GALACTOSEMIA

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 (see below). Galactose plays an important role in the formation of glycoproteins, glycolipids, and glycosaminoglycans.

Galatactosemia is the altered metabolism of galactose due to deficient enzyme activity or impaired liver function resulting in elevated blood galactose concentration. 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. There are numerous variants where GALT activity is impaired, but not absent.

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 to the parenchymal cells of the kidney, liver, and brain. The injury can begin prenatally in the affected fetus via transplacental galactose from the diet of the heterozygous mother or by endogenous production of galactose in the fetus.   Because of this endogenous production of galactose, dietary restriction alone may not be sufficient to prevent the adverse outcomes related with this disease.

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

Physical Exam: Infants appear jaundiced, with hepatomegaly, lethargy, and hypotonia. They can have edema and ascites, a 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

Outcome: Most states include galactosemia in their newborn screen. However, affected infants may become symptomatic before screening results are available. With proper dietary management, most patients are healthy and intellectually normal during childhood, but frequently develop symptoms during adolescence.

1. Neurodevelopment- Problems with speech and language function; dietary compliance and RBC galactose-1-P levels do not appear to affect IQ. Focal findings such as tremor, ataxia, and dysmetria (inability to control actions)
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

Genetics: This is an autosomal recessive disease 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 mean there is no disease.

Screening: An infant with a positive newborn screen should be changed immediately to a soy-based infant formula and the screen should be repeated. If the second screen is positive, a quantitative assay of erythrocyte GALT confirms the diagnosis and 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).

*Research is currently being undertaken to attempt to elucidate the optimal cut-offs for further work-up after positive newborn screening in order to reduce false positives and stress on healthcare resources.

Management: 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. 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.

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 Directions: Galactosemia is a classic example of a pediatric metabolic disorder that may be studied as a model to understand biochemical pathways, early screening, biochemical diagnosis, and genetic disorders.  Much remains to be discovered, however, with regard to the pathophysiology of the morbidity caused by this disorder.  Future research must seek to explore the mechanisms by which deficits and disease are caused in order to develop better treatments and prevention of these deficits.  For example, exploration into the epigenetic effects of the disease has yielded insight into key-altered genes in galactosemia that cause errors in cell signaling and other cellular functions whose full significance is not yet well-understood.
 
 
 

References:

1. Sutton VR. Galactosemia. Up To Date. 2002.
2. Bosch A. Glassical Galactosaemia Revisited. J Inherit Metab Dis (2006) 29:516-525
3. Hinman AR. The Importance of Newborn Screening. Pediatrics. Sep 2001; 108(3): 821
4. Behrman: Nelson Textbook of Pediatrics, 16^th ed (2002). Philadelphia: W.B. Saunders Company.
5. Elsea S. Lucas R. The Mousetrap: What We Can Learn When the Mouse Model Does Not Mimic the Human Disease. ILAR Journal. V43(2) 2002
6. Guerrero NV. Risk factors for premature ovarian failure in females with galactosemia. Journal of Pediatrics. Dec 2000; 137(6): 833-841.
7. Coman D et al. Galactosemia, a Single Gene Disorder with Epigenetic Consequences. Pediatric Research. Vol. 67(3) 2010
8. Freer D et al. Newborn Screening for Galactosemia: A Review of 5 Years of Data and Audit of a Revised Reporting Approach. Pediatric Clinical Chemistry. 56:3. 437-444 (2010)