A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism

Eva Morava-Kozicz, Ron A. Wevers, Vincent Cantagrel, Lies H. Hoefsloot, Lihadh Al-Gazali, Jeroen Schoots, Arno Van Rooij, Karin Huijben, Connie M.A. Van Ravenswaaij-Arts, Marjolein C.J. Jongmans, Jolanta Sykut-Cegielska, Georg F. Hoffmann, Peter Bluemel, MacIej Adamowicz, Jeroen Van Reeuwijk, Bobby G. Ng, Jorieke E.H. Bergman, Hans Van Bokhoven, Christian Körner, Dusica Babovic-VuksanovicMichel A. Willemsen, Joseph G. Gleeson, Ludwig Lehle, Arjan P.M. De Brouwer, Dirk J. Lefeber

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.

Original languageEnglish (US)
Pages (from-to)3210-3220
Number of pages11
JournalBrain
Volume133
Issue number11
DOIs
StatePublished - Nov 1 2010

Fingerprint

Dolichol
Glycosylation
Congenital Disorders of Glycosylation
Cerebellar Ataxia
Phenotype
Endoplasmic Reticulum
Oxidoreductases
Steroids
Coloboma
Vision Disorders
Dermatitis
Optic Nerve
Glaucoma
Cataract
Cerebellum
Polysaccharides
Liver Diseases
Anemia
Molecular Biology
Fetus

Keywords

  • cataract
  • CDG type Iq
  • coloboma
  • congenital disorders of glycosylation
  • dolichol metabolism
  • glaucoma
  • glycosylation
  • polyprenol reductase
  • SRD5A3
  • SRD5A3-CDG
  • vermis hypoplasia

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Morava-Kozicz, E., Wevers, R. A., Cantagrel, V., Hoefsloot, L. H., Al-Gazali, L., Schoots, J., ... Lefeber, D. J. (2010). A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain, 133(11), 3210-3220. https://doi.org/10.1093/brain/awq261

A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. / Morava-Kozicz, Eva; Wevers, Ron A.; Cantagrel, Vincent; Hoefsloot, Lies H.; Al-Gazali, Lihadh; Schoots, Jeroen; Van Rooij, Arno; Huijben, Karin; Van Ravenswaaij-Arts, Connie M.A.; Jongmans, Marjolein C.J.; Sykut-Cegielska, Jolanta; Hoffmann, Georg F.; Bluemel, Peter; Adamowicz, MacIej; Van Reeuwijk, Jeroen; Ng, Bobby G.; Bergman, Jorieke E.H.; Van Bokhoven, Hans; Körner, Christian; Babovic-Vuksanovic, Dusica; Willemsen, Michel A.; Gleeson, Joseph G.; Lehle, Ludwig; De Brouwer, Arjan P.M.; Lefeber, Dirk J.

In: Brain, Vol. 133, No. 11, 01.11.2010, p. 3210-3220.

Research output: Contribution to journalArticle

Morava-Kozicz, E, Wevers, RA, Cantagrel, V, Hoefsloot, LH, Al-Gazali, L, Schoots, J, Van Rooij, A, Huijben, K, Van Ravenswaaij-Arts, CMA, Jongmans, MCJ, Sykut-Cegielska, J, Hoffmann, GF, Bluemel, P, Adamowicz, M, Van Reeuwijk, J, Ng, BG, Bergman, JEH, Van Bokhoven, H, Körner, C, Babovic-Vuksanovic, D, Willemsen, MA, Gleeson, JG, Lehle, L, De Brouwer, APM & Lefeber, DJ 2010, 'A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism', Brain, vol. 133, no. 11, pp. 3210-3220. https://doi.org/10.1093/brain/awq261
Morava-Kozicz, Eva ; Wevers, Ron A. ; Cantagrel, Vincent ; Hoefsloot, Lies H. ; Al-Gazali, Lihadh ; Schoots, Jeroen ; Van Rooij, Arno ; Huijben, Karin ; Van Ravenswaaij-Arts, Connie M.A. ; Jongmans, Marjolein C.J. ; Sykut-Cegielska, Jolanta ; Hoffmann, Georg F. ; Bluemel, Peter ; Adamowicz, MacIej ; Van Reeuwijk, Jeroen ; Ng, Bobby G. ; Bergman, Jorieke E.H. ; Van Bokhoven, Hans ; Körner, Christian ; Babovic-Vuksanovic, Dusica ; Willemsen, Michel A. ; Gleeson, Joseph G. ; Lehle, Ludwig ; De Brouwer, Arjan P.M. ; Lefeber, Dirk J. / A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. In: Brain. 2010 ; Vol. 133, No. 11. pp. 3210-3220.
@article{b31a7bda544d4baebfc63887629682ca,
title = "A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism",
abstract = "Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.",
keywords = "cataract, CDG type Iq, coloboma, congenital disorders of glycosylation, dolichol metabolism, glaucoma, glycosylation, polyprenol reductase, SRD5A3, SRD5A3-CDG, vermis hypoplasia",
author = "Eva Morava-Kozicz and Wevers, {Ron A.} and Vincent Cantagrel and Hoefsloot, {Lies H.} and Lihadh Al-Gazali and Jeroen Schoots and {Van Rooij}, Arno and Karin Huijben and {Van Ravenswaaij-Arts}, {Connie M.A.} and Jongmans, {Marjolein C.J.} and Jolanta Sykut-Cegielska and Hoffmann, {Georg F.} and Peter Bluemel and MacIej Adamowicz and {Van Reeuwijk}, Jeroen and Ng, {Bobby G.} and Bergman, {Jorieke E.H.} and {Van Bokhoven}, Hans and Christian K{\"o}rner and Dusica Babovic-Vuksanovic and Willemsen, {Michel A.} and Gleeson, {Joseph G.} and Ludwig Lehle and {De Brouwer}, {Arjan P.M.} and Lefeber, {Dirk J.}",
year = "2010",
month = "11",
day = "1",
doi = "10.1093/brain/awq261",
language = "English (US)",
volume = "133",
pages = "3210--3220",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism

AU - Morava-Kozicz, Eva

AU - Wevers, Ron A.

AU - Cantagrel, Vincent

AU - Hoefsloot, Lies H.

AU - Al-Gazali, Lihadh

AU - Schoots, Jeroen

AU - Van Rooij, Arno

AU - Huijben, Karin

AU - Van Ravenswaaij-Arts, Connie M.A.

AU - Jongmans, Marjolein C.J.

AU - Sykut-Cegielska, Jolanta

AU - Hoffmann, Georg F.

AU - Bluemel, Peter

AU - Adamowicz, MacIej

AU - Van Reeuwijk, Jeroen

AU - Ng, Bobby G.

AU - Bergman, Jorieke E.H.

AU - Van Bokhoven, Hans

AU - Körner, Christian

AU - Babovic-Vuksanovic, Dusica

AU - Willemsen, Michel A.

AU - Gleeson, Joseph G.

AU - Lehle, Ludwig

AU - De Brouwer, Arjan P.M.

AU - Lefeber, Dirk J.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.

AB - Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.

KW - cataract

KW - CDG type Iq

KW - coloboma

KW - congenital disorders of glycosylation

KW - dolichol metabolism

KW - glaucoma

KW - glycosylation

KW - polyprenol reductase

KW - SRD5A3

KW - SRD5A3-CDG

KW - vermis hypoplasia

UR - http://www.scopus.com/inward/record.url?scp=78049471683&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78049471683&partnerID=8YFLogxK

U2 - 10.1093/brain/awq261

DO - 10.1093/brain/awq261

M3 - Article

C2 - 20852264

AN - SCOPUS:78049471683

VL - 133

SP - 3210

EP - 3220

JO - Brain

JF - Brain

SN - 0006-8950

IS - 11

ER -