DOI: https://doi.org/10.7705/biomedica.v38i0.3454

Enfermedad por almacenamiento de glucógeno de tipo III en pacientes colombianos: caracterización clínica y molecular

Carolina Mantilla, Mónica Toro, María Elsy Sepúlveda, Margarita Insuasty, Diana di Filippo, Juan Álvaro López, Carolina Baquero, María Cristina Navas, Andrés Augusto Arias

Resumen


Introducción. La enfermedad por almacenamiento de glucógeno de tipo III es una alteración autosómica recesiva, en la cual las mutaciones del gen AGL causan una deficiencia en la enzima desramificadora de glucógeno. Se caracteriza por hipoglucemia, hepatomegalia y miopatías progresivas. El análisis molecular del gen AGL ha evidenciado mutaciones que difieren según la población estudiada. En la actualidad, no existen reportes que describan mutaciones en el AGL de pacientes colombianos con esta condición.
Objetivo. Describir las características clínicas y moleculares de diez pacientes colombianos con enfermedad por almacenamiento del glucógeno de tipo III.
Materiales y métodos. Se analizaron diez pacientes pediátricos colombianos con la enfermedad y se hizo su estudio genético mediante la secuenciación de las regiones que codifican y las intrónicas circundantes del gen AGL con el método de Sanger.
Resultados. Todos los pacientes tenían el fenotipo clásico de la enfermedad. El estudio genético reveló la mutación p.Arg910X en dos pacientes. Uno presentó la mutación p.Glu1072AspfsX36 y otro resultó heterocigoto compuesto con las mutaciones p.Arg910X y p.Glu1072AspfsX36. Asimismo, en tres pacientes se detectó la deleción de los exones 4, 5 y 6 del gen AGL. Los estudios de simulación computacional predijeron que estos defectos eran patogénicos. En tres pacientes no se encontraron mutaciones en las regiones amplificadas.
Conclusión. Se encontraron mutaciones y deleciones que explican el fenotipo clínico de los pacientes. Este es el primer reporte en el que se describe el fenotipo clínico y el espectro de mutaciones en el gen AGL de pacientes colombianos, lo cual es importante para ofrecer un apropiado pronóstico, y asesoría genética al paciente y a su familia.


Palabras clave


enfermedad del almacenamiento de glucógeno de tipo III/diagnóstico; glucógeno; sistema de la enzima desramificadora del glucógeno; glucogenólisis

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Referencias


1. Wolfsdorf JI, Weinstein DA. Glycogen storage diseases. Rev Endocr Metab Disord. 2003;4:95-102.
2. Shin YS. Glycogen storage disease: Clinical, biochemical, and molecular heterogeneity. Semin Pediatr Neurol. 2006;13:115-20. https://doi.org/10.1016/j.spen.2006.06.007
3. Ozen H. Glycogen storage diseases: New perspectives. World J Gastroenterol. 2007;13:2541-53. https://doi.org/10.3748/wjg.v13.i18.2541
4. Cheng A, Zhang M, Okubo M, Omichi K, Saltiel AR. Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. Hum Mol Genet. 2009;18:2045-52. https://doi.org/10.1093/hmg/ddp128
5. Endo Y, Fateen E, Aoyama Y, Horinishi A, Ebara T, Murase T, et al. Molecular characterization of Egyptian patients with glycogen storage disease type IIIa. J Hum Genet. 2005;50:538-42. https://doi.org/10.1007/s10038-005-0291-3
6. Shen JJ, Chen YT. Molecular characterization of glycogen storage disease type III. Curr Mol Med. 2002;2:167-75. https://doi.org/10.2174/1566524024605752
7. Haagsma EB, Smit GP, Niezen-Koning KE, Gouw AS, Meerman L, Slooff MJ. Type IIIb glycogen storage disease associated with end-stage cirrhosis and hepatocellular carcinoma. The Liver Transplant Group. Hepatology. 1997;25:537-40. https://doi.org/10.1002/hep.510250307
8. Sentner CP, Hoogeveen IJ, Weinstein DA, Santer R, Murphy E, McKiernan PJ, et al. Glycogen storage disease type III: Diagnosis, genotype, management, clinical course and outcome. J Inherit Metab Dis. 2016;39:697-704. https://doi.org/10.1007/s10545-016-9932-2
9. Rousseau-Nepton I, Okubo M, Grabs R, Consortium FC, Mitchell J, Polychronakos C, et al. A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: A case series. CMAJ. 2015;187:E68-73. https://doi.org/10.1503/cmaj.140840
10. Mili A, Ben Charfeddine I, Mamai O, Abdelhak S, Adala L, Amara A, et al. Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III. J Hum Genet. 2012;57:170-5. https://doi.org/10.1038/jhg.2011.122
11. Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT. A single-base deletion in the 3’-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Eur J Hum Genet. 1997;5:266-70.
12. Santer R, Kinner M, Steuerwald U, Kjaergaard S, Skovby F, Simonsen H, et al. Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands. Eur J Hum Genet. 2001;9:388-91. https://doi.org/10.1038/sj.ejhg.5200632
13. Talente GM, Coleman RA, Alter C, Baker L, Brown BI, Cannon RA, et al. Glycogen storage disease in adults. Ann Intern Med. 1994;120:218-26.
14. Lucchiari S, Santoro D, Pagliarani S, Comi GP. Clinical, biochemical and genetic features of glycogen debranching enzyme deficiency. Acta Myol. 2007;26:72-4.
15. van Hoof F, Hers HG. The subgroups of type 3 glycogenosis. Eur J Biochem. 1967;2:265-70. https://doi.org/10.1111/j.1432-1033.1967.tb00134.x
16. Ding JH, de Barsy T, Brown BI, Coleman RA, Chen YT. Immunoblot analyses of glycogen debranching enzyme in different subtypes of glycogen storage disease type III. J Pediatr. 1990;116:95-100.
17. Yang-Feng TL, Zheng K, Yu J, Yang BZ, Chen YT, Kao FT. Assignment of the human glycogen debrancher gene to chromosome 1p21. Genomics. 1992;13:931-4. https://doi.org/10.1016/0888-7543(92)90003-B
18. Yang BZ, Ding JH, Enghild JJ, Bao Y, Chen YT. Molecular cloning and nucleotide sequence of cDNA encoding human muscle glycogen debranching enzyme. J Biol Chem. 1992;267:9294-9.
19. Bao Y, Yang BZ, Dawson TL Jr, Chen YT. Isolation and nucleotide sequence of human liver glycogen debranching enzyme mRNA: Identification of multiple tissue-specific isoforms. Gene. 1997;197:389-98. https://doi.org/10.1016/S0378-1119(97)00291-6
20. Lucchiari S, Fogh I, Prelle A, Parini R, Bresolin N, Melis D, et al. Clinical and genetic variability of glycogen storage disease type IIIa: Seven novel AGL gene mutations in the Mediterranean area. Am J Med Genet. 2002;109:183-90. https://doi.org/10.1002/ajmg.10347
21. Horinishi A, Okubo M, Tang NL, Hui J, To KF, Mabuchi T, et al. Mutational and haplotype analysis of AGL in patients with glycogen storage disease type III. J Hum Genet. 2002;47:55-9. https://doi.org/10.1007/s100380200000
22. Okubo M, Horinishi A, Suzuki Y, Murase T, Hayasaka K. Compound heterozygous patient with glycogen storage disease type III: Identification of two novel AGL mutations, a donor splice site mutation of Chinese origin and a 1-bp deletion of Japanese origin. Am J Med Genet. 2000;93:211-4. https://doi.org/10.1016/S0378-1119(97)00291-6
23. Okubo M, Horinishi A, Takeuchi M, Suzuki Y, Sakura N, Hasegawa Y, et al. Heterogeneous mutations in the glycogen-debranching enzyme gene are responsible for glycogen storage disease type IIIa in Japan. Hum Genet. 2000;106:108-15.
24. Ogimoto A, Okubo M, Okayama H, Shin YS, Endo Y, Ebara T, et al. A Japanese patient with cardiomyopathy caused by a novel mutation R285X in the AGL gene. Circ J. 2007;71:1653-6. https://doi.org/10.1253/circj.71.1653
25. Endo Y, Fateen E, El Shabrawy M, Aoyama Y, Ebara T, Murase T, et al. Egyptian glycogen storage disease type III - identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId. Clin Chem Lab Med. 2009;47:1233-8. https://doi.org/10.1515/CCLM.2009.281
26. Goldstein JL, Austin SL, Boyette K, Kanaly A, Veerapandiyan A, Rehder C, et al. Molecular analysis of the AGL gene: Identification of 25 novel mutations and evidence of genetic heterogeneity in patients with glycogen storage disease type III. Genet Med. 2010;12:424-30. https://doi.org/10.1097/GIM.0b013e3181d94eaa
27. Aoyama Y, Ozer I, Demirkol M, Ebara T, Murase T, Podskarbi T, et al. Molecular features of 23 patients with glycogen storage disease type III in Turkey: A novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations. J Hum Genet. 2009;54:681-6. https://doi.org/10.1038/jhg.2009.100
28. Sentner CP, Vos YJ, Niezen-Koning KN, Mol B, Smit GP. Mutation analysis in glycogen storage disease type III patients in the Netherlands: Novel genotype-phenotype relationships and five novel mutations in the AGL gene. JIMD Rep. 2013;7:19-26. https://doi.org/10.1007/8904_2012_134
29. Zimmermann A, Rossmann H, Bucerzan S, Grigorescu-Sido P. A novel nonsense mutation of the AGL gene in a Romanian patient with glycogen storage disease type IIIa. Case Rep Genet. 2016;2016:8154910. https://doi.org/10.1155/2016/8154910
30. Rhouma FB, Messai H, Hsouna S, Halim NB, Cherif W, Fadhel SB, et al. History of settlement of villages from Central Tunisia by studying families sharing a common founder glycogenosis type III mutation. Mitochondrial DNA A DNA MappSeq Anal. 2016;27:3194-8. https://doi.org/10.3109/19401736.2015.1007331
31. Lu C, Qiu Z, Sun M, Wang W, Wei M, Zhang X. Spectrum of AGL mutations in Chinese patients with glycogen storage disease type III: Identification of 31 novel mutations. J Hum Genet. 2016;61:641-5. https://doi.org/10.1038/jhg.2016.24
32. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073-81. https://doi.org/10.1038/nprot.2009.86
33. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;7:20. https://doi.org/10.1002/0471142905.hg0720s76
34. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310-5. https://doi.org/10.1038/ng.2892
35. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS Recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37:564-9. https://doi.org/10.1002/humu.22981
36. den Dunnen JT. Sequence variant descriptions: HGVS nomenclature and mutalyzer. Curr Protoc Hum Genet. 2016;90:7.13.1-7.13.19. https://doi.org/10.1002/cphg.2
37. Aradhya S, Lewis R, Bonaga T, Nwokekeh N, Stafford A, Boggs B, et al. Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders. Genet Med. 2012;14:594-603. https://doi.org/10.1038/gim.2011.65
38. Retterer K, Scuffins J, Schmidt D, Lewis R, Pineda Álvarez D, Stafford A, et al. Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort. Genet Med. 2015;17:623-9. https://doi.org/10.1038/gim.2014.160
39. Dagli A, Sentner CP, Weinstein DA. Glycogen storage disease type III. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. Gene Reviews. Washington, D.C.: University of Washington; 1993.
40. Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med. 2010;12:446-63.
https://doi.org/10.1097/GIM.0b013e3181e655b6
41. Coleman RA, Winter HS, Wolf B, Gilchrist JM, Chen YT. Glycogen storage disease type III (glycogen debranching enzyme deficiency): Correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med. 1992;116:896-900. https://doi.org/10.7326/0003-4819-116-11-896
42. Maire I, Baussan C, Moatti N, Mathieu M, Lemonnier A. Biochemical diagnosis of hepatic glycogen storage diseases: 20 years French experience. Clin Biochem. 1991;24:169-78. https://doi.org/10.1016/0009-9120(91)90511-C
43. Lucchiari S, Pagliarani S, Salani S, Filocamo M, Di Rocco M, Melis D, et al. Hepatic and neuromuscular forms of glycogenosis type III: Nine mutations in AGL. Hum Mutat. 2006;27:600-1. https://doi.org/10.1002/humu.9426
44. Lucchiari S, Donati MA, Melis D, Filocamo M, Parini R, Bresolin N, et al. Mutational analysis of the AGL gene: Five novel mutations in GSD III patients. Hum Mutat. 2003;22:337. https://doi.org/10.1002/humu.9177
45. Zhang W, Cui H, Wong LJ. Application of next generation sequencing to molecular diagnosis of inherited diseases. Top Curr Chem. 2014;336:19-45. https://doi.org/10.1007/128_2012_325
46. Yubero D, Brandi N, Ormazabal A, García-Cazorla A, Pérez-Dueñas B, Campistol J, et al. Targeted next generation sequencing in patients with inborn errors of metabolism. PLoS One. 2016;11:e0156359. https://doi.org/10.1371/journal.pone.0156359
47. Silva AL, Romao L. The mammalian nonsense-mediated mRNA decay pathway: To decay or not to decay! Which players make the decision? FEBS Lett. 2009;583:499-505.
https://doi.org/10.1016/j.febslet.2008.12.058
48. Horinishi A, Murase T, Okubo M. Novel intronic polymorphisms (IVS6-73A/G and IVS21+124A/G) in the glycogen-debranching enzyme (AGL) gene. Hum Mutat. 2000;16:279. https://doi.org/10.1002/1098-1004(200009)16:
3<279::AID-HUMU32>3.0.CO;2-X
49. Shamseldin HE, Al-Dosari M, Al-Jbali L, Rahbeeni Z, Qari A, Hashem M, et al. Study of consanguineous populations can improve the annotation of SNP databases. Eur J Med Genet. 2011;54:118-20. https://doi.org/10.1016/j.ejmg.2010.10.009


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Revista Biomédica -  https://doi.org/10.7705/issn.0120-4157
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