Metabolik Bozuklukların Gökkuşağı: Konjenital Glikozilasyon Defekti Tanılı 11 Vakanın Değerlendirilmesi

Yıl 2023, Cilt: 23 Sayı: 3, 233 - 242, 24.10.2023

Sebile Kılavuz , Fatma Derya Bulut , Deniz Kor , Berna Şeker , Atıl Bişgin , Fadli Demir , Bahriye Atmış , Derya Alabaz , H. Neslihan Önenli Mungan

https://doi.org/10.26650/jchild.2023.1345981

Öz

Giriş: Konjenital glikozilasyon kusurları (CDG), immün, merkezi sinir, endokrin ve kas-iskelet sistemlerini içeren multi sistemik belirtilerle ortaya çıkar. Bugüne kadar toplamda 137 farklı CDG türü tespit edilmiştir.
Materyal ve Metod: Çukurova Üniversitesi Çocuk Metabolizma ve Beslenme Bilim Dalı’nda 2013 ve 2019 yılları arasında takip edilen ve CDG tanısı alan hastalar çalışmaya dahil edildi. Hastaların kayıtları geriye dönük olarak incelendi ve demografik klinik, laboratıvar ve radyolojik bulguları kayıt edilerek değerlendirildi.
Bulgular: Toplam 11 hastanın (Dört PMM2-CDG, bir MPI-CDG, bir DOLKCDG, bir B4GALT1-CDG, üç TMEM165-CDG ve bir PIGN-CDG) tanı anındaki ortalama yaşları 6.94 yıl (11 ay ile 22 yıl arası) idi. Hastaların %45’i (5 kişi) erkekti. Hastaların %63’ünde ağırlık ve boy, 5. persentilin altında bulunmaktaydı. %82’sinde yüksek karaciğer enzimleri, %82’sinde nörogelişimsel gecikme, %72’sinde serebellar atrofi ve %72’sinde büyüme geriliği gözlendi. Ek olarak, hastaların %73’ünde hepatomegali ve trombositopeni, %63’ünde ise böbrek tutulumu tespit edildi. PMM2 genindeki homozigot p.V129M (c.385G>A) mutasyonu, 4 hastada PMM2-CDG tanısını doğruladı. Ayrıca, MPI geninde p. I399T (c.1193T>C) homozigot mutasyonu, DOLK geninde p. Y441S (c.1322A>C) homozigot mutasyonu, TMEM165 geninde p. Arg126Cys (c.376C>T) homozigot mutasyonu, B4GALT1 geninde novel bir p.Tyr239* (c.717T>G) mutasyonu ve PIGN geninde novel bir p. Thr266Ala (c.2356A>G) mutasyonu tespit edildi.
Sonuç: Konjenital glikozilasyon defektleri çeşitli klinik spektruma sahip olup, onları “genetik metabolik bozuklukların gökkuşağı” olarak adlandırmamıza sebep olmaktadır. Çalışmamızda PMM2-CDG en yaygın görülen tip iken, diğer tiplerden sadece birkaç örnek bulunmaktadır. Konjenital glikozilasyon defektlerinin ana özellikleri arasında ters meme uçları ve anormal yağ yastıkçıkları yer almaktadır. Vakaların karmaşıklığı ve DOLK-CDG, PIGNCDG ve TMEM-165-CDG tanılarının nadirliği, bu araştırmanın dikkat çeken yönlerini oluşturmaktadır.

Anahtar Kelimeler

glikozilasyon, konjenital glikozilasyon kusurları, PMM2, MPI, DOLK, TMEM-165, PIGN, CDG

Evaluation of Patients Diagnosed with Congenital Glycosylation Defects: A Rainbow of Inherited Metabolic Disorders

Öz

Introduction: Congenital glycosylation defects (CDGs) manifest with multisystemic symptoms involving the immune, central nervous, endocrine, and musculoskeletal systems. A total of 137 distinct CDG types have been identified to date.
Materials and Methods: Patients diagnosed with CDG in the Division of Pediatric Metabolism and Nutrition, at Çukurova University, between 2013 and 2019 were included in the study. The patients’ files were retrospectively reviewed, and demographic, clinical, laboratory and radiological findings and molecular analyses were recorded and evaluated.
Results: The mean age at diagnosis for a total of 11 (6 Female; 5 Male) patients (Four with PMM2-CDG, one with MPI-CDG, one with DOLK-CDG, one with B4GALT1-CDG, three with TMEM165-CDG, and one with PIGNCDG) was 6.94 years (ranging from 11 months to 22 years). Amongst the patients, 45% (5 individuals) were male. Sixty-three percent of patients exhibited low weight and height (below the 5th percentile). Elevated liver enzymes were observed in 82% of cases, while 82% showed neurodevelopmental delay, 72% had cerebellar atrophy, and 72% experienced growth retardation. Additionally, 73% of patients displayed hepatomegaly and thrombocytopenia, and 63% had renal involvement. An homozygous p.V129M (c.385G>A) mutation in the PMM2 gene confirmed PMM2-CDG diagnosis in four patients. Furthermore, distinct homozygous mutations were detected: p. I399T (c.1193T>C) in the MPI gene, p. Y441S (c.1322A>C) in the DOLK gene, p. Arg126Cys (c.376C>T) in the TMEM165 gene, a novel p. Tyr239* (c.717T>G) mutation in the B4GALT1 gene, and a novel p. Thr266Ala (c.2356A>G) mutation in the PIGN gene.
Conclusion: CDGs exhibit a diverse clinical spectrum, earning them the moniker “the rainbow” of hereditary metabolic disorders. While PMM2- CDG is the most prevalent subtype, only a few instances of other subtypes have been documented. Inverted nipples and abnormal fat pads are primary features of CDGs. The intricate nature of our cases and the rarity of DOLK-CDG, PIGN-CDG, and TMEM-165-CDG diagnoses stand out as notable aspects of this report.

Anahtar Kelimeler

glycosylation, congenital glycosylation defects, PMM2, MPI, DOLK, TMEM-165, PIGN, CD

Kaynakça

• 1. Jaeken J. Congenital disorders of glycosylation. Handb Clin Neurol 2013;113:1737-43. google scholar
• 2. Ondruskova N, Cechova A, Hansikova H, Honzik T, Jaeken J. Congenital disorders of glycosylation: Still “hot” in 2020. Biochim Biophys Acta Gen Subj 2021;1865(1):129751. google scholar
• 3. Jaeken J, van Eijk HG, van der Heul C, Corbeel L, Eeckels R, Eggermont E. Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognised genetic syndrome. Clin Chim Acta 1984;144(2-3):245-7. google scholar
• 4. Wopereis S, Grunewald S, Morava E, Penzien JM, Briones P, Garcia-Silva MT, et al. Apolipoprotein C-III isofocusing in the diagnosis of genetic defects in O-glycan biosynthesis. Clin Chem 2003;49(11):1839-45. google scholar
• 5. Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta 2009;1792(9):825-6. google scholar
• 6. Makhamreh MM, Cottingham N, Ferreira CR, Berger S, Al-Kouatly HB. Non-immune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review. J Inherit Metab Dis 2020;43(2):223-33. google scholar
• 7. Paprocka J, Jezela-Stanek A, Tylki-Szymanska A, Grunewald S. Congenital Disorders of Glycosylation from a Neurological Perspective. Brain Sci 2021;11(1). google scholar
• 8. Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurological aspects of human glycosylation disorders. Annu Rev Neurosci 2015;38:105-25. google scholar
• 9. Lam C, Krasnewich DM. Pmm2-Cdg. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993. google scholar
• 10. Yildiz Y, Arslan M, Celik G, Kasapkara CS, Ceylaner S, Dursun A, et al. Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe. Am J Med Genet A 2020;182(4):705-12. google scholar
• 11. Schiff M, Roda C, Monin ML, Arion A, Barth M, Bednarek N, 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):843-51. google scholar
• 12. Barone R, Carrozzi M, Parini R, Battini R, Martinelli D, Elia M, 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):154-64. google scholar
• 13. 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):236-9. google scholar
• 14. Kasapkara CS, Baris Z, Kilic M, Yuksel D, Keldermans L, Matthijs G, Jaeken J. PMM2-CDG and sensorineural hearing loss. J Inherit Metab Dis 2017;40(5):629-30. google scholar
• 15. Cechova A, Altassan R, Borgel D, Bruneel A, Correia J, Girard M, et al. Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation. J Inherit Metab Dis 2020;43(4):671-93. google scholar
• 16. Pelletier VA, Galeano N, Brochu P, Morin CL, Weber AM, Roy CC. Secretory diarrhea with protein-losing enteropathy, enterocolitis cystica superficialis, intestinal lymphangiectasia, and congenital hepatic fibrosis: a new syndrome. J Pediatr 1986;108(1):61-5. google scholar
• 17. Hertz-Pannier L, Dechaux M, Sinico M, Emond S, Cormier-Daire V, Saudubray JM, et al. Congenital disorders of glycosylation type I: a rare but new cause of hyperechoic kidneys in infants and children due to early microcystic changes. Pediatr Radiol 2006;36(2):108-14. google scholar
• 18. Buczkowska A, Swiezewska E, Lefeber DJ. Genetic defects in dolichol metabolism. J Inherit Metab Dis 2015;38(1):157-69. google scholar
• 19. Lieu MT, Ng BG, Rush JS, Wood T, Basehore MJ, Hegde M, et al. Severe, fatal multisystem manifestations in a patient with dolichol kinase-congenital disorder of glycosylation. Mol Genet Metab 2013;110(4):484-9. google scholar
• 20. Kranz C, Sun L, Eklund EA, Krasnewich D, Casey JR, Freeze HH. CDG-Id in two siblings with partially different phenotypes. Am J Med Genet A 2007;143A(13):1414-20. google scholar
• 21. Kranz C, Jungeblut C, Denecke J, Erlekotte A, Sohlbach C, Debus google scholar
• V, et al. A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy. Am J Hum Genet 2007;80(3):433-40. google scholar
• 22. Kapusta L, Zucker N, Frenckel G, Medalion B, Ben Gal T, Birk E, et al. From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG). Heart Fail Rev 2013;18(2):187-96. google scholar
• 23. Barone R, Fiumara A, Jaeken J. Congenital disorders of glycosylation with emphasis on cerebellar involvement. Semin Neurol 2014;34(3):357-66. google scholar
• 24. Hansske B, Thiel C, Lubke T, Hasilik M, Honing S, Peters V, et al. Deficiency of UDP-galactose:N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId. J Clin Invest 2002;109(6):725-33. google scholar
• 25. Peters V, Penzien JM, Reiter G, Korner C, Hackler R, Assmann B, et al. Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy. Neuropediatrics 2002;33(1):27-32. google scholar
• 26. Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh TC, et al. Characterisation of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis. Genome Med 2018;10(1):3. google scholar
• 27. Maydan G, Noyman I, Har-Zahav A, Neriah ZB, Pasmanik-Chor M, Yeheskel A, et al. Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J Med Genet 2011;48(6):383-9. google scholar
• 28. Fleming L, Lemmon M, Beck N, Johnson M, Mu W, Murdock D, et al. Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy. Am J Med Genet A 2016;170A(1):77-86. google scholar
• 29. Zeevaert R, de Zegher F, Sturiale L, Garozzo D, Smet M, Moens M, et al. Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165. JIMD Rep 2013;8:145-52. google scholar
• 30. Foulquier F, Amyere M, Jaeken J, Zeevaert R, Schollen E, Race V, et al. TMEM165 deficiency causes a congenital disorder of glycosylation. Am J Hum Genet 2012;91(1):15-26. google scholar