Pathway | Enzyme deficiency | Gene | Inheritance | Relative prevalence | Hematologic features* | Syndromic features |
Glycolysis | Pyruvate kinase (PK) | PKLR | AR | Rare | Chronic hemolysis, variable severity | None |
Hexokinase (HK) | HK1 | AR | Very rare | Chronic hemolysis, variable severity | None | |
Glucose phosphate isomerase (GPI) | GPI | AR | Very rare | Chronic hemolysis, variable severity | Some have neuromuscular impairment (hypotonia, dysarthria, intellectual impairment) | |
Phosphofructokinase (PFK) | PFKM | AR | Very rare | Chronic hemolysis, generally mild | Some have exercise-induced myopathy | |
Aldolase | ALDOA | AR | Very rare | Chronic hemolysis, variable severity | Some have developmental delay and/or rhabdomyolysis | |
Triosephosphate isomerase | TPI1 | AR | Very rare | Chronic hemolysis, variable severity | Typically manifests as a progressive, fatal, multisystem disease, with spasticity, hypotonia, motor retardation, weakness, and paraparesis | |
Phosphoglycerate kinase (PGK) | PGK1 | X-linked | Very rare | Chronic hemolysis in males, variable hemolysis in females | Some males have motor regression, expressive aphasia, seizures, and progressive extrapyramidal disease; some have exertional rhabdomyolysis | |
Hexose monophosphate (HMP) shunt and glutathione synthesis | Glucose 6 phosphate dehydrogenase (G6PD) | G6PD | X-linked | Common | Intermittent hemolysis with oxidant injury or chronic hemolysis | Rare cases of neutrophil dysfunction |
Glutathione reductase (GSR) | GSR | Unclear | Very rare | Hemolysis with neonatal jaundice | None | |
Glutamate-cysteine ligase (GCS, also called gamma-glutamyl-cysteine synthetase [GCL]) | GCLC | AR | Very rare | Chronic hemolysis, generally mild | Some have severe neurologic dysfunction with spinocerebellar degeneration and aminoaciduria | |
Glutathione synthase (GSS) | GSS | AR | Very rare | Chronic hemolysis, exacerbated by oxidant exposures | Some have metabolic acidosis presenting in the newborn period and progressive cerebral and cerebellar degeneration | |
Nucleotide metabolism | Pyrimidine 5' nucleotidase (P5'N) | NT5C3A | AR | Very rare (but most common disorder of nucleotide metabolism) | Chronic hemolysis, mild to moderate; splenomegaly and intermittent jaundice; basophilic stippling on the blood film | None |
Adenosine deaminase (ADA) excess¶ | ADA | AD | Very rare | Chronic hemolysis, typically mild | None | |
Adenylate kinase (AK) | AK1 | AR | Very rare | Chronic hemolysis, moderate to severe | Some have developmental delay |
RBC: red blood cell; AR: autosomal recessive; AD: autosomal dominant.
* These heritable metabolic enzyme deficiencies are also referred to as hereditary nonspherocytic hemolytic anemia (HNSHA), to distinguish them from hereditary spherocytosis.
¶ Homozygous ADA deficiency causes severe combined immunodeficiency (SCID), an autosomal recessive condition. Hemolysis occurs with ADA variants that cause increased enzyme activity.