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An 11-year-old boy born to a consanguineous marriage presented with severe pallor, and splenomegaly. Laboratory workups were suggestive of Coombs negative hemolytic anemia (Table I). He had a history of neonatal hyperbilirubinemia warranting an exchange transfusion, followed by global developmental delay with sensory neural hearing loss (neurological sequelae of bilirubin encephalopathy). He also had a history of blood transfusion in infancy. A homozygous missense variant in exon 6 of the GPI gene was detected by NGS, which has also been previously reported to cause neurologic impairment and HNSHA [2].

A 9-year-old boy, product of consanguineous marriage, presented with severe pallor and splenomegaly. He had a history of exchange transfusion for hyperbilirubinemia in the neonatal period and also needed repeated blood transfusions for anemia. Laboratory workup (Table I) did not reveal a cause for hemolysis. NGS detected a homozygous nonsense variation in exon 4 of the　AK1　(adenylate kinase)　gene, previously reported to cause hemolytic anemia [3].

A 9-month-old girl, product of consanguineous marriage, presented with severe pallor and splenomegaly. She had neonatal hyperbilirubinemia and required exchange transfusion. Her elder sibling had a history of neonatal exchange transfusion; he died at 1.5 years of age due to severe anemia with jaundice. Investigations were suggestive of Coombs negative hemolysis (Table I). A homozygous missense variant in exon 4 of　the PKLR (pyruvate kinase L/R)　gene was detected by NGS, which can lead to HNSHA.

All children are presently receiving nutritional supple-mentation and intermittent transfusions. RBC enzymopathies arise from mutations in genes coding for RBC metabolic enzymes. Deficiency of these enzymes leads to impaired cellular energy and/or increases the levels of oxidative stress, leading to premature removal of RBCs in the spleen and decreased red blood cell survival [1]. There are enzymes other than G6PD and PK, which are involved in nucleotide metabolism. The important ones are pyrimidine-5-nucleotidase (pyrimidine metabolism) and adenylate kinase and adenosine deaminase (purine metabolism) [1]. The clinical features of enzymopathies are highly variable, ranging from fully compensated hemolysis to severe transfusion-dependent hemo-lytic anemia. The severity of anemia may worsen during infec-tions, oxidant exposure any other physiological stress [2-4].

Enzymopathies pose a diagnostic challenge and patients may undergo repeated unsuccessful investigations over the years. Some clues include the presence of normocytic/macrocytic anemia with signs of hemolysis like indirect hyperbilirubinemia and reticulocytosis, along with a history of episodic/repeated blood transfusion for anemia. The diagnosis of a RBC enzymopathy is mainly based on exclusion; a negative DCT, a normal OFT, no specific RBC morphological abnormalities, and no evidence for abnormal hemoglobin [5]. Timely targeted NGS would help in the confirmation of diagnosis [2].

Treatment remains mainly supportive. Splenectomy is indicated in severe cases. Restoration of normal enzyme levels following bone marrow transplantation has been occasionally reported [5]. A novel treatment including enzyme activator is under development and this might provide a new option for the severe phenotype [6].