Red blood cell (RBC) metabolic enzyme deficiencies

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

The two most common enzyme disorders are G6PD and PK deficiencies. Some deficiencies (not listed) are of doubtful clinical significance, including 6-phosphogluconate dehydrogenase (6PGD gene) and glutathione peroxidase (GPX1 gene). Individuals with these deficiencies may have some or all of the clinical features. Refer to UpToDate for detailed discussions. Hematologist consultation is often advisable.

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.

Graphic 139280 Version 2.0

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Red blood cell (RBC) metabolic enzyme deficiencies