Table 2.

Selected Metabolic Disorders Presenting with Fasting Intolerance in the Differential Diagnosis of GSD III

Gene(s)DisorderMOIClinical & Biochemical Findings
ALDOB Hereditary fructose intolerance ARHypoglycemia on fructose/sucrose/sorbitol ingestion; GI symptoms; liver dysfunction (incl ↑ bilirubin & prolonged clotting time, hypoalbuminemia) & renal tubular dysfunction; absence of hyperlipidemia
FBP1 Fructose-1,6-bisphosphatase deficiency AR(Hypo)ketotic hypoglycemia w/↑ lactate usually triggered by fasting ± concurrent infection; biochemical tests normal between attacks; no muscle involvement
G6PC1
SLC37A4 		GSD Ia & GSD Ib ARGSD III & GSD I may be indistinguishable in infancy but some important differences may help distinguish them: GSD III does not usually have ↑ uric acid & lactate seen in GSD I; in contrast to GSD I, ketotic hypoglycemia is seen in GSD III, & ketones are grossly ↑ in morning urine samples of untreated persons; hypoglycemia & hypertriglyceridemia are more severe in GSD I than in GSD III; persons w/GSD I usually lack muscle symptoms & may show nephromegaly; in contrast to GSD III, neutropenia can be seen in GSD Ib.
GALT
GALE
GALK 		Classic galactosemia, epimerase deficiency galactosemia, & galactokinase deficiency (OMIM 230200)ARLiver dysfunction & hypoglycemia on (ga)lactose ingestion; GI symptoms; ↑ bilirubin & prolonged clotting time, hypoalbuminemia, renal tubular dysfunction; absence of hyperlipidemia & muscle involvement
GBE1 GSD IV ARLack of severe hypoglycemia until end-stage liver disease; liver cirrhosis may present early in infancy; clinical presentation is extremely heterogenous.
GYS2 GSD 0a (OMIM 240600)ARAbsence of hepatomegaly together w/postprandial hyperglycemia & hyperlactatemia in GSD0a
PHKA1
PHKA2
PHKB
PHKG2 		Phosphorylase kinase deficiency causing GSD IX 1AR
XL 2		The phenotypes of GSD VI & GSD IX are clinically indistinguishable. Affected persons present w/ketotic hypoglycemia & hepatomegaly & do not have ↑ serum CK, but ↓ stamina, ↓ muscle strength, & muscle pain may occur. Blood lactate is usually normal. AST & ALT are usually not as high as in GSD III.
PYGL GSD VI AR
SLC2A2 GSD XI (OMIM 227810)ARPostprandial hyperglycemia & renal tubular disease (Fanconi syndrome) incl glucosuria, w/hypophosphatemic rickets
Various
(e.g.,
ACADM
ACADVL
ETFA
ETFB
ETFDH)		Mitochondrial fatty acid oxidation disorders (e.g., MCAD, VLCAD, MADD 3)ARHypoketotic hypoglycemia after prolonged fasting; absence of hyperlipidemia; specific plasma acylcarnitine & urine organic acid profiles

ALT = alanine transaminase; AR = autosomal recessive; AST = aspartate aminotransferase; CK = creatine kinase; GI = gastrointestinal; GSD = glycogen storage disease; MADD = multiple acyl-CoA dehydrogenase deficiency; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; VLCAD = very long-chain acyl-coenzyme a dehydrogenase deficiency; XL = X-linked

1.

Phosphorylase kinase (PhK) is responsible for activation of hepatic glycogen phosphorylase that cleaves the terminal glucose moieties from the glycogen chain.

2.

PHKA2-related liver PhK deficiency and PHKA1-related muscle PhK deficiency are inherited in an X-linked manner. PHKB-related liver and muscle PhK deficiency and PHKG2-related liver PhK deficiency are inherited in an autosomal recessive manner.

3.

MADD is caused by biallelic pathogenic variants in ETFA, ETFB, or ETFDH. MCAD is caused by biallelic pathogenic variants in ACADM. VLCAD is caused by biallelic pathogenic variants in ACADVL.

From: Glycogen Storage Disease Type III

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