Advertisement

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

  • Bobby G. Ng
  • Hunter R. Underhill
  • Lars Palm
  • Per Bengtson
  • Jean-Michel Rozet
  • Sylvie Gerber
  • Arnold Munnich
  • Xavier Zanlonghi
  • Cathy A. Stevens
  • Martin Kircher
  • Deborah A. Nickerson
  • Kati J. Buckingham
  • Kevin D. Josephson
  • Jay Shendure
  • Michael J. Bamshad
  • University of Washington Center for Mendelian Genomics
  • Hudson H. Freeze
  • Erik A. EklundEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 44)

Abstract

Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.

Keywords

CDG DPAGT1 Early-onset epilepsy Exome sequencing Glycosylation Intellectual disability 

Abbreviations

CDG

Congenital disorder of glycosylation

CMS

Congenital myasthenic syndrome

DPAGT1

Dolichyl-phosphate GlcNAc phosphotransferase 1

EEG

Electroencephalogram

EOEE

Early-onset epileptic encephalopathy

GlcNAc

N-acetyl glucosamine

IEF

Isoelectric focusing

LC/MS

Liquid chromatography/mass spectrometry

MRI

Magnetic resonance imaging

N-linked

Asparagine linked

PMM2

Phosphomannomutase 2

TF

Transferrin

Notes

Acknowledgments

This work was supported by the National Institutes of Health (R01DK099551) and The Rocket Fund to HHF, Retina France Association to JMR and ALF, Crafoordska stiftelsen, Regionala fonder and SUS stiftelser och donationer to EAE. Sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute grant HG006493 to Drs. Debbie Nickerson, Michael Bamshad, and Suzanne Leal. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

References

  1. Adamowicz M, Chmielinska E, Kaluzny L et al (2011) Clinical and biochemical characterization of the second CDGIJ (DPAGT1-CDG) patient. J Inherit Metab Dis 34:S181CrossRefGoogle Scholar
  2. Barba C, Darra F, Cusmai R, Procopio E, Dionisi Vici C, Keldermans L, Vuillaumier-Barrot S, Lefeber DJ, Guerrini R, CDG Group (2016) Congenital disorders of glycosylation presenting as epileptic encephalopathy with migrating partial seizures in infancy. Dev Med Child Neurol 58:1085–1091CrossRefGoogle Scholar
  3. Carrera IA, Matthijs G, Perez B, Cerda CP (2012) DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype. Am J Med Genet A 158A:2027–2030CrossRefGoogle Scholar
  4. de Zegher F, Jaeken J (1995) Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res 37:395–401CrossRefGoogle Scholar
  5. Eklund EA, Freeze HH (2005) Essentials of glycosylation. Semin Pediatr Neurol 12:134–143CrossRefGoogle Scholar
  6. Fiumara A, Barone R, Del Campo G, Striano P, Jaeken J (2016) Electroclinical features of early-onset epileptic encephalopathies in congenital disorders of glycosylation (CDGs). JIMD Rep 27:93–99CrossRefGoogle Scholar
  7. Freeze HH, Eklund EA, Ng BG, Patterson MC (2012) Neurology of inherited glycosylation disorders. Lancet Neurol 11:453–466CrossRefGoogle Scholar
  8. Freeze HH, Eklund EA, Ng BG, Patterson MC (2015) Neurological aspects of human glycosylation disorders. Annu Rev Neurosci 38:105–125CrossRefGoogle Scholar
  9. Ganetzky R, Izumi K, Edmondson A, Muraresku CC, Zackai E, Deardorff M, Ganesh J (2015) Fetal akinesia deformation sequence due to a congenital disorder of glycosylation. Am J Med Genet A 167A:2411–2417CrossRefGoogle Scholar
  10. Hamici S, Bastaki F, Khalifa M (2017) Exome sequence identified a c.320A > G ALG13 variant in a female with infantile epileptic encephalopathy with normal glycosylation and random X inactivation: review of the literature. Eur J Med Genet 60:541–547CrossRefGoogle Scholar
  11. Helander A, Stodberg T, Jaeken J, Matthijs G, Eriksson M, Eggertsen G (2013) Dolichol kinase deficiency (DOLK-CDG) with a purely neurological presentation caused by a novel mutation. Mol Genet Metab 110:342–344CrossRefGoogle Scholar
  12. Henrissat B, Surolia A, Stanley P (2015) A genomic view of glycobiology. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Darvill AG, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH (eds) Essentials of glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 89–97Google Scholar
  13. Imtiaz F, Al-Mostafa A, Al-Hassnan ZN (2012) Further delineation of the phenotype of congenital disorder of glycosylation DPAGT1-CDG (CDG-Ij) identified by homozygosity mapping. JIMD Rep 2:107–111CrossRefGoogle Scholar
  14. Iqbal Z, Shahzad M, Vissers LE, van Scherpenzeel M, Gilissen C, Razzaq A, Zahoor MY, Khan SN, Kleefstra T, Veltman JA, de Brouwer AP, Lefeber DJ, van Bokhoven H, Riazuddin S (2013) A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype. Eur J Hum Genet 21:844–849CrossRefGoogle Scholar
  15. Izquierdo-Serra M, Martinez-Monseny AF, Lopez L, Carrillo-Garcia J, Edo A, Ortigoza-Escobar JD, Garcia O, Cancho-Candela R, Carrasco-Marina ML, Gutierrez-Solana LG, Cuadras D, Muchart J, Montero R, Artuch R, Perez-Cerda C, Perez B, Perez-Duenas B, Macaya A, Fernandez-Fernandez JM, Serrano M (2018) Stroke-like episodes and cerebellar syndrome in phosphomannomutase deficiency (PMM2-CDG): evidence for hypoglycosylation-driven channelopathy. Int J Mol Sci 19CrossRefGoogle Scholar
  16. Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, Snoeck L, Corbeel L, Eggermont E, Eeckels R (1980) Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG deficiency, increased arylsulphatase A and increased CSF protein: a new syndrome? Pediatr Res 14:179CrossRefGoogle Scholar
  17. Jaeken J, Lefeber D, Matthijs G (2015) Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation. Eur J Hum Genet 23(12). doi:  https://doi.org/10.1038/ejhg.2015.177
  18. Kasem E, Kurihara T, Tabuchi K (2018) Neurexins and neuropsychiatric disorders. Neurosci Res 127:53–60CrossRefGoogle Scholar
  19. Linssen M, Mohamed M, Wevers RA, Lefeber DJ, Morava E (2013) Thrombotic complications in patients with PMM2-CDG. Mol Genet Metab 109:107–111CrossRefGoogle Scholar
  20. Marini C, Hardies K, Pisano T, May P, Weckhuysen S, Cellini E, Suls A, Mei D, Balling R, Jonghe PD, Helbig I, Garozzo D, EuroEPINOMICS Consortium AR Working Group, Guerrini R (2017) Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects. Am J Med Genet A 173:1119–1123CrossRefGoogle Scholar
  21. Miller BS, Freeze HH (2003) New disorders in carbohydrate metabolism: congenital disorders of glycosylation and their impact on the endocrine system. Rev Endocr Metab Disord 4:103–113CrossRefGoogle Scholar
  22. Ng BG, Buckingham KJ, Raymond K, Kircher M, Turner EH, He M, Smith JD, Eroshkin A, Szybowska M, Losfeld ME, Chong JX, Kozenko M, Li C, Patterson MC, Gilbert RD, Nickerson DA, Shendure J, Bamshad MJ, University of Washington Center for Mendelian Genomics, Freeze HH (2013) Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am J Hum Genet 92:632–636CrossRefGoogle Scholar
  23. Ng BG, Shiryaev SA, Rymen D, Eklund EA, Raymond K, Kircher M, Abdenur JE, Alehan F, Midro AT, Bamshad MJ, Barone R, Berry GT, Brumbaugh JE, Buckingham KJ, Clarkson K, Cole FS, O'Connor S, Cooper GM, Van Coster R, Demmer LA, Diogo L, Fay AJ, Ficicioglu C, Fiumara A, Gahl WA, Ganetzky R, Goel H, Harshman LA, He M, Jaeken J, James PM, Katz D, Keldermans L, Kibaek M, Kornberg AJ, Lachlan K, Lam C, Yaplito-Lee J, Nickerson DA, Peters HL, Race V, Regal L, Rush JS, Rutledge SL, Shendure J, Souche E, Sparks SE, Trapane P, Sanchez-Valle A, Vilain E, Vollo A, Waechter CJ, Wang RY, Wolfe LA, Wong DA, Wood T, Yang AC, University of Washington Center for Mendelian Genomics, Matthijs G, Freeze HH (2016) ALG1-CDG: clinical and molecular characterization of 39 unreported patients. Hum Mutat 37:653–660CrossRefGoogle Scholar
  24. Perez-Palma E, Helbig I, Klein KM, Anttila V, Horn H, Reinthaler EM, Gormley P, Ganna A, Byrnes A, Pernhorst K, Toliat MR, Saarentaus E, Howrigan DP, Hoffman P, Miquel JF, De Ferrari GV, Nurnberg P, Lerche H, Zimprich F, Neubauer BA, Becker AJ, Rosenow F, Perucca E, Zara F, Weber YG, Lal D (2017) Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies. J Med Genet 54:598–606CrossRefGoogle Scholar
  25. Prestegard JH, Liu J, Widmalm G (2015) Oligosaccharides and polysaccharides. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Darvill AG, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH (eds) Essentials of glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 31–40Google Scholar
  26. Schorling DC, Rost S, Lefeber DJ, Brady L, Muller CR, Korinthenberg R, Tarnopolsky M, Bonnemann CG, Rodenburg RJ, Bugiani M, Beytia M, Kruger M, van der Knaap M, Kirschner J (2017) Early and lethal neurodegeneration with myasthenic and myopathic features: a new ALG14-CDG. Neurology 89:657–664CrossRefGoogle Scholar
  27. Seeberger PH (2015) Monosaccharide diversity. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Darvill AG, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH (eds) Essentials of glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 19–30Google Scholar
  28. Simon MT, Ng BG, Friederich MW, Wang RY, Boyer M, Kircher M, Collard R, Buckingham KJ, Chang R, Shendure J, Nickerson DA, Bamshad MJ, University of Washington Center for Mendelian Genomics, Van Hove JLK, Freeze HH, Abdenur JE (2017) Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency. Mitochondrion 34:84–90CrossRefGoogle Scholar
  29. Stanley P, Taniguchi N, Aebi M (2015) N-glycans. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Darvill AG, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH (eds) Essentials of glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 99–111Google Scholar
  30. Timal S, Hoischen A, Lehle L, Adamowicz M, Huijben K, Sykut-Cegielska J, Paprocka J, Jamroz E, van Spronsen FJ, Korner C, Gilissen C, Rodenburg RJ, Eidhof I, Van den Heuvel L, Thiel C, Wevers RA, Morava E, Veltman J, Lefeber DJ (2012) Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum Mol Genet 21:4151–4161CrossRefGoogle Scholar
  31. UniProt Consortium (2015) UniProt: a hub for protein information. Nucleic Acids Res 43:D204–D212CrossRefGoogle Scholar
  32. Vuillaumier-Barrot S (2005) Molecular diagnosis of congenital disorders of glycosylation. Ann Biol Clin (Paris) 63:135–143Google Scholar
  33. Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, Gilmore R, Freeze HH (2003) Deficiency of UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1 Phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij. Hum Mutat 22:144–150CrossRefGoogle Scholar
  34. Wurde AE, Reunert J, Rust S, Hertzberg C, Haverkamper S, Nurnberg G, Nurnberg P, Lehle L, Rossi R, Marquardt T (2012) Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG): extending the clinical and molecular spectrum of a rare disease. Mol Genet Metab 105:634–641CrossRefGoogle Scholar
  35. Yuste-Checa P, Vega AI, Martin-Higueras C, Medrano C, Gamez A, Desviat LR, Ugarte M, Perez-Cerda C, Perez B (2017) DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress. PLoS One 12:e0179456CrossRefGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Bobby G. Ng
    • 1
  • Hunter R. Underhill
    • 2
  • Lars Palm
    • 3
  • Per Bengtson
    • 4
  • Jean-Michel Rozet
    • 5
  • Sylvie Gerber
    • 5
  • Arnold Munnich
    • 6
  • Xavier Zanlonghi
    • 7
  • Cathy A. Stevens
    • 8
  • Martin Kircher
    • 9
  • Deborah A. Nickerson
    • 9
  • Kati J. Buckingham
    • 10
  • Kevin D. Josephson
    • 11
  • Jay Shendure
    • 9
    • 12
  • Michael J. Bamshad
    • 9
    • 10
  • University of Washington Center for Mendelian Genomics
  • Hudson H. Freeze
    • 1
  • Erik A. Eklund
    • 1
    • 13
    Email author
  1. 1.Sanford Burnham Prebys Medical Discovery InstituteLa JollaUSA
  2. 2.Division of Medical GeneticsUniversity of UtahSalt Lake CityUSA
  3. 3.Division of PediatricsSkane University HospitalMalmöSweden
  4. 4.Clinical ChemistrySkane University HospitalLundSweden
  5. 5.Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic DiseasesImagine and Paris Descartes UniversityParisFrance
  6. 6.Department of Genetics, Hôpital Necker-Enfants Malades, APHPParis Descartes UniversityParisFrance
  7. 7.Clinique Jules VernesNantesFrance
  8. 8.Department of PediatricsUniversity of Tennessee College of MedicineChattanoogaUSA
  9. 9.Department of Genome SciencesUniversity of WashingtonSeattleUSA
  10. 10.Department of PediatricsUniversity of WashingtonSeattleUSA
  11. 11.Gundersen Health SystemLaCrosseUSA
  12. 12.Howard Hughes Medical InstituteUniversity of WashingtonSeattleUSA
  13. 13.Division of PediatricsLund UniversityLundSweden

Personalised recommendations