2022.11.14 | Questions 7-8
Classic Galactosemia
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Questions
Question 7
A 5-day-old girl tests positive for galactosemia on newborn screening. Follow up testing shows absent erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity and a homozygous Q188R variant in GALT. Which of the following should be avoided in this patient's diet?
Question 8
Which of the following complications is the patient in Question 7 most likely to face as an adult as a result of her galactosemia, assuming adherence to treatment recommendations?
Explanation
This patient has classic galactosemia (CG), a disorder of galactose metabolism due to autosomal recessive mutations in galactose-1-phosphate uridylyltransferase (GALT). The p.Q188R variant is the most frequent pathogenic missense variant associated with CG.
Galactose is one of the three main dietary monosaccharides (Fig. 1). The predominant sugar in human breast milk is lactose, a disaccharide that consists of galactose and glucose. As both lactose and galactose must be restricted from this patient’s diet, breastfeeding is contraindicated. The patient should be started on soy-based formula, which is free of lactose and contains calcium and vitamin D. After weaning from soy-based formula, calcium and vitamin D should be supplemented as necessary.
Left untreated, infants with CG may develop serious complications including liver failure, E. coli sepsis, and failure to thrive. Cataracts may also develop in untreated patients with CG due to accumulation of galactitol (Fig. 2), though early-onset cataracts are generally reversible upon initiation of diet.
Prognosis & Outcome in Treated Patients
Even when adequately treated from an early age, patients with CG are prone to developmental delays that affect speech, gross motor, and fine motor function. Furthermore, most females with CG develop hypergonadatropic hypogonadism or premature ovarian insufficiency (POI) (Question 8). POI may manifest as delayed puberty, primary amenorrhea, or early menopause. The mechanism by which this occurs is not well understood, though one possibility is that accumulation of galactose 1-phosphate or another galactose metabolite triggers apoptosis of oocytes. Adult patients with CG are also at increased risk for osteopenia, possibly due to dietary restrictions and POI (which is associated with low estrogen levels) in women.
💡Gals (Girls) act old (i.e. POI, osteoporosis) in Gal-act-o-semia.
Regarding the other answer choices in Question 8, Parkinson’s disease is seen in association with Gaucher disease. Hepatic adenomas, a precursor to hepatocellular carcinoma, can be seen in glycogen storage disease type 1. Type 1 diabetes mellitus is an autoimmune disorder that does not have a well-established monogenic etiology.
Learning objective
Classic galactosemia (CG) is a disorder of galactose metabolism that presents in infancy and is detectable on newborn screening. Teenagers and adults with CG are predisposed to POI and osteoporosis despite dietary treatment. Treatment involves restricting both galactose and lactose, the main dietary source of galactose.
References
Genereviews (Galactosemia)
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → d. Single Gene Disorders → ix. Metabolic disease → (4) Carbohydrate metabolism disorders (page 3)