Imerslund-Gräsbeck syndrome in a child with a novel compound heterozygous mutations in the AMN gene: a case report.
AMN gene
Anemia
Case report
Imerslund-Gräsbeck syndrome
Oral vitamin B12
Journal
Italian journal of pediatrics
ISSN: 1824-7288
Titre abrégé: Ital J Pediatr
Pays: England
ID NLM: 101510759
Informations de publication
Date de publication:
27 Sep 2024
27 Sep 2024
Historique:
received:
07
11
2023
accepted:
03
09
2024
medline:
28
9
2024
pubmed:
28
9
2024
entrez:
28
9
2024
Statut:
epublish
Résumé
Imerslund-Gräsbeck syndrome (IGS) is an autosomal recessive disorder characterized by selective vitamin B12 malabsorption, resulting in vitamin B12 deficiency and impaired reabsorption of proximal tubular proteins.This case highlights a previously unidentified compound heterozygous variant in the Amnionless (AMN) gene that causes IGS syndrome and underscores the importance of long-term oral vitamin B12 replacement therapy in managing the condition. In this retrospective analysis, we present the clinical data of a 3-year and 6-month-old female child diagnosed with IGS at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China, in November 2018. The child was admitted to the hospital due to a history of anemia persisting for over a month. There was no previous significant medical history. The admission examination revealed megaloblastic anemia with proteinuria. Serum vitamin B12 levels were decreased, while folic acid and renal function were normal. The patient was diagnosed with megaloblastic anemia and started long-term oral vitamin B12 replacement therapy. Throughout the follow-up period, blood tests consistently showed normal results, while proteinuria persisted. In November 2019, the child and her parents underwent whole exome sequencing analysis, which revealed a novel compound heterozygous variant in the AMN gene: c.162 + 1G > A and c.922 C > T (p.Q308X) in the child, c.162 + 1G > A in the father, and c.922 C > T (p.Q308X) in the mother. Therefore, this child was further diagnosed with IGS. In this case, whole exome sequencing proves to be highly practical in daily healthcare for diagnosing and refining rare or ultra-rare diseases with ambiguous phenotypes or genetic diversity. It is also valuable for prognostic evaluation and personalized management. Additionally, the oral vitamin B12 treatment demonstrated positive clinical effects for the child, offering a new option for patients unable to undergo intramuscular vitamin B12 replacement therapy.
Sections du résumé
BACKGROUND
BACKGROUND
Imerslund-Gräsbeck syndrome (IGS) is an autosomal recessive disorder characterized by selective vitamin B12 malabsorption, resulting in vitamin B12 deficiency and impaired reabsorption of proximal tubular proteins.This case highlights a previously unidentified compound heterozygous variant in the Amnionless (AMN) gene that causes IGS syndrome and underscores the importance of long-term oral vitamin B12 replacement therapy in managing the condition.
CASE PRESENTATION
METHODS
In this retrospective analysis, we present the clinical data of a 3-year and 6-month-old female child diagnosed with IGS at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China, in November 2018. The child was admitted to the hospital due to a history of anemia persisting for over a month. There was no previous significant medical history. The admission examination revealed megaloblastic anemia with proteinuria. Serum vitamin B12 levels were decreased, while folic acid and renal function were normal. The patient was diagnosed with megaloblastic anemia and started long-term oral vitamin B12 replacement therapy. Throughout the follow-up period, blood tests consistently showed normal results, while proteinuria persisted. In November 2019, the child and her parents underwent whole exome sequencing analysis, which revealed a novel compound heterozygous variant in the AMN gene: c.162 + 1G > A and c.922 C > T (p.Q308X) in the child, c.162 + 1G > A in the father, and c.922 C > T (p.Q308X) in the mother. Therefore, this child was further diagnosed with IGS.
CONCLUSIONS
CONCLUSIONS
In this case, whole exome sequencing proves to be highly practical in daily healthcare for diagnosing and refining rare or ultra-rare diseases with ambiguous phenotypes or genetic diversity. It is also valuable for prognostic evaluation and personalized management. Additionally, the oral vitamin B12 treatment demonstrated positive clinical effects for the child, offering a new option for patients unable to undergo intramuscular vitamin B12 replacement therapy.
Identifiants
pubmed: 39334390
doi: 10.1186/s13052-024-01757-z
pii: 10.1186/s13052-024-01757-z
doi:
Substances chimiques
AMN protein, human
0
Vitamin B 12
P6YC3EG204
Membrane Proteins
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
191Informations de copyright
© 2024. The Author(s).
Références
Gurlek Gokcebay D, Akpinar Tekgunduz S, Cavdarli B. Imerslund Gr ä sbeck syndrome presentation with microangiopathic hmolytic America in a child. Eur J Med Genet. 2020;63(6):103880. https://doi.org/10.1016/j.ejmg.2020.103880 .
doi: 10.1016/j.ejmg.2020.103880
pubmed: 32045704
Kalantry S, Manning S, Haub O, Tomihara Newberger C, Lee HG, Fangman J. et alNat Genet. 2001;27:412–6. https://doi.org/10.1038/86912 .
doi: 10.1038/86912
Fyfe JC, Madsen M, Hojrup P, Christensen EI, Tanner SM, A de la Chapelle, et al. Blood. 2004;103:1573–9. https://doi.org/10.1182/blood-2003-08-2852 .
doi: 10.1182/blood-2003-08-2852
pubmed: 14576052
Larsen C, Etzerodt A, Madsen M, Skj ø dt K, Moestrup SK. Andersen CBF Structural Assembly of the megalton-sized receiver for internal vitamin B12uptake and kidney protein reabsorption. Nat Commun. 2018;9(1):5204. https://doi.org/10.1038/s41467-018-07468-4 .
doi: 10.1038/s41467-018-07468-4
pubmed: 30523278
pmcid: 6283879
The Human Gene Mutation Database. http://www.hgmd.cf.ac.uk/ac/index.php . Accessed 20 September 2023.
Montgomery E, Sayer JA, Baines LA, Hynes AM, Vega-Warner V, Johnson S, Goodship JA, Otto EA. Novel compound heterozygous mutations in AMN cause Imerslund-Gräsbeck syndrome in two half-sisters: a case report. BMC Med Genet. 2015;16:35. https://doi.org/10.1186/s12881-015-0181-2 .
doi: 10.1186/s12881-015-0181-2
pubmed: 26040326
pmcid: 4630879
Gangarossa S, Romano V, Schilirò G. Efficacy of oral administration of high-dose cobamamide in a patient with Imerslund-Gräsbeck syndrome. Pediatr Hematol Oncol. 1996 Jul-Aug; 13(4):387-9. https://doi.org/10.3109/08880019609030846 . PMID: 8837146.
Kingma SDK, Neven J, Bael A, Meuwissen MEC, van den Akker M. Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases. Orphanet J Rare Dis. 2023;18(1):291. https://doi.org/10.1186/s13023-023-02889-x . PMID: 37710296; PMCID: PMC10500774.
doi: 10.1186/s13023-023-02889-x
pubmed: 37710296
pmcid: 10500774
Pacitto A, Prontera P, Stangoni G, et al. Imerslund-Gräsbeck Syndrome in an infant with a Novel Intronic variant in the AMN Gene: a Case Report. Int J Mol Sci. 2019;20(3):527. https://doi.org/10.3390/ijms20030527 .
doi: 10.3390/ijms20030527
pubmed: 30691194
pmcid: 6387074
Elshinawy M, Gao HH, Al Nabhani DM, Al Tahli KA. Clinical and molecular characteristics of imerslund gr ä sbeck syndrome: First report of a novel Frameshift variant in Exon 11 of AMN gene Int J Lab Hematol 2021; 43 (5): 1009–1015. https://doi.org/10.1111/ijlh.13473
Densupsoontorn N, Sanpakit K, Vijarnsorn C, Pataragarn A, Kangwanpornsiri C, Jatutipsompol C, Tirepongporn H, Jirapinyo P, Shah NP, Sturm AC, Tanner SM. Imerslund Gr ä Sbeck syndrome: new mutation in Annionless Pediatric Int. 2012; 54 (3): e19–21. https://doi.org/10.1111/j.1442-200X.2011.03482.x
Namour F, Dobrololjski G, Chery C, Audonnet S, Feillet F, Sperl W, Gueant JL. Luminal expression of cubilin is paid in Imerslund Glasbeck syndrome with compound AMN mutations in intron 3 and exon 7 Haematologica 2011; 96 (11): 1715-9. https://doi.org/10.3324/haematol.2011.043984 Epub 2011 Jul 12.
De Filippo G, Rendina D, Rocco V, Esposito T, Gianfrancesco F, Strazzullo P. Imerslund-Gräsbeck syndrome in a 25-month-old Italian girl caused by a homozygous mutation in AMN. Ital J Pediatr. 2013;39:58. https://doi.org/10.1186/1824-7288-39-58 .
doi: 10.1186/1824-7288-39-58
pubmed: 24044590
pmcid: 3848621
Broides A, Yerushalmi B, Levy R, Hadad N, Kaplung N, Tanner SM, Chapelle Ade L, Levy J. Imerslund Rasbeck syndrome associated with current aphthous stomatitis and defective neutral function. J Pediatr Hematol Oncol. 2006;28(11):715–9. https://doi.org/10.1097/01.mph.0000243656.25938.7b .
doi: 10.1097/01.mph.0000243656.25938.7b
pubmed: 17114957
Xi W, Cao L, Huo H, et al. Clinical analysis of siblings with Imerslund-Gräsbeck syndrome. Chin Med J. 2021;101(40):3351–4. https://doi.org/10.3760/cma.j.cn112137-20210709-01537 .
doi: 10.3760/cma.j.cn112137-20210709-01537
Qin HC, Liu YY, Feng Y, Xiao JW, Wen XH. Two cases of Imerslund-Grasbeck syndrome with AMN gene mutation [J]. Chin J Pediatr Hematol Oncol. 2023;28(02):127–31.
Zhai SH, Wang YF, Mao YN, et al. Imerslund-Gräsbeck syndrome with multiple peptic ulcers: a case report. Chin Clin Case Outcomes Database. 2023;05(01):E00333–00333. https://doi.org/10.3760/cma.j.cmcr.2023.e00333 .
doi: 10.3760/cma.j.cmcr.2023.e00333
Yang L, Huang D, Xu D, et al. Imerslund-Gräsbeck syndrome: a case report and literature review. Chin J Practical Pediatr. 2022;37(13):1029–31. https://doi.org/10.3760/cma.j.cn101070-20210409-00409 .
doi: 10.3760/cma.j.cn101070-20210409-00409
Li GX, Pan X, Lu J, et al. Clinical and genetic analysis of Imerslund-Gräsbeck syndrome caused by compound heterozygous variation of AMN gene. J Clin Pediatr. 2021;39(04):276–8. https://doi.org/10.3969/j.issn.1000-3606.2021.04.009 .
doi: 10.3969/j.issn.1000-3606.2021.04.009
Liu LB, Gao XJ, Ma YJ, Jia SL, Chen RR, Li J. Clinical and gene mutation analysis of a case of Imerslund-Gräsbeck syndrome [J]. J Clin Pediatr. 2019;37(11):851–3.
Serra G, Antona V, D’Alessandro MM, Maggio MC, Verde V, Corsello G. Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town. Ital J Pediatr. 2021;47(1):138. https://doi.org/10.1186/s13052-021-01080-x . PMID: 34134742; PMCID: PMC8207710.
doi: 10.1186/s13052-021-01080-x
pubmed: 34134742
pmcid: 8207710
Altay C, Cetin M, Gümrük F, Irken G, Yetgin S, Laleli Y. Familial selective vitamin B12 malabsorption (Imerslund-Gräsbeck syndrome) in a pool of Turkish patients. Pediatr Hematol Oncol. 1995 Jan-Feb; 12(1):19–28. https://doi.org/10.3109/08880019509029524 . PMID: 7703038.
Kalantry S, Manning S, Haub O, Tomihara-Newberger C, Lee HG, Fangman J, Disteche CM, Manova K, Lacy E. The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain. Nat Genet. 2001; 27(4):412-6. https://doi.org/10.1038/86912 . PMID: 11279523.
Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency–an update. Haematologica. 2006;91(11):1506–12. Epub 2006 Oct 17. PMID.
pubmed: 17043022
Bor MV, Cetin M, Aytaç S, Altay C, Nexo E. Nonradioactive vitamin B12 absorption test evaluated in controls and in patients with inherited malabsorption of vitamin B12. Clin Chem. 2005;51(11):2151–5. https://doi.org/10.1373/clinchem.2005.055509 . Epub 2005 Sep 15. PMID: 16166166.
doi: 10.1373/clinchem.2005.055509
pubmed: 16166166
United States Department Agriculture. USDA National Nutrient Database for Standard Reference. http://ndb.nal.usda.gov/ . Accessed Dec 13, 2016.
Technical University of Denmark-National Food Institute. Danish food composition database. http://www.foodcomp.dk/v7/fcdb_default.asp . Accessed Dec 13, 2016.
Udagawa T, Harita Y, Miura K, Mitsui J, Ode KL, Morishita S, Urae S, Kanda S, Kajiho Y, Tsurumi H, Ueda HR, Tsuji S, Saito A, Oka A. Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. Sci Rep. 2018;8(1):2351. https://doi.org/10.1038/s41598-018-20731-4 . PMID: 29402915; PMCID: PMC5799345.
doi: 10.1038/s41598-018-20731-4
pubmed: 29402915
pmcid: 5799345
Dipasquale V, Serra G, Corsello G, Romano C. Standard and Specialized Infant Formulas in Europe: Making, Marketing, and Health Outcomes. Nutr Clin Pract. 2020;35(2):273–281. https://doi.org/10.1002/ncp.10261 . Epub 2019 Feb 11. PMID: 30742336.
Serra G, Giuffrè M, Piro E, Corsello G. The social role of pediatrics in the past and present times. Ital J Pediatr. 2021;47(1):239. https://doi.org/10.1186/s13052-021-01190-6 . PMID: 34922600; PMCID: PMC8684095.
doi: 10.1186/s13052-021-01190-6
pubmed: 34922600
pmcid: 8684095
Piro E, Serra G, Antona V, Giuffrè M, Giorgio E, Sirchia F, Schierz IAM, Brusco A, Corsello G. Novel LRPPRC compound heterozygous mutation in a child with early-onset Leigh syndrome french-canadian type: case report of an Italian patient. Ital J Pediatr. 2020;46(1):140. https://doi.org/10.1186/s13052-020-00903-7 . PMID: 32972427; PMCID: PMC7517646.
doi: 10.1186/s13052-020-00903-7
pubmed: 32972427
pmcid: 7517646
Schierz IAM, Serra G, Antona V, Persico I, Corsello G, Piro E. Infant developmental profile of Crisponi syndrome due to compound heterozygosity for CRLF1 deletion. Clin Dysmorphol. 2020;29(3):141–143. https://doi.org/10.1097/MCD.0000000000000325 . PMID: 32433043.