Disorders of Fructose and Galactose Metabolism

Fructose Path & Benign Spill - Sweet & Simple

• Normal Fructose Path:
  • Fructose + ATP $\xrightarrow{\text{Fructokinase (KHK)}}$ Fructose-1-Phosphate (F1P) + ADP
  • F1P $\xrightarrow{\text{Aldolase B}}$ Dihydroxyacetone Phosphate (DHAP) + Glyceraldehyde
• Essential Fructosuria (Benign Fructosuria):
  • Deficiency: Fructokinase (hepatic KHK).
  • Inheritance: Autosomal Recessive.
  • Pathophysiology: Fructose accumulates in blood & urine (fructosuria).
  • Clinical: Asymptomatic, benign condition. Fructose spills into urine.
  • Diagnosis: Urine positive for reducing sugars (e.g., Benedict's test); negative for glucose (glucose oxidase test).
  • 📌 Mnemonic: Kind Herbert's Kids (KHK) spill sugar, but are fine!

⭐ Essential fructosuria is a benign, asymptomatic condition often detected incidentally by a positive urine test for reducing substances, while the glucose-specific urine test is negative.

HFI Havoc - Fructose's Fury

• Defect: Autosomal recessive, Aldolase B deficiency.
• Accumulation: Fructose-1-Phosphate (F-1-P) in liver, kidney, intestine.
• Pathophysiology:
  • F-1-P traps $PO_4^{3-}$ $\rightarrow$ ↓ ATP, ↓ $P_i$.
  • Inhibits gluconeogenesis & glycogenolysis $\rightarrow$ severe hypoglycemia.
• Onset: Symptoms post fructose/sucrose/sorbitol ingestion (weaning, juices).
• Clinical Features:
  • Severe hypoglycemia, vomiting, jaundice, hepatomegaly.
  • Lactic acidosis, hyperuricemia.
  • Chronic: Failure to thrive, liver/kidney failure, sweet aversion.
• Diagnosis:
  • Clinical; urine reducing substances (+ve Clinitest, -ve GOD).
  • Genetic test (ALDOB) or liver biopsy (enzyme assay).
  • ⚠️ Fructose tolerance test: DANGEROUS.
• Management: Lifelong dietary elimination of fructose, sucrose, sorbitol.
• 📌 Mnemonic: HFI = Hypoglycemia, F-1-P ↑, Inhibition of pathways.

⭐ Fructose-1-phosphate accumulation is key in HFI: traps phosphate, depletes ATP, inhibits gluconeogenesis & glycogenolysis.

Galactose Path & Lens Alert - Milky Way Minors

• Galactose (from milk) metabolism: GALK → GALT → GALE.
• Galactokinase (GALK) Deficiency:
  • $GALK1$ defect. ↑ Galactose leads to ↑ Galactitol.
  • Key: Infantile cataracts, galactosuria.
  • Spares liver/brain. Rx: Galactose-free diet.
• UDP-Galactose-4-Epimerase (GALE) Deficiency:
  • $GALE$ defect.
  • Peripheral (benign): Asymptomatic; RBC/WBC enzyme defect.
  • Generalized (rare): Severe; mimics classic galactosemia.
• 📌 Lens Alert: Galactitol accumulation causes osmotic damage, leading to cataracts.

⭐ GALK deficiency: cataracts are primary; liver & brain typically spared (unlike GALT deficiency).

GALT's Grave Gala - Toxic Milk Mayhem

Classic Galactosemia: Severe autosomal recessive disorder from Galactose-1-Phosphate Uridyltransferase (GALT) enzyme deficiency. Results in toxic accumulation of Galactose-1-Phosphate and Galactitol.

• Pathophysiology:

• Clinical Features (Neonatal onset after milk ingestion):

  • Jaundice, hepatosplenomegaly, liver failure
  • Vomiting, diarrhea, failure to thrive (FTT)
  • Cataracts (oil-droplet, develop rapidly)
  • Aminoaciduria, renal tubular dysfunction
  • Lethargy, hypotonia; intellectual disability if untreated

  ⭐ High risk of neonatal E. coli sepsis.

• Diagnosis:

  • ↑ Blood galactose, ↑ Galactose-1-P in RBCs
  • ↓ GALT enzyme activity in RBCs (confirmatory)
  • Urine: +ve reducing substances (non-glucose)
  • Newborn screening (NBS) crucial.

• Management:

  • Prompt initiation of galactose-restricted (lactose-free) diet.
  • Soy-based formula.
  • Monitor for long-term complications (e.g., premature ovarian insufficiency in females, developmental delay). 📌 GALT: Grave Ailments from Lactose Toxicity.

High‑Yield Points - ⚡ Biggest Takeaways

• Essential Fructosuria: Fructokinase defect; benign, asymptomatic, urinary fructose (reducing substance).
• Hereditary Fructose Intolerance (HFI): Aldolase B defect; severe hypoglycemia, jaundice post-fructose. Fructose-1-P toxic.
• Classic Galactosemia: GALT defect; cataracts, hepatomegaly, E. coli sepsis. Galactose-1-P toxic.
• Galactokinase Deficiency: GALK defect; infantile cataracts from galactitol. Otherwise milder.
• Aldolase B & GALT defects: toxic phosphorylated intermediates accumulate.
• Key treatment: Strict dietary restriction of offending sugars.
• Cataracts in galactosemia (GALT/GALK) from galactitol accumulation.