the mild phenotype and was associated with a less severe underglycosylation of serum Tf at MALDI-MS analyses. Despite their different disease severity, all patients had progressive (olivo)ponto-cerebellar atrophy that was the hallmark clinical feature for the diagnosis. A mild neurological phenotype of PMM2-CDG marked by preserved ambulatory ability and autonomy and associated with L32R mutation is particularly frequent in Italy. PMM2-CDG should be considered in patients with even mild developmental disability and/or unexplained progressive cerebellar atrophy.

The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

“…Val129Met and Val231Met are among the most frequent mutations and have been encountered in several countries. The genotypes Val129Met/Arg141His and Val231Met/Arg141His including these mutant alleles have been associated with severe phenotypes in unrelated families, in seven and eighteen reported cases, respectively [11,15,16,17,18,19]. …”

From gestalt to gene: early predictive dysmorphic features of PMM2-CDG

“…We observed that a prominent jaw develops in place of retrognathia, which is more prevalent in infancy, and antevertes nares, observed in certain patients at early ages, seems to be linked to a prominent nose in older children. A coarse facial appearance, described in older patients,10 may be due to the confluence of a prominent jaw and a wide mouth. Its prevalence increases with age in our cohort.…”

“…and most patients are double heterozygous. This hinders the possibility of establishing correlations between phenotype and genotype18–21 41 43 despite some previous reports suggesting milder clinical phenotypes related to some specific mutations 10. However, at the clinical level, there are validated scores to graduate systemic involvement (NPCRS), cerebellar syndrome (ICARS) and cerebellar atrophy (MVRD).…”

Serum transferrin carrying the xeno‐tetrasaccharide NeuAc‐Gal‐GlcNAc2 is a biomarker of ALG1‐CDG

“…The most common glycosylation pathway to be disrupted, asparagine (N)-linked glycosylation, today has over 50 known subtypes (Scott et al 2014) the most common being PMM2-CDG (former CDG-Ia) (Barone et al 2014; Monin et al 2014). The phenotypes of CDG patients vary considerably both between and within a given subtype, but often include neurological involvement (developmental delay/intellectual disability, cerebellar hypoplasia, epilepsy), liver disease, coagulopathy, intestinal disease and hormonal dysregulation (Freeze et al 2015).…”