Table 2a.

Disorders (and Associated Genes) of Interest in the Differential Diagnosis of Fructose-1,6-Bisphosphatase Deficiency

Gene(s)Disorder 1Differential Diagnosis Disorder: Features Overlapping w/FBP1 DeficiencyDistinguishing Between FBP1 Deficiency & Differential Diagnosis Disorder
ACAT1 Beta-ketothiolase deficiency
(OMIM 203750)		Ketolytic defect characterized by ketotic hypoglycemia or hyperglycemia & metabolic acidosisIn BKD: ↑ of specific metabolites on urine organic acids by GCMS can include 2-methylacetocetate, 2-methyl-3-hydroxybutyryl CoA, & tiglylglycine.
ALDOB Hereditary fructose intolerance 2
  • When weaned onto sucrose- or fructose-containing foods, infants can manifest nausea, bloating, vomiting, sweating, abdominal pain, & growth restriction.
  • Chronic liver & renal disease occur in untreated children.
  • Overall, HFI has a more chronic course than FBP1D.
  • Children w/HFI have strong aversion to sweets & often have renal tubular dysfunction, (not seen in FBP1D).
  • Children w/FBP1D do not have GI symptoms or FTT w/chronic fructose ingestion.
G6PC1
SLC37A4 		Glycogen storage disease type I 3
  • Accumulation of glycogen & fat in liver & kidneys, resulting in hepatomegaly & renomegaly
  • Untreated infants present at age 3-4 mos w/hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, &/or hypoglycemic seizures.
Detection of glycerol in FBP1D (on urine organic acid analysis) is useful in differentiating the disorders.
PC Pyruvate carboxylase deficiency 4Episodes of acute vomiting, tachypnea, & acidosis are usually precipitated by metabolic stress or infection; episodes may be very similar to FBP1D (w/↑ lactate-to-pyruvate ratio, hyperalaninemia, hypoglycemia, & metabolic acidosis).The neurologic involvement, severe ID, & recurrent seizures characteristic of PCD types A & B are not observed in FBP1D.
PGM1 PGM1-CDG
(See Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview.)		Presents more commonly w/rhabdomyolysis; however, episodic hypoglycemia & metabolic acidosis may also occur.
  • Short stature, birth defects (incl cleft palate, bifid uvula), & dilated cardiomyopathy may be present in PGM1-CDG.
  • Transferrin isoforms are abnormal & aid in diagnosis of PGM1-CDG.
MultipleFatty acid oxidation
defects (FAODs)		FAODs can present in neonates w/hypoglycemia, hyperammonemia, & ↓/absent ketones.
  • Typically hypoketotic hypoglycemia
  • ↑ acylcarnitine in MS/MS
MultipleMitochondrial respiratory chain disorders & Krebs cycle disordersMultisystem involvement in which the most metabolically active organs are most affected (e.g., brain, liver, kidney, heart)Mitochondrial disorders have a more chronic course than FBP1D.

BKD = beta-ketothiolase deficiency; CDG = congenital disorder of glycosylation; FBP1D = FBP1 deficiency; FTT = failure to thrive; HFI = hereditary fructose intolerance; ID = intellectual disability; MS/MS = tandem mass spectrometry; PCD = pyruvate carboxylase deficiency

1.

Disorders included in this table are inherited in an autosomal recessive manner with the exception of mitochondrial respiratory chain and Krebs cycle disorders, which may be inherited in an autosomal recessive manner, an autosomal dominant manner, or by maternal inheritance.

2.

Hereditary fructose intolerance is due to deficiency of enzyme aldolase B, which facilitates the breakdown of fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde.

3.

GSDI is due to the deficiency of enzyme glucose-6-phosphatase.

4.

Pyruvate carboxylase enzyme aids in the irreversible carboxylation of pyruvate to oxaloacetate.

From: Fructose-1,6-Bisphosphatase Deficiency

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