GALACTOSEMIA

Definition: Milk and dairy products contain lactose (glucose + galactose), the major dietary source of galactose. The metabolism of galactose produces fuel for cellular metabolism through its conversion to glucose-1-phosphate. Galactose also 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.
 
Disorder
Enzyme Deficiency
Symptoms
Description
* Classic Galactosemia Galactose-1-phospate uridyl transferase (GALT) Liver and renal dysfunction, cataracts, abnormal neurodevelopment, premature ovarian failure Most common and most severe form. 
Galactokinase Deficiency Galactokinase Bilateral cataracts, will resolve with dietary therapy Benign 
Generalized UDPgalactose-4-epimerase Deficiency Uridine diphosphate galactose 4-epimerase Similar to classic galactosemia with additional findings of hypotonia and nerve deafness Benign variant is common, when the defect is localized to red blood cells- no treatment required

* Classic galactosemia refers to the complete deficiency of the GALT enzyme. There are numerous variants where GALT activity is impaired, but not absent.

Classic Galactosemia: (Incidence- 1/60,000)

Symptoms appear early in the neonate. 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 by transplacental galactose from the diet of the heterozygous mother or by endogenous production of galactose in the fetus.

Clinical Symptoms:

· Jaundice (74%)

· Vomiting (47%)

· Hepatomegaly (43%)

· Failure to thrive (29%)

· Lethargy (16%)

· Sepsis (10%)- E.coli is the principle cause of early mortality

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 LFT’s, 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
Genetics: This is an autosomal recessive disease with over 150 mutations identified. Prenatal diagnosis can be made with a GALT assay in fibroblasts cultured from amniotic fluid or a chorionic villus biopsy. Mutation analysis is usually not useful for prognosis or therapy because the phenotype does not necessarily correlate with genotype.

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).
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:

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

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    References:

    1. Sutton VR. Galactosemia. Up To Date. 2002.
    2. Hinman AR. The Importance of Newborn Screening. Pediatrics. Sep 2001; 108(3): 821
    3. Behrman: Nelson Textbook of Pediatrics, 16th ed (2002). Philadelphia: W.B. Saunders Company.
    4. Guerrero NV. Risk factors for premature ovarian failure in females with galactosemia. Journal of Pediatrics. Dec 2000; 137(6): 833-841.