GM2 gangliosidoses: evaluation of clinical, biochemical and genetic findings of patients with three novel mutations

Yıl 2021, Cilt: 46 Sayı: 3, 1201 - 1207, 30.09.2021

Berrak Bilginer Gürbüz , Fatma Derya Bulut , Habibe Koç Uçar , Esra Sarıgeçili , Bilge Sarıkepe Özge Özalp Yüreğir

https://doi.org/10.17826/cumj.945717

Öz

Purpose: The aim of this study is to evaluate the diagnosis characteristics, clinic findings, phenotypical and genotypical features of children with GM2 gangliosidoses.
Materials and Methods: The file records of 14 patients diagnosed with GM2 gangliosidoses in our clinic were retrospectively reviewed. The GM2 gangliosidoses diagnosis was confirmed by determining the levels of serum total hexosaminidase and β-hexosaminidase activity with genetic analysis.
Results: We identified a total of seven different mutations, three of which were novel (one in the HEXA gene and two in the HEXB gene) in 14 patients. We found a high frequency of c.1100_1111del (p.Gly367_Tyr370del) mutation in HEXA affected patients. The mean age at diagnosis was 13.46.3 months and 14.24.2 months for patients with Tay–Sachs disease (TSD) and Sandhoff disease (SD) respectively. Neuroregression was present in 92.9% of our patients. Of the 14 patients, 11 had epilepsy, 10 had developmental delay, 6 had hyperacusis, 6 had cherry-red spots and 6 had macrocephaly, but none of the patients had organomegaly.
Conclusion: GM2 gangliosidoses disease should be considered for children with developmental regression and/or delay. For early diagnosis, enzyme analysis and gene detection should be performed in children with suspected GM2 gangliosidoses in the presence of clinical findings.

Anahtar Kelimeler

Lysosomal storage disorders, GM2 gangliosidoses, hexosaminidase, Tay-Sachs disease, Sandhoff disease

GM2 gangliosidozis: üç yeni mutasyonlu hastaların klinik, biyokimyasal ve genetik bulgularının değerlendirilmesi

Öz

Amaç: Bu çalışmanın amacı, GM2 gangliosidozlu çocukların tanı özelliklerini, klinik bulgularını, fenotipik ve genotipik özelliklerini değerlendirmektir.
Gereç ve Yöntem: Kliniğimizde GM2 gangliosidoz tanısı alan 14 hastanın dosya kayıtları retrospektif olarak incelendi. GM2 gangliosidoz tanısı; serum total heksosaminidaz ile β-heksosaminidaz aktivitesi düzeyleri ve genetik analiz ile doğrulandı.
Bulgular: On dört hastada üçü novel (biri HEXA geninde ve ikisi HEXB geninde) olmak üzere toplam yedi farklı mutasyon saptandı. HEXA mutasyonu olan hastalarda c.1100_1111del (p.Gly367_Tyr370del) mutasyonu yüksek sıklıkta bulundu. Tay-Sachs (TSD) ve Sandhoff (SD) tanılı hastaların ortalama tanı yaşı sırasıyla 13,4±6,3 ay ve 14,2±4,2 aydı. Hastaların %92.9'unda nöroregresyon mevcuttu. On dört hastanın 11'inde epilepsi, 10'unda gelişim geriliği, 6'sında hiperakuzi, 6'sında cherry-red spot ve 6'sında makrosefali saptanırken, hiçbir hastada organomegali görülmedi.
Sonuç: Gelişim geriliği ve/veya gecikmesi olan çocuklarda GM2 gangliosidoz hastalığı akla gelmelidir. GM2 gangliosidoz şüphesi olan çocuklarda klinik bulgular varlığında erken tanı için enzim analizi ve gen tespiti yapılmalıdır.

Anahtar Kelimeler

Lizozomal depo hastalıkları, GM2 gangliosidoz, hekzosaminidaz, Tay-Sachs hastalığı; Sandhoff hastalığı

Kaynakça

• 1. Leal AF, Benincore-Florez E, Solano-Galarza D, et al. GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies. Int J Mol Sci 2020;21(17). DOI: 10.3390/ijms21176213.
• 2. Gort L, de Olano N, Macias-Vidal J, Coll MA, Spanish GMWG. GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients. Gene 2012;506(1):25-30. DOI: 10.1016/j.gene.2012.06.080.
• 3. Cachon-Gonzalez MB, Zaccariotto E, Cox TM. Genetics and Therapies for GM2 Gangliosidosis. Curr Gene Ther 2018;18(2):68-89. DOI: 10.2174/1566523218666180404162622.
• 4. Er E CE, Yazıcı H, Eraslan C, Sözmen E, Kalkan Uçar S, Çoker M. An Evalution of the Demographic and Clinical Characterictics of Patients with GM2 Gangliosidosis. . J Pediatr Res 2018;5:12-16.
• 5. Masingue M, Dufour L, Lenglet T, et al. Natural History of Adult Patients with GM2 Gangliosidosis. Ann Neurol 2020;87(4):609-617. DOI: 10.1002/ana.25689.
• 6. Virgolini MJ, Feliziani C, Cambiasso MJ, Lopez PH, Bollo M. Neurite atrophy and apoptosis mediated by PERK signaling after accumulation of GM2-ganglioside. Biochim Biophys Acta Mol Cell Res 2019;1866(2):225-239. DOI: 10.1016/j.bbamcr.2018.10.014.
• 7. Karimzadeh P, Jafari N, Nejad Biglari H, et al. GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series). Iran J Child Neurol 2014;8(3):55-60. (https://www.ncbi.nlm.nih.gov/pubmed/25143775).
• 8. Jain A, Kohli A, Sachan D. Infantile Sandhoff's disease with peripheral neuropathy. Pediatr Neurol 2010;42(6):459-61. DOI: 10.1016/j.pediatrneurol.2010.02.007.
• 9. Venugopalan P, Joshi SN. Cardiac involvement in infantile Sandhoff disease. J Paediatr Child Health 2002;38(1):98-100. DOI: 10.1046/j.1440-1754.2002.00765.x.
• 10. Sheth J, Datar C, Mistri M, Bhavsar R, Sheth F, Shah K. GM2 gangliosidosis AB variant: novel mutation from India - a case report with a review. BMC Pediatr 2016;16:88. DOI: 10.1186/s12887-016-0626-6.
• 11. Hall P, Minnich S, Teigen C, Raymond K. Diagnosing Lysosomal Storage Disorders: The GM2 Gangliosidoses. Curr Protoc Hum Genet 2014;83:17 16 1-8. DOI: 10.1002/0471142905.hg1716s83.
• 12. Liu M, Huang D, Wang H, Zhao L, Wang Q, Chen X. Clinical and Molecular Characteristics of Two Chinese Children with Infantile Sandhoff Disease and Review of the Literature. J Mol Neurosci 2020;70(4):481-487. DOI: 10.1007/s12031-019-01409-6.
• 13. Tavasoli AR, Parvaneh N, Ashrafi MR, Rezaei Z, Zschocke J, Rostami P. Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations. Orphanet J Rare Dis 2018;13(1):130. DOI: 10.1186/s13023-018-0876-5.
• 14. Smith NJ, Winstone AM, Stellitano L, Cox TM, Verity CM. GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed. Dev Med Child Neurol 2012;54(2):176-82. DOI: 10.1111/j.1469-8749.2011.04160.x.
• 15. Barness LA, Henry K, Kling P, Laxova R, Kaback M, Gilbert-Barness E. A 7-year old white-male boy with progressive neurological deterioration. Am J Med Genet 1991;40(3):271-9. DOI: 10.1002/ajmg.1320400305.
• 16. Saouab R, Mahi M, Abilkacem R, et al. A case report of Sandhoff disease. Clin Neuroradiol 2011;21(2):83-5. DOI: 10.1007/s00062-010-0035-4.