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

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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.

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Acknowledgments

The Authors thank the families of the patients for their collaboration, Dr. G. Belfiore (University Hospital Policlinico Catania) for helping with selection MRI figures and Mrs. L. Keldermans (Centre for Human Genetics, Leuven) for her contribution to PMM2 molecular analyses. RB and AF (University of Catania) thank Association “Baco di Rame” for the support to the Centre for Metabolic Diseases Policlinico Catania. The Association “La vita e’ un dono” is acknowledged for supporting the fellowship of DM (OPBG-Rome). RP acknowledges Fondazione Pierfranco e Luisa Mariani, Milano, for the support to the Centre for Metabolic Disorders at Fondazione MBBM, San Gerardo Hospital, Monza. This study was partially financed by the Sixth Framework program of the European Union (Euroglycanet: LSHM-CT-2005-512131).

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standard

The study was conducted according to the disposals of the local research ethics board.

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Authors and Affiliations

  1. Pediatric Neurology Policlinico, University of Catania, Via Santa Sofia, 78, 95123, Catania, Italy

    Rita Barone & A. Fiumara

  2. Institute for Maternal and Child Health, IRCCS Burlo Garofolo Trieste, Trieste, Italy

    M. Carrozzi

  3. Center for Metabolic Diseases MBBM Foundation, San Gerardo Hospital, Monza, Italy

    R. Parini

  4. Department of Developmental Neuroscience, IRCCS Stella Maris, Calambrone Pisa, Italy

    R. Battini

  5. Unit of Metabolism, Department of Pediatrics, Bambino Gesu Children’s Hospital Rome, Rome, Italy

    D. Martinelli

  6. IRCCS Oasi Maria SS, Troina, Italy

    M. Elia

  7. Department of Pediatrics, University of Turin, Turin, Italy

    M. Spada

  8. Pediatric Clinic, University of Cagliari, Cagliari, Italy

    F. Lilliu

  9. Centre for Rare Diseases, University Hospital Udine, Udine, Italy

    G. Ciana

  10. Department of Pediatrics, University of Padua, Padua, Italy

    A. Burlina

  11. Pediatric Neurology, University “La Sapienza” Rome, Rome, Italy

    V. Leuzzi

  12. Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute Genoa, Genoa, Italy

    M. Leoni & M. Di Rocco

  13. Institute for Polymers, Composites and Biomaterials IPCB, CNR Catania, Catania, Italy

    L. Sturiale & D. Garozzo

  14. Centre for Human Genetics, KU Leuven, Leuven, Belgium

    G. Matthijs

  15. Centre for Metabolic Diseases, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium

    J. Jaeken

Authors
  1. Rita Barone
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  2. M. Carrozzi
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  3. R. Parini
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  4. R. Battini
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  5. D. Martinelli
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  6. M. Elia
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  7. M. Spada
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  8. F. Lilliu
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  9. G. Ciana
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  11. V. Leuzzi
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  12. M. Leoni
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  13. L. Sturiale
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  14. G. Matthijs
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  15. J. Jaeken
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  16. M. Di Rocco
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  17. D. Garozzo
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Correspondence to Rita Barone.

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Barone, R., Carrozzi, M., Parini, R. et al. A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. J Neurol 262, 154–164 (2015). https://doi.org/10.1007/s00415-014-7549-7

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  • DOI: https://doi.org/10.1007/s00415-014-7549-7

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