Neurological Presentation in Pediatric Patients with Congenital Disorders of Glycosylation Type Ia[*]

Abstract

Objective

Congenital disorders of glycosylation (CDG), formerly called carbohydrate-deficient glycoprotein syndromes, constitute a newly identified group of multisystem disorders characterized by defective glycosylation of N-glycosylated proteins. The objective of this work was to describe precisely neurological findings in patients with type Ia CDG (CDG-Ia) and to compare our results with the literature.

Study Design

We retrospectively reviewed neurological and neurodevelopmental, neuroimaging, and genetic features in ten patients with CDG-Ia who mainly presented with neurological abnormalities during childhood and therefore were referred to a neuropediatrician or a neurogeneticist.

Results

Neurological manifestations had a static clinical course, dominated by mental retardation and cerebellar dysfunction, and acute episodes: stroke-like episodes and seizures. However, microcephaly, retinopathy, and polyneuropathy were progressive. All patients had severe global neurodevelopmental delay: only one was able to walk alone at ten years of age and only one could read. Marked heterogeneity in manifestations and delay of diagnosis was noted across the patients. Cerebellar hypoplasia was found by magnetic resonance imaging in all ten patients and olivopontocerebellar hypoplasia in four patients. As in the literature, there was no clear phenotype-mutation correlation.

Conclusion

Our findings confirm the importance of a precise and complete description of the neurological and neuroradiological phenotype delineating the phenotype of CDG-Ia to increase the likelihood of diagnosing the disease.

Congenital disorders of glycosylation Type Ia - mental retardation - ataxia - cerebellar atrophy - olivopontocerebellar atrophy

References

• 1 Aebi M, Hennet T. Congenital disorders of glycosylation: genetic model systems lead the way.  Trends Cell Biol. 2001;  11 136-141
• 2 Akaboshi S, Ohno K, Takeshita K. Neuroradiological findings in the carbohydrate-deficient glycoprotein syndrome.  Neuroradiology. 1995;  37 491-495
• 3 Antoun H, Villeneuve N, Gelot A, Panisset S, Adamsbaum C. Cerebellar atrophy: an important feature of carbohydrate deficient glycoprotein syndrome type 1.  Pediatr Radiol. 1999;  29 194-198
• 4 Barone R, Pavone L, Fiumara A, Bianchini R, Jaeken J. Developmental patterns and neuropsychological assessment in patients with carbohydrate-deficient glycoconjugate syndrome type IA (phosphomannomutase deficiency).  Brain Dev. 1999;  21 260-263
• 5 Blennow G, Jaeken J, Wiklund L. Neurological findings in the carbohydrate-deficient glycoprotein syndrome.  Acta Paediatr Scand. 1991;  14 14-19
• 6 Casteels I, Spileers W, Leys A, Lagae L, Jaeken J. Evolution of ophthalmic and electrophysiological findings in identical twin sisters with the carbohydrate deficient glycoprotein syndrome type 1 over a period of 14 years.  Br J Ophthalmol. 1996;  80 900-902
• 7 De Lonlay P, Seta N, Barrot S, Chabrol B, Drouin V, Gabriel B M. et al . A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases.  J Med Genet. 2001;  38 14-19
• 8 Di Rocco M, Barone R, Adami A, Burlina A, Carrozzi M, Dionisi-Vici C. et al . Carbohydrate-deficient glycoprotein syndromes: the Italian experience.  J Inherit Metab Dis. 2000;  23 391-395
• 9 Drouin-Garraud V, Belgrand M, Grunewald S, Seta N, Dacher J N, Henocq A. et al . Neurological presentation of a congenital disorder of glycosylation CDG-Ia: implications for diagnosis and genetic counseling.  Am J Med Genet. 2001;  101 46-49
• 10 Garel C, Baumann C, Besnard M, Ogier H, Jaeken J, Hassan M. Carbohydrate-deficient glycoprotein syndrome type-I: a new cause of dysostosis multiplex.  Skeletal Radiol. 1998;  27 43-45
• 11 Grünewald S, Imbach T, Huijben K, Rubio-Gozalbo M E, Verrips A, de Klerk J B. et al . Clinical and biochemical characteristics of congenital disorder of glycosylation type Ic, the first recognized endoplasmic reticulum defect in N-glycan synthesis.  Ann Neurol. 2000;  47 776-781
• 12 Grünewald S, Schollen E, Van Schaftingen E, Jaeken J, Matthijs G. High residual activity of PMM2 in patient's fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency).  Am J Hum Genet. 2001;  68 347-354
• 13 Hagberg B A, Blennow G, Kristiansson B, Stibler H. Carbohydrate-deficient glycoprotein syndromes: peculiar group of new disorders.  Pediatr Neurol. 1993;  9 255-262
• 14 Holzbach U, Hanefeld F, Helms G, Hanicke W, Frahm J. Localized proton magnetic resonance spectroscopy of cerebral abnormalities in children with carbohydrate-deficient glycoprotein syndrome.  Acta Paediatr. 1995;  84 781-786
• 15 Horslen S, Clayton P, Harding B, Hall N, Keir G, Winchester B. Olivopontocerebellar atrophy of neonatal onset and disialotransferrin developmental deficiency syndrome.  Arch Dis Child. 1991;  66 1027-1032
• 16 Imbach T, Grünewald S, Schenk B, Burda P, Schollen E, Wevers R A. et al . Multiallelic origin of congenital disorder of glycosylation (CDG)-Ic.  Hum Genet. 2000;  106 538-545
• 17 Imbach T, Schenk B, Schollen E, Burda P, Stutz A, Grünewald S. et al . Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.  J Clin Invest. 2000;  105 233-239
• 18 Jaeken J, Stibler H, Hagberg B. The carbohydrate-deficient glycoprotein syndrome. A new inherited multisystemic disease with severe nervous system involvement.  Acta Paediatr Scand Suppl. 1991;  375 1-71
• 19 Jaeken J, Artigas J, Barone R, Fiumara A, de Koning T J, Poll-The B T. et al . Phosphomannomutase deficiency is the main cause of carbohydrate deficient glycoprotein syndrome with type I isoelectrofocusing pattern of serum sialotransferrins.  J Inherit Metab Dis. 1997;  20 447-449
• 20 Jaeken J, Carchon H. What's new in congenital disorders of glycosylation?.  Europ J Paediatr Neurol. 2000;  4 163-167
• 21 Jensen P R, Hansen F J, Skovby F. Cerebellar hypoplasia in children with the carbohydrate-deficient glycoprotein syndrome.  Neuroradiology. 1995;  37 328-330
• 22 Kim S, Westphal V, Srikrishna G, Mehta D P, Peterson S, Filiano J. et al . Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie).  J Clin Invest. 2000;  105 191-198
• 23 Kjaergaard S, Kristiansson B, Stibler H, Freeze H H, Schwartz M, Martinsson T, Skovby F. Failure of short-term mannose therapy of patients with carbohydrate-deficient glycoprotein syndrome type 1 A.  Acta Paediatr. 1998;  87 884-888
• 24 Korner C, Knauer R, Stephani U, Marquardt T, Lehle L, von Figura K. Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichol-P-Man:Man(5)GlcNAc(2)-PP-dolichol mannosyltransferase.  EMBO J. 1999;  18 6816-6822
• 25 Kranz C, Denecke J, Lehrman M A, Ray S, Kienz P, Kreissel G. et al . A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If).  J Clin Invest. 2001;  108 1613-1619
• 26 Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman J J, Van Schaftingen E. Mutations in PMM2, a phosphomannomutase gene on chromosome 16 p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome).  Nat Genet. 1997;  16 88-92
• 27 Matthijs G, Schollen E, Van Schaftingen E, Cassiman J J, Jaeken J. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1 A.  Am J Hum Genet. 1998;  62 542-550
• 28 Matthijs G, Schollen E, Bjursell C, Erlandson A, Freeze H, Imbiaz F. et al . Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia).  Hum Mutat. 2000;  16 386-394
• 29 Pavone L, Fiumara A, Barone R, Rizzo R, Buttita P, Dobyns W B, Jaeken J. Olivopontocerebellar atrophy leading to recognition of carbohydrate-deficient glycoprotein syndrome type I.  J Neurol. 1996;  700-705
• 30 Pearl P L, Krasnewich D. Neurologic course of congenital disorders of glycosylation.  J Child Neurol. 2001;  16 409-413
• 31 Petersen M B, Brostrom K, Stibler H, Skovby F. Early manifestations of the carbohydrate-deficient glycoprotein syndrome type I.  J Pediatr. 1993;  122 66-70
• 32 Schachter H. The clinical relevance of glycobiology.  J Clin Invest. 2001;  108 1579-1582
• 33 Schenk B, Imbach T, Frank C G, Grubenmann C E, Raymond G V, Hurvitz H. et al . MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If.  J Clin Invest. 2001;  108 1687-1695
• 34 Seta N, Barnier A, Hochedez F, Besnard M A, Durand G. Diagnostic value of Western blotting in carbohydrate-deficient glycoprotein syndrome.  Clinica Chimica Acta. 1996;  254 131-140
• 35 Steinlin M, Blaser S, Boltshauser E. Cerebellar involvement in metabolic disorders: a pattern-recognition approach.  Neuroradiology. 1998;  40 347-354
• 36 Stibler H, Blennow G, Kristiansson B, Lindehammer H, Hagberg B. Carbohydrate-deficient glycoprotein syndrome: clinical expression in adults with a new metabolic disease.  J Neurol Neurosurg Psychiatry. 1994;  57 552-556
• 37 Van Ommen C H, Peters M, Barth P G, Vreken P, Wanders R J, Jaeken J. Carbohydrate-deficient glycoprotein syndrome type 1 a: a variant phenotype with borderline cognitive dysfunction, cerebellar hypoplasia, and coagulation disturbances.  J Pediatr. 2000;  136 400-403
• 38 Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I.  FEBS Lett. 1995;  377 318-320
• 39 Young G, Driscoll C. Coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome: case report and review of the literature.  Am J Hematol. 1999;  60 66-69

1 E. M.C. and Y. M. contributed equally to this paper.