Galactosemia

From Iusmgenetics

Contents 1 Galactosemia 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

[edit] Galactosemia

[edit] General background information

• Galactosemia encompasses 3 autosomal recessive disorders: galactose 1-p uridyltransferase (GALT), galactokinase, epimerase
  • Galactokinase deficiency: 1 / 150K
  • Epimerase deficiency: rare
  • Note the locus heterogeneity
• Galactosemia is a syndrome of galactose toxicity
• Galactosemia incidence is 1 / 62K

[edit] Mode of inheritance

• Autosomal recessive

[edit] Single important gene

• There are actually three important enzymes that can cause galactosemia when defective: galactose 1-p uridyltransferase (GALT), Galactokinase, Epimerase
• 

[edit] Etiology

• Accumulation of two products cause disease states: Gal-1-P and Galactitol.
• Depletion of UDP causes disease state, too.
• Galactose-1-phosphate causes liver toxicity.
• Galactitol causes cataracts.
• Classic Galactosemia can be caused by two different alleles: the "inactive allele" or the "variant / Duarte allele" in galactose 1-p uridyltransferase (GALT)
  • Inactive allele: Gln188Arg
    • 70% of inactive alleles have this mutation
    • Allele frequency of 1/278
  • Variant / Duarte allele: Asn314Asp
    • causes 50% activity of the GALT
• Compound heterozygotes (one inactive allele and one duarte allele) require treatment but only for the first year of life
• Los Angeles alleles produce GALT with 140% activity and do not cause disease.
• 

[edit] Pathogenesis

[edit] Phenotypic information

• GALT deficiency: classic galactosemia:
  • Symptoms of galactosemia present soon after consumption of galactose-containing (milk or milk-based) foods:
    • Vomitting, refusal to feed, failure to thrive, lethargy, liver disease (hepatomegally, jaundice), cataracts, edema, sepsis, encephalopathy, developmental delay (mental retardation), seizures, brain damage
  • Note that brain damage is irreversible
  • Galactosemia is a serious, emergent newborn screening result.
    • May be fatal if left untreated.
    • Symptoms can begin to show even before the screen results have been returned.

• Galactokinase deficiency
  • Mild
  • Catracts
  • No liver involvement
  • No mental retardation

• Epimerase deficiency
  • Similar to classic galactosemia

[edit] Diagnosis

• Galactosemia is part of the newborn screen.
  • There are two methods for screening: elevated galactose / gal-1-p levels in blood OR test for deficient GALT enzyme activity in RBCs
  • The GALT enzyme activity level is susceptible to heat exposure and false positives may arise.
  • However, GALT enzyme activity is accurate at any time but galactose / gal-1-p levels requires the ingestion of milk (otherwise it might generate a false negative).

[edit] Treatment

• Galactose-free diet
  • Begin a galactose-free diet as soon as there is a suspicion of galactosemia--even if screening results aren't back yet.
  • Proper diet can reverse most newborn symptoms and prevent many sequelae (liver disease, mental retardation, cataracts).
• IQ often declines with age
• Females can have gonadal dysfunction
• Many foods contain galactose (fruits and vegetables), thus, strict control is a long-term problem.

[edit] Recent research

[edit] 5 important facts

[edit] Not to be confused with

[edit] Questions and answers