Understanding the Clinical and Biochemical Aspects of Galactosemia

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine

and I'm Rahul Damania from Cleveland Clinic Children’s Hospital and we are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

Welcome to our Episode of a 4-day-old with jaundice and vomiting.

Here's the case presented by Rahul:

A full-term 4-day-old boy presents to the ED after recently being discharged from the newborn nursery. Per mom, the patient "look yellow" and was having difficulty with feeding. The mother states that the patient would be increasingly sleepy, and will only latch to the breast for five minutes. The patient has been having decreased wet diapers, and the stool is loose and non-bloody. Mother was concerned today as the child continue to look yellow, especially in the eyes, had four episodes of vomiting, and overall was acting lethargic. The patient presented to the emergency room afebrile, tachypneic, and tachycardic. The patient was noted to have initial serum glucose of 70. As the patient was increasingly dehydrated, laboratory testing was difficult to obtain. The infant was fussy for the caregivers. The patient was resuscitated with 2 x 10 per kilo boluses and responded well. Point of care ultrasound noted normal four-chamber cardiac anatomy and squeeze. Given the instability of the patient, a RAM cannula was initiated, and the patient presented to the PICU.

To summarize key elements from this case, this 4-day-old infant has:

• an acute presentation of jaundice and poor feeding
• Prominent GI symptoms and dehydration
• A sepsis-like presentation with hemodynamic instability responsive to fluids
• All of which brings up a concern for inborn error of metabolism, likely galactosemia.
• This episode will be organized…
• Clinical Presentation
• Laboratory Findings & Biochemistry
• Management of Galactosemia

Rahul, let's start with a short multiple choice question:

• Of the following biochemical enzymes, which of the following is deficient in classic galactosemia?
• A. UDP Glucoronyl Transferase
• B. Aldolase B
• C. Galactose 1 Uridyl Transferase
• D. Galactokinase

The correct answer is C. Galactose 1 Uridyl Transferase aka GALT. Classic galactosemia is caused by a complete deficiency of galactose-1-phosphate uridyl transferase (GALT). We should contrast this with galactokinase deficiency. These two present quite differently — GALT deficiency presents like our patient with jaundice, vomiting, hepatomegaly, renal dysfunction, and sepsis. Galactokinase deficiency has less of systemic symptoms and these patients similar to GALT deficiency have cataracts that are usually bilateral and resolved with dietary therapy. To go through our other answer choices, remember that Aldolase B is the rate-limiting enzyme in fructose metabolism, thus a deficiency in this enzyme would cause hereditary fructose intolerance.

With this lead in question, let’s pivot into the biochemistry of galactose and review key lab findings in our patient with galactosemia. Rahul, can you give us a quick summary of how galactose is metabolized in our body?

Galactose is a sugar found primarily in human milk and milk products as part of the disaccharide lactose.

Lactose is hydrolyzed to glucose and galactose by the intestinal enzyme lactase.

The galactose then is converted to glucose for use as an energy source, however it needs a series of reactions:

1. Galactokinase → which catalyzes the rxn galactose to galactose 1 PO4
2. Our rate limiting enzyme Galactose-1-phosphate uridyl transferase (GALT). GALT helps place a sugar moiety on galactose 1 PO4 to turn it into glucose 1 Phos which can then be utilized in glycolysis or glycogenesis.

A complete deficiency in GALT is known as classic galactosemia. If unrecognized, these patients typically develop typically have failure to thrive, liver and kidney dysfunction, and sepsis. If detected later in life or even if treated with dietary modification, these children can have cataracts, abnormal neurodevelopment, and even premature ovarian failure.

So these children can get cataracts, why is that?

Yes, this is interesting and seen in many abnormalities of sugar metabolism. Cataracts may be present at birth but generally appear after two weeks as a result of increased accumulation of a sugar alcohol, galactitol, that is derived from the abnormally metabolized galactose, which ends up depositing in the lens. Cataracts usually are bilateral and can resolve with dietary therapy.

This is a great basic science review, let’s get back to our case now and go into the lab findings which were found in our patient. Remember thus far, the patient came to the PICU on RAM cannula after resuscitation due to hemodynamic instability…

Yes, so this patient’s labs were notable for transaminitis, an elevated PT to 51.3, and an INR of 5.5. He was treated empirically with intravenous (IV) antibiotics and fresh frozen plasma with little change in status, and liver transplantation was discussed with the parents early in his course. On DOL 4, 6, his NBS was reported as having low GALT activity, concerning for galactosemia, and he was placed on a galactose-restricted diet. An RBC enzyme testing for GALT and DNA testing were sent. Notably, his blood culture resulted, and was noted to have gram-negative rods, which ended up being pan sensitive E Coli.

This is a classic presentation of Galactosemia, can you go break down his labs & presentation a bit?

Yes, among infants with galactosemia who present with sepsis, the most common organism is Escherichia coli  - this is seen in about 76 percent of cases. Less frequent findings are coagulopathy, ascites, and seizures. Please note, the principal cause of early mortality in classic galactosemia is sepsis, most often caused by Escherichia coli.

To summarize, classic galactosemia should be considered in any newborn who presents with the findings noted in our case which include — jaundice, vomiting, hepatomegaly, poor feeding, failure to thrive, lethargy, diarrhea, or sepsis; it should also be suspected in any infant with a positive newborn screening (NBS) test. It is important to note, that affected infants may become symptomatic before NBS results are available.

Great point, say you have an NBS which notes an abnormal GALT enzyme or a high clinical suspicion. What is the gold standard for diagnosis?

The demonstration of nearly complete absence of galactose-1-phosphate uridyl transferase (GALT) activity in red blood cells (RBCs) is the gold standard for diagnosis. A quantitative assay of RBC GALT activity (using a fluoroimmunoassay or radioimmunoassay) is necessary to confirm the diagnosis.

It is important to note that quantitative assay of RBC GALT activity may be affected for as long as three months by any RBC transfusion, so holding an extra red top during the initial presentation is important when you have a broad differential.

Once we have confirmed the diagnosis or even have a very high index of suspicion, what is our management framework in these children?

Supportive care & hallmarks of critical care are very important. The main goal of long-term treatment of classic galactosemia is to minimize dietary galactose intake. Galactose should be excluded from the diet as soon as galactosemia is suspected. Other initial care should be provided as needed to treat jaundice, sepsis, and abnormalities of the liver, kidneys, and central nervous system. Supportive therapy typically includes hydration, antibiotics, and treatment of coagulopathy, although problems usually resolve quickly after the dietary treatment is begun.

It is important to have close communication with the metabolic team as well as your dietitians in the PICU. These children are typically placed on soy-based infant formulas appropriate for galactosemia which include Alsoy, Isomil, Nursoy, and ProSobee.

Lactose-free infant formulas should not be used, because they have not been proven to be safe for patients with galactosemia.

The dietary component is very important as long-term you will be monitoring these children’s neurodevelopment, growth, ovarian function, and vision.

In a survey of 177 patients with galactosemia who were at least six years old and had no other cause for poor outcome, 45 percent had developmental delay and many affected children had speech and language problems. Moreover, premature ovarian failure occurred in most females with classic galactosemia, affecting 81 percent of females in this study.

Great discussion today! If you’re interested in more inborn errors of metabolism feel free to check out our episodes on this podcast topic would integrate with our past episode, Acute Metabolic Emergencies in the PICU.

Let’s summarize today’s podcast:

1. Classic galactosemia is caused by complete deficiency of galactose-1-phosphate uridyl transferase (GALT). It is an autosomal-recessive disorder and detected on NBS in all states in the US.
2. Newborns with a positive screening test for galactosemia should be changed immediately to a soy-based infant formula pending confirmation of the diagnosis.
3. Infants with classic galactosemia usually present in the first few days after initiation of galactose-containing human breast milk or cow's milk-based feedings. Signs and symptoms include jaundice, vomiting, hepatomegaly, failure to thrive, poor feeding, lethargy, diarrhea, and sepsis (particularly due to Escherichia coli).

This concludes our episode on the approach to Galactosemia. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

References

• National Newborn Screening and Genetics Resource Center; 2002 Newborn Screening and Genetic Testing Symposium.
• Lak R, Yazdizadeh B, Davari M, et al. Newborn screening for galactosaemia. Cochrane Database Syst Rev 2017; 12:CD012272.
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• Welling L, Bernstein LE, Berry GT, et al. International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. J Inherit Metab Dis 2017; 40:171.