Biallelic hypomorphic variants in CAD cause uridine-responsive macrocytic anaemia with elevated haemoglobin-A2.
anaemia
genetic disorders
haemoglobin
paediatric
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
20 Nov 2023
20 Nov 2023
Historique:
revised:
14
10
2023
received:
28
08
2023
accepted:
08
11
2023
medline:
21
11
2023
pubmed:
21
11
2023
entrez:
20
11
2023
Statut:
aheadofprint
Résumé
Biallelic pathogenic variants in CAD, that encode the multienzymatic protein required for de-novo pyrimidine biosynthesis, cause early infantile epileptic encephalopathy-50. This rare disease, characterized by developmental delay, intractable seizures and anaemia, is amenable to treatment with uridine. We present a patient with macrocytic anaemia, elevated haemoglobin-A2 levels, anisocytosis, poikilocytosis and target cells in the blood smear, and mild developmental delay. A next-generation sequencing panel revealed biallelic variants in CAD. Functional studies did not support complete abrogation of protein function; however, the patient responded to uridine supplement. We conclude that biallelic hypomorphic CAD variants may cause a primarily haematological phenotype.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fundación Ramón Areces Ciencias de la Vida
ID : CIVP20A6610
Organisme : Generalitat Valenciana
Organisme : MCIN/AEI
ID : PID2021-128468NB-I00
Informations de copyright
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Ng BG, Wolfe LA, Ichikawa M, Markello T, He M, Tifft CJ, et al. Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors. Hum Mol Genet. 2015;24(11):3050-3057.
Koch J, Mayr JA, Alhaddad B, Rauscher C, Bierau J, Kovacs-Nagy R, et al. CAD mutations and uridine-responsive epileptic encephalopathy. Brain. 2017;140(2):279-286.
Zhou L, Xu H, Wang T, Wu Y. A patient with CAD deficiency responsive to uridine and literature review. Front Neurol. 2020;11:64.
Frederick A, Sherer K, Nguyen L, Ali S, Garg A, Haas R, et al. Triacetyluridine treats epileptic encephalopathy from CAD mutations: a case report and review. Ann Clin Transl Neurol. 2021;8(1):284-287.
McGraw CM, Mahida S, Jayakar P, Koh HY, Taylor A, Resnick T, et al. Uridine-responsive epileptic encephalopathy due to inherited variants in CAD: a tale of two siblings. Ann Clin Transl Neurol. 2021;8(3):716-722.
Russo R, Marra R, Andolfo I, Manna F, De Rosa G, Rosato BE, et al. Uridine treatment normalizes the congenital dyserythropoietic anemia type II-like hematological phenotype in a patient with homozygous mutation in the CAD gene. Am J Hematol. 2020;95(11):1423-1426.
Al-Otaibi A, AlAyed A, Al Madhi A, Saeed L, Ng BG, Freeze HH, et al. Uridine monophosphate (UMP)-responsive developmental and epileptic encephalopathy: a case report of two siblings and a review of literature. Mol Genet Metab Rep. 2022;30:100835.
Peng X, Xia LP, Zhang HJ, Zhang J, Yu SQ, Wang S, et al. A treatable genetic disease caused by CAD mutation. Front Pediatr. 2022;10:771374.
Zhou L, Deng J, Stenton SL, Zhou J, Li H, Chen C, et al. Case report: rapid treatment of uridine-responsive epileptic encephalopathy caused by CAD deficiency. Front Pharmacol. 2020;11:608737.
Rymen D, Lindhout M, Spanou M, Ashrafzadeh F, Benkel I, Betzler C, et al. Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation. Genet Med. 2020;22(10):1589-1597.
Del Caño-Ochoa F, Ng BG, Abedalthagafi M, Almannai M, Cohn RD, Costain G, et al. Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy. Genet Med. 2020;22(10):1598-1605.
Del Caño-Ochoa F, Ng BG, Rubio-Del-Campo A, Mahajan S, Wilson MP, Vilar M, et al. Beyond genetics: deciphering the impact of missense variants in CAD deficiency. J Inherit Metab Dis. 2023;46(6):1170-1185.
Shefer Averbuch N, Steinberg-Shemer O, Dgany O, Krasnov T, Noy-Lotan S, Yacobovich J, et al. Targeted next generation sequencing for the diagnosis of patients with rare congenital anemias. Eur J Haematol. 2018;101(3):297-304.
Noy-Lotan S, Krasnov T, Dgany O, Jeison M, Yanir AD, Gilad O, et al. Incorporation of somatic panels for the detection of haematopoietic transformation in children and young adults with leukaemia predisposition syndromes and with acquired cytopenias. Br J Haematol. 2021;193(3):570-580.
Goldberg L, Simon AJ, Rechavi G, Lev A, Barel O, Kunik V, et al. Congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene. Pediatr Blood Cancer. 2020;67(6):e28237.
Gilad O, Shemer OS, Dgany O, Krasnov T, Nevo M, Noy-Lotan S, et al. Molecular diagnosis of α-thalassemia in a multiethnic population. Eur J Haematol. 2017;98(6):553-562.
Shen JJ, Wortmann SB, de Boer L, Kluijtmans LAJ, Huigen M, Koch J, et al. The role of clinical response to treatment in determining pathogenicity of genomic variants. Genet Med. 2021;23(3):581-585.