title: 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.
authors.affiliation: Pediatric Neurology Policlinico, University of Catania, Via Santa Sofia, 78, 95123, Catania, Italy, rbarone@unict.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Barone
authors.forename: M
authors.initials: M
authors.lastname: Carrozzi
authors.forename: R
authors.initials: R
authors.lastname: Parini
authors.forename: R
authors.initials: R
authors.lastname: Battini
authors.forename: D
authors.initials: D
authors.lastname: Martinelli
authors.forename: M
authors.initials: M
authors.lastname: Elia
authors.forename: M
authors.initials: M
authors.lastname: Spada
authors.forename: F
authors.initials: F
authors.lastname: Lilliu
authors.forename: G
authors.initials: G
authors.lastname: Ciana
authors.forename: A
authors.initials: A
authors.lastname: Burlina
authors.forename: V
authors.initials: V
authors.lastname: Leuzzi
authors.forename: M
authors.initials: M
authors.lastname: Leoni
authors.forename: L
authors.initials: L
authors.lastname: Sturiale
authors.forename: G
authors.initials: G
authors.lastname: Matthijs
authors.forename: J
authors.initials: J
authors.lastname: Jaeken
authors.forename: M
authors.initials: M
authors.lastname: Di Rocco
authors.forename: D
authors.initials: D
authors.lastname: Garozzo
authors.forename: A
authors.initials: A
authors.lastname: Fiumara
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D009849:Olivopontocerebellar Atrophies / Q000209:etiology / Q000473:pathology*; D010641:Phenotype; D017875:Phosphotransferases (Phosphomutases) / Q000235:genetics*; D012720:Severity of Illness Index; D014168:Transferrin / Q000032:analysis; D055815:Young Adult
chemical_list: D014168:Transferrin; D017875:Phosphotransferases (Phosphomutases); C519582:phosphomannomutase 2, human