A newborn baby refuses breast milk since the 2nd day of birth but accepts glucose water. He develops vomiting and severe jaundice by the 5th day. Benedict’s test was positive for urine, and blood glucose was low. The most likely cause is due to the deficiency of:

Correct Answer: A. Galactose-1-phosphate uridyl transferase

This is classic galactosemia (galactose-1-phosphate uridyltransferase deficiency), the most common and severe form. The clinical triad is pathognomonic: refusal of breast milk (lactose = glucose + galactose), vomiting, and severe jaundice by day 5. The positive Benedict's test indicates reducing sugars in urine (galactose is a reducing sugar, unlike glucose which requires glucose oxidase). Low blood glucose occurs because galactose accumulation impairs hepatic gluconeogenesis and glycogenolysis.

The enzyme deficiency blocks the conversion of galactose-1-phosphate to UDP-galactose, causing toxic accumulation of galactose-1-phosphate in liver, lens, and brain. This leads to hepatomegaly, cataracts (osmotic stress from galactitol via aldose reductase), intellectual disability, and hypoglycemia. The clinical presentation within 48–72 hours of milk feeding is the discriminating feature—this is the only galactosemia form that presents this acutely in neonates.

Per Indian pediatric guidelines (IAP), neonatal screening for galactosemia is now recommended in many tertiary centers. Early diagnosis via elevated galactose-1-phosphate in blood spots and positive urine reducing substances (Benedict's test) followed by enzyme assay confirmation is critical. Immediate management: switch to lactose-free formula (soy-based or lactose-free cow's milk). Prognosis depends on age at diagnosis; early intervention prevents intellectual disability and cataracts.

Why the other options are wrong

B. UDP galactose-4-epimerase — This enzyme deficiency causes the benign form of galactosemia (UDP-galactose-4-epimerase deficiency). Affected individuals have elevated galactose but remain asymptomatic because the enzyme block occurs downstream; galactose-1-phosphate does not accumulate to toxic levels. They may show only infantile cataracts or neonatal jaundice, not the acute systemic presentation with hypoglycemia and vomiting seen here. This is a trap because students may confuse it with the severe form. C. Aldose reductase — Aldose reductase deficiency does not cause galactosemia. This enzyme converts galactose to galactitol in the polyol pathway. Its deficiency would actually prevent galactitol accumulation and thus prevent osmotic cataracts—the opposite of what we see. Aldose reductase is relevant to galactosemia pathophysiology (it causes cataracts), but its deficiency is not the primary cause. This is a distractor testing knowledge of the polyol pathway. D. Galactokinase — Galactokinase deficiency causes the mildest form of galactosemia, presenting only with infantile cataracts (galactose accumulates and is shunted to galactitol via aldose reductase). There is no hepatomegaly, no intellectual disability, no hypoglycemia, and no vomiting—the systemic toxicity is absent. The clinical picture here (acute illness, hypoglycemia, severe jaundice) is incompatible with galactokinase deficiency, making this a clear distractor.

High-Yield Facts

Mnemonics

Three Galactosemias by Severity GALT (Galactose-1-phosphate uridyltransferase) = Grave (systemic, day 2–5); UDP-epimerase = Unfortunately benign (asymptomatic); Galactokinase = Kindest (cataracts only). Use when differentiating which enzyme deficiency causes which clinical picture. Galactosemia Red Flags in Newborn MILk refusal + Jaundice + Hypoglycemia = GALT deficiency. If only cataracts → think galactokinase. If asymptomatic → think UDP-epimerase. Use at the bedside when a newborn refuses breast milk.

NBE Trap

NBE pairs milk refusal + jaundice + hypoglycemia with galactokinase deficiency in some older textbooks, but the acute systemic presentation is pathognomonic for GALT deficiency. The trap is confusing the three forms by severity—students may pick galactokinase thinking "galactosemia = cataracts" without recognizing that only GALT causes the acute neonatal illness described here.

Clinical Pearl

In Indian neonatal practice, a newborn who refuses breast milk within 48–72 hours and develops jaundice + hypoglycemia is galactosemia until proven otherwise. Immediate urine dipstick (Benedict's test) and blood galactose-1-phosphate screening can be done at any tertiary center; switching to soy formula while awaiting confirmation prevents irreversible neurological damage. Early diagnosis is the difference between a normal child and one with intellectual disability.

_Reference: Robbins Ch. 5 (Genetic Disorders); KD Tripathi Ch. 12 (Carbohydrate Metabolism); Harrison Ch. 431 (Disorders of Carbohydrate Metabolism)_