Biallelic hypomorphic variants in CAD cause uridine-responsive macrocytic anaemia with elevated haemoglobin-A2

Orna Steinberg-Shemer*, Joanne Yacobovich, Sharon Noy-Lotan, Orly Dgany, Tanya Krasnov, Assaf Barg, Yuval E. Landau, Katya Kneller, Raz Somech, Oded Gilad, Dafna Brik Simon, Naama Orenstein, Shai Izraeli, Francisco del Caño-Ochoa, Hannah Tamary, Santiago Ramón-Maiques

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalBritish Journal of Haematology
DOIs
StateAccepted/In press - 2023

Keywords

  • anaemia
  • genetic disorders
  • haemoglobin
  • paediatric

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