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.Do you want to add Medilib to your home screen?