Galactosemia

Normal metabolic pathway for galactose in humans. 
https://en.wikipedia.org/wiki/Galactosemia

Introduction

During normal digestion of milk and dairy products, the body breaks down lactose, a disaccharide into glucose and galactose. The metabolism of galactose produces fuel for cellular metabolism through its conversion to glucose-1-phosphate in a series of reactions commonly referred to as the Leloir pathway. Galactose plays an important role in the formation of glycoproteins, glycolipids, and glycosaminoglycans.

Pathophysiology

An elevated blood galactose concentration is the result of altered metabolism of galactose due to a genetic deficiency in enzyme activity or secondary hypergalactosemia due to liver disease (congenital hepatitis, patent ductus venosus, congenital hepatic AVM). This review will focus on galatactosemia caused by deficient enzyme activity. Galactosemia results from the deficiency of one of three different enzymes, each with a distinct phenotype.

Classic galactosemia (Incidence- 1/60,000) refers to the complete deficiency of the GALT enzyme, inherited in an autosomal recessive pattern with over 150 mutations currently identified. Prenatal diagnosis can be made with a GALT assay in fibroblasts cultured from amniotic fluid or a chorionic villus biopsy and may be undertaken if high index of suspicion or positive family history is present. Mutation analysis is usually not useful for prognosis or therapy because the phenotype does not necessarily correlate with genotype. Additionally, because of the high number of identified mutations, negative results of genetic panels do not exclude the possibility of disease. There are numerous variants where GALT activity is impaired, but not absent, resulting in mild or absent symptoms (such as the Duarte variant).

Signs/Symptoms

Symptoms appear early in the neonate as the average newborn normally receives up to 20% caloric intake as lactose. Without the GALT enzyme, the infant is unable to metabolize galactose-1-phosphate, and the resulting accumulation leads to injury in the kidney, liver, and brain. The injury can begin prenatally in the affected fetus via transplacental delivery of galactose or by endogenous production of galactose in the fetus.

Presenting Symptoms include: Jaundice (74%), Vomiting (47%), Hepatomegaly (43%), Failure to thrive (29%), Lethargy (16%), Sepsis (10%), particularly due to E.coli, is the principle cause of early mortality (exam favorite!)

A mutation common in Hispanic/African American individuals is associated with a milder presentation and these children can present later in childhood.

Physical Exam: hepatomegaly, hypotonia, edema, ascites, full fontanelle, encephalopathy, and excessive bruising or bleeding.

Lab Findings

1. Liver dysfunction- conjugated/unconjugated hyperbilirubinemia, abnormal LFTs, coagulopathy, increased plasma aa (phenylalanine, tyrosine, methionine)
2. Renal tubular dysfunction- metabolic acidosis, galactosuria and glycosuria, albuminuria
3. Abnormal carbohydrate metabolism- increased plasma galactose and RBC galactose-1-P concentration, increased blood and urine galactitol levels
4. Hemolytic anemia

Diagnosis

Most states include galactosemia in their newborn screen. However, many babies who test positive on the newborn screen do not have classical galactosemia, so it is important to consider the secondary causes of hypergalactosemia. 

An infant with a positive newborn screen should be changed immediately to a soy-based infant formula and evaluated for signs of sepsis and hepatic failure. The screen should also be repeated. If the second screen is positive, the gold standard for diagnosis is a quantitative assay of erythrocyte GALT which measures the level of enzyme activity.

1. Fluorimetric assay- Can give a false negative if within three months of blood transfusion. This assay does not detect galactokinase or epimerase deficiency. Can also cause a false positive if G6PD deficient.
2. GALT electrophoresis- Helps to distinguish between classic galactosemia and the “Duarte variant”, where some enzyme activity is present.
3. Bacterial inhibition assay- Detects elevated blood galactose. Can result in false negatives with poor feeding, soy intake, or antibiotic use. Galactose can also be mildly elevated in normal newborns (6-10 mg/dl).

If the RBC GALT assay is normal, evaluate for GALK and GALE abnormalities.

Conversely, affected infants may become symptomatic before screening results are available. Testing the urine for reducing substances (such as galactose) is a quick test which can be done in the pediatrician's office to gauge the level of suspiscion for galactosemia, however this test should be interpreted carefully as it can result in false positives and negatives.

Prognosis

With proper dietary management, most patients with classic galactosemia are healthy and intellectually normal during childhood, but frequently develop symptoms during adolescence and adulthood. It is not clear why dietary restriction of galactose fails to prevent long-term complications, current theories include the impact of endogenous production of galactose, accumulation of galactose-1-phosphate or abnormal galactosylation.

1. Neurodevelopment- Problems with speech and language function; dietary compliance and RBC galactose-1-P levels do not appear to affect IQ (averages from 70-90). Focal findings such as tremor, ataxia, and dysmetria
2. Ovarian failure- Premature ovarian failure (81%), increased LH/FSH consistent with hypergonadotrophic hypogonadism
3. Cataracts- Sublenticular cataracts (30%), detected after two weeks of age, the result of galactitol deposition in the lens
4. Notably, some reports have described age-related decreases in IQ

Management

If a neonate presents in crisis and classical galactosemia is suspected or confirmed, restriction of dietary galactose should be always be started immediately. Additionally, Vitamen K supplementation, FFP administration, initiation of antibiotics with good gram negative coverage and implementation of phototherapy should be considered.

The treatment for galactosemia is to minimize dietary galactose by excluding milk and dairy products. Soy formulas can be used but remember, some lactose free formulas do contain galactose. Parents should also be reminded to ask pharmacists about galactose content in medications. Fruits and legumes are insignificant sources of galactose and do not need to be restricted. After 1 year, calcium should be supplemented. Blood and urine concentrations of galactose remain elevated in classic galactosemia, with dietary restriction, due to endogenous galactose production.

Some physicians have raised the idea that lactose/galactose restriction can be relaxed in adulthood since endogenous galactose production slows with age, others even suggest continued galactose restriction is harmful, however both of these claims are controversial.

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Follow-Up

While traditionally, the follow-up care of patients affected by galactosemia was centered around the monitoring of biochemical markers, the inability to treat long-term effects based on those markers has caused a shift in focus towards the early detection and treatment of functional deficits using a multi-disciplinary approach.

1. Every 6 month testing of RBC galactose-1-P (every 3 months up to 3 years)
2. Annual evaluation of speech and cognitive function after age two
3. Eye exams every six months up to 3 years and then annually for cataract detection
4. Yearly dietary assessment
5. FSH, LH, estradiol measurement in girls at age 10

Future Treatment

Due to the theorized role of galactose-1-phosphate in long-term complications seen in classical galactosemia, several galactokinase (GALK) inhibitors have been identified and are currently in animal trials. Researchers are hopeful that GALK inhibition could prevent build-up of galactose-1-phostphate and thus decrease disease burden.

 
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References

1. Bosch A. Classical Galactosaemia Revisited. J Inherit Metab Dis (2006) 29:516-525.
2. Berry G. Galactosemia: When is it a newborn screening emergency? Mol Genet and Metab (2012) 106:7-11.
3. Kaye C. Newborn Screening Fact Sheets. Pediatrics (2006) 118:e947-e948.