TY - JOUR
T1 - A nationwide survey of PMM2-CDG in Italy
T2 - High frequency of a mild neurological variant associated with the L32R mutation
AU - Barone, Rita
AU - Carrozzi, M.
AU - Parini, R.
AU - Battini, R.
AU - Martinelli, D.
AU - Elia, M.
AU - Spada, M.
AU - Lilliu, F.
AU - Ciana, G.
AU - Burlina, A.
AU - Leuzzi, V.
AU - Leoni, M.
AU - Sturiale, L.
AU - Matthijs, G.
AU - Jaeken, J.
AU - Di Rocco, M.
AU - Garozzo, D.
AU - Fiumara, A.
PY - 2015
Y1 - 2015
N2 - 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 (MALDIMS). 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)pontocerebellar 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.
AB - 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 (MALDIMS). 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)pontocerebellar 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.
KW - CDG
KW - Congenital disorders of glycosylation
KW - Mild neurological variant
KW - Pharmacological chaperones
KW - PMM2 gene mutation
KW - Severe phenotype
KW - Transferrin glycosylation
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U2 - 10.1007/s00415-014-7549-7
DO - 10.1007/s00415-014-7549-7
M3 - Article
C2 - 25355454
AN - SCOPUS:84926685520
VL - 262
SP - 154
EP - 164
JO - Journal of Neurology
JF - Journal of Neurology
SN - 0340-5354
IS - 1
ER -