Phosphomannomutase 2 deficiency: clinical, biochemical and molecular analyses in 22 Czech patients
Authors:
A. Čechová; N. Ondrušková; M. Tesařová; H. Hansíková; J. Zeman; T. Honzík
Authors place of work:
Klinika dětského a dorostového lékařství 1. LF UK a VFN, Praha
Published in the journal:
Čes-slov Pediat 2018; 73 (6): 365-374.
Category:
Summary
Introduction:
PMM2-CDG is the most common autosomal recessive N-glycosylation disorder with more than 900 patients described worldwide. It is caused by a deficiency of the phosphomannomutase 2 enzyme (PMM2) which catalyzes the second step of the mannose pathway, namely the conversion of mannose-6-phosphate to mannose-1-phosphate. The clinical presentation is characterised by encephalopathy, neuropathy, typical dysmorphism, cerebellar atrophy and coagulopathy. We present the results of clinical, biochemical and molecular analyses in patients diagnosed in the Czech Republic.
Results:
Since 2002, a total of 22 Czech patients from 18 families with PMM2 deficiency have been diagnosed. The age range of the patients spans from 9 months to 29 years with a median of 14 years, except two patients who died during infancy. Muscle hypotonia, intellectual disability of varying severity, strabismus, ataxia, bone deformities, and coagulopathy were observed in all patients. Cerebellar atrophy was documented in 94% of the investigated patients. The characteristic dysmorphism (inverted nipples and atypical fat pads) were present in 82% of the patients. Nine patients suffered from seizures, and three patients showed transient neurological deterioration after stroke-like episodes. In all the patients, increased amount of hypoglycosylated transferrin was found by isoelectric focusing. The diagnosis of the PMM2-CDG was confirmed at enzymatic and/or at molecular levels. Molecular analyses revealed that all patients are compound heterozygotes for a total of 10 different mutations in PMM2, and that 71% of our patients´ alleles have one of the two most frequent genetic variants (c.422G>A, c.338C>T).
Conclusion:
The estimated incidence of PMM2-CDG is 1:20,000, suggesting that this disorder is underdiagnosed in the Czech Republic. PMM2-CDG must be considered in differential diagnosis of patients with cerebellar atrophy even if they do not manifest characteristic dysmorphism. We plan to include our patients in a longitudinal international multicenter observational study and potentially the upcoming clinical trial with LipoM1P (lipomised mannose-1-phosphate).
KEY WORDS:
CDG syndrome, phosphomannomutase 2, PMM2-CDG, isoelectric focusing, cerebellar atrophy, coagulopathy
Zdroje
1. Corfield A, Berry M. Current aspects of eukaryotic glycosylation. Trends Biochem Sci 2015; 40: 351–359.
2. Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta (BBA) – General Subjects 1999; 1473 (1): 4–8.
3. Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol 2012; 13 (7): 448–462.
4. Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, et al. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG-deficiency, increased serum arylsulphatase A and increased CSF protein: a new syndrome? Pediatr Res 1980; 14: 179.
5. Ng BG, Freeze HH. Perspectives on glycosylation and its congenital disorders. Trends Genet 2018.
6. Hennet T, Cabalzar J. Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction. Trends Biochem Sci 2015; 40 (7): 377–384.
7. Jaeken J, Van Eijk H, Van der Heul C, et al. Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta 1984; 144 (2–3): 245–247.
8. Wopereis S, Grünewald S, Huijben KM, et al. Transferrin and apolipoprotein C-III isofocusing are complementary in the diagnosis of N- and O-glycan biosynthesis defects. Clin Chem 2007; 53 (2):1 80–187.
9. Lacey JM, Bergen HR, Magera MJ, et al. Rapid determination of transferrin isoforms by immunoaffinity liquid chromatography and electrospray mass spectrometry. Clin Chem 2001; 47 (3): 513–518.
10. Aebi M, Helenius A, Schenk B, et al. Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: An updated nomenclature for CDG. Glycoconj J 1999; 16 (11): 669–671.
11. Jaeken J, Hennet T, Matthijs G, et al. CDG nomenclature: time for a change! Biochim Biophys Acta – Mol Basis of Dis 2009; 1792 (9): 825–826.
12. Thiel C, Körner C. Therapies and therapeutic approaches in congenital disorders of glycosylation. Glycoconj J 2013; 30 (1): 77–84.
13. Grünewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta – Mol Basis of Dis 2009; 1792 (9): 827–834.
14. Hagberg BA, Blennow G, Kristiansson B, et al. Carbohydrate-deficient glycoprotein syndromes: peculiar group of new disorders. Pediatr Neurol 1993; 9 (4): 255–262.
15. de Lonlay P, Seta N, Barrot S, et al. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet 2001; 38 (1): 14–19.
16. van de Kamp JM, Lefeber DJ, Ruijter GJ, et al. Congenital disorder of glycosylation type Ia presenting with hydrops fetalis. J Med Genet 2007; 44 (4): 277–280.
17. Wolthuis D, van Asbeck E, Kozicz T, et al. Abnormal fat distribution in PMM2-CDG. Mol Genet Metab 2013; 110 (3): 411–413.
18. Kjaergaard S, Schwartz M, Skovby F. Congenital disorder of glycosylation type Ia (CDG-Ia): phenotypic spectrum of the R141H/F119L genotype. Arch Dis Child 2001; 85 (3): 236–239.
19. Vuilleumier-Barrot S, Isidor B, Dupré T, et al. Expanding the spectrum of PMM2-CDG phenotype. In: JIMD Reports – Case and Research Reports. Vol. 5, edn.: Springer, 2011: 123–125.
20. Giurgea I, Michel A, Le Merrer M, et al. Underdiagnosis of mild congenital disorders of glycosylation type Ia. Pediatr Neurol 2005; 32 (2): 121–123.
21. Pancho C, Garcia-Cazorla A, Varea V, et al. Congenital disorder of glycosylation type Ia revealed by hypertransaminasemia and failure to thrive in a young boy with normal neurodevelopment. J Pediatr Gastroenterol Nutr 2005; 40 (2): 230–232.
22. Shanti B, Silink M, Bhattacharya K, et al. Congenital disorder of glycosylation type Ia: Heterogeneity in the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency. J Inherit Metab Dis 2009; 32 (1): 241–251.
23. Damen G, de Klerk H, Huijmans J, et al. Gastrointestinal and other clinical manifestations in 17 children with congenital disorders of glycosylation type Ia, Ib, and Ic. J Pediatr Gastroenterol Nutr 2004; 38 (3): 282–287.
24. Schiff M, Roda C, Monin M-L, et al. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature. J Med Genet 2017; 54 (12): 843–851.
25. Antoun H, Villeneuve N, Gelot A, et al. Cerebellar atrophy: an important feature of carbohydrate deficient glycoprotein syndrome type 1. Pediatr Radiol 1999; 29 (3): 194–198.
26. Neumann LM, von Moers A, Kunze J, et al. Congenital disorder of glycosylation type 1a in a macrosomic 16-month-old boy with an atypical phenotype and homozygosity of the N216I mutation. Eur J Pediatr 2003; 162 (10): 710–713.
27. Funke S, Gardeitchik T, Kouwenberg D, et al. Perinatal and early infantile symptoms in congenital disorders of glycosylation. Am J Med Genet Part A 2013; 161 (3): 578–584.
28. 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 2015; 262 (1):154–164.
29. Izquierdo-Serra M, Martinez-Monseny AF, Lopez L, et al. Stroke-like episodes and cerebellar syndrome in phosphomannomutase deficiency (PMM2-CDG): evidence for hypoglycosylation-driven channelopathy. Int J Mol Sci 2018; 19 (2): 619.
30. Monin M-L, Mignot C, De Lonlay P, et al. 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype. Orphanet J Rare Dis 2014; 9 (1): 207.
31. Edwards M, McKenzie F, O‘callaghan S, et al. Prenatal diagnosis of congenital disorder of glycosylation type Ia (CDG–Ia) by cordocentesis and transferrin isoelectric focussing of serum of a 27–week fetus with non–immune hydrops. Prenat Diagn 2006; 26 (10): 985–988.
32. de Diego V, Martínez-Monseny AF, Muchart J, et al. Longitudinal volumetric and 2D assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase deficiency (PMM2-CDG). J Inherit Metab Dis 2017; 40(5):709–713.
33. Hutchesson A, Gray R, Spencer D, et al. Carbohydrate deficient glycoprotein syndrome; multiple abnormalities and diagnostic delay. Arch Dis Child 1995; 72 (5): 445–446.
34. van der Knaap MS, Wevers RA, Monnens L, et al. Congenital nephrotic syndrome: a novel phenotype of type I carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 1996; 19 (6): 787–791.
35. Coman D, McGill J, MacDonald R, et al. Congenital disorder of glycosylation type 1a: three siblings with a mild neurological phenotype. J Clin Neurosci 2007; 14 (7): 668–672.
36. Jamroz E, Adamek D, Paprocka J, et al. CDG type Ia and congenital cytomegalovirus infection: two coexisting conditions. J Child Neurol 2009; 24 (1): 13–18.
37. Silva MG, De Castro J, Stibler H, et al. Prenatal hypertrophic cardiomyopathy and pericardial effusion in carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 1996; 19 (2): 257–259.
38. Marquardt T, Hülskamp G, Gehrmann J, et al. Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia. Eur J Pediatr 2002; 161 (10): 524–527.
39. Aronica E, van Kempen A, Van der Heide M, et al. Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. Acta Neuropathol 2005; 109 (4): 433–442.
40. Schoffer KL, O‘sullivan JD, McGill J. Congenital disorder of glycosylation type Ia presenting as early–onset cerebellar ataxia in an adult. Mov Disord 2006; 21 (6): 869–872.
41. Wurm D, Hänsgen A, Kim Y-J, et al. Early fatal course in siblings with CDG-Ia (caused by two novel mutations in the PMM2 gene): clinical, molecular and autopsy findings. Eur J Pediatr 2007; 166 (4): 377–378.
42. Ong BB, Gole GA, Robertson T, et al. Retinal hemorrhages associated with meningitis in a child with a congenital disorder of glycosylation. Forensic Sci Med Pathol 2009; 5 (4): 307–312.
43. Grünewald S, Schollen E, Van Schaftingen E, et al. High residual activity of PMM2 in patients’ fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). Am J Hum Genet 2001; 68 (2): 347–354.
44. Arnoux J, Boddaert N, Valayannopoulos V, et al. Risk assessment of acute vascular events in congenital disorder of glycosylation type Ia. Mol Genet Metab 2008; 93 (4): 444–449.
45. Perez-Duenas B, García-Cazorla A, Pineda M, et al. Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations. Eur J Paediatr Neurol 2009; 13 (5): 444-451.
46. Enns GM, Steiner RD, Buist N, et al. Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins. J Pediatr 2002; 141 (5): 695–700.
47. Grünewald S, De Vos R, Jaeken J. Abnormal lysosomal inclusions in liver hepatocytes but not in fibroblasts in congenital disorders of glycosylation (CDG). J Inherit Metab Dis 2003; 26 (1): 49–54.
48. de Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res 1995; 37 (4 Pt 1): 395–401.
49. Miller BS, Duffy MM, Addo OY, et al. rhIGF-1 therapy for growth failure and IGF-1 deficiency in congenital disorder of glycosylation Ia (PMM2 deficiency). J Investig Med High Impact Case Rep 2013 Sep 5; 1 (3): 2324709613503316.
50. Jaeken J, Hagberg B, Strømme P. Clinical presentation and natural course of the carbohydrate–deficient glycoprotein syndrome. Acta Pædiatrica 1991; 80: 6–13.
51. Pineda M, Pavia C, Vilaseca M, et al. Normal pubertal development in a female with carbohydrate deficient glycoprotein syndrome. Arch Dis Child 1996; 74 (3): 242.
52. Krasnewich D, O‘Brien K, Sparks S. Clinical features in adults with congenital disorders of glycosylation type Ia (CDG–Ia). Am J Med Genet Part C Semin Med Genet 2007; 145c (3): 302–306.
53. de la Morena-Barrio ME, Hernández-Caselles T, Corral J, et al. GPI-anchor and GPI-anchored protein expression in PMM2-CDG patients. Orphanet J Rare Dis 2013; 8 (1): 170.
54. Linssen M, Mohamed M, Wevers R, et al. Thrombotic complications in patients with PMM2-CDG. Mol Genet Metab 2013; 109 (1): 107–111.
55. Ono H, Sakura N, Yamashita K, et al. Novel nonsense mutation (R194X) in the PMM2 gene in a Japanese patient with congenital disorder of glycosylation type Ia. Brain Dev 2003; 25 (7): 525–528.
56. Le Bizec C, Vuillaumier–Barrot S, Barnier A, et al. A new insight into PMM2 mutations in the French population. Hum Mutat 2005; 25 (5): 504–505.
57. Westphal V, Peterson S, Patterson M, et al. Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia. Genet in Medicine 2001; 3 (6): 393.
58. Schollen E, Keldermans L, Foulquier F, et al. Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. Molec Genet Metab 2007; 90 (4): 408–413.
59. Kjaergaard S, Skovby F, Schwartz M. Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1. Eur J Hum Genet 1998; 6 (4): 331.
60. Matthijs G, Schollen E, Van Schaftingen E, et al. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A. Am J Hum Genet 1998; 62 (3): 542–550.
61. Pirard M, Matthijs G, Heykants L, et al. Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. FEBS Letters 1999; 452 (3): 319–322.
62. Schollen E, Kjaergaard S, Legius E, et al. Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia). Eur J Hum Genet 2000; 8 (5): 367.
Štítky
Neonatology Paediatrics General practitioner for children and adolescentsČlánok vyšiel v časopise
Czech-Slovak Pediatrics
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