Sebile KILAVUZ, Fatma Derya BULUT, Deniz KOR, Berna ŞEKER, Atıl BİŞGİN, Fadli DEMİR, Bahriye ATMIŞ, Derya ALABAZ, H. Neslihan ÖNENLİ MUNGAN

Metabolik Bozuklukların Gökkuşağı: Konjenital Glikozilasyon Defekti Tanılı 11 Vakanın Değerlendirilmesi

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

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.

Keywords:

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

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