Handbook of Genetic Counseling/Galactosemia

Galactosemia

Introduction

• Disorder of galactose metabolism
• Usually caused by deficient activity of enzyme galactose-phosphate uridyltransferase (GALT)
• Autosomal recessive inheritance

Diagnosis

• Detected in virtually 100% of affected infants if included in newborn screen
• Presents with poor suck, failure to thrive, bleeding diathesis, and jaundice, hypoglycemia, hepatocellular damage, and hyperammonemia
• If untreated in infants can result in
  • Liver damage
  • Sepsis
  • Mental retardation
• If suspected remove lactose from diet while tests are pending
• If placed on lactose - galactose restricted diet than symptoms quickly resolve and can prevent permanent damage
• Despite early treatment still at increased risk for
  • developmental delays
  • speech problems
  • abnormalities of motor function
  • poor growth
  • poor intellectual function
  • premature ovarian failure in women
• With continued dietary management-- many individuals with galactosemia have good health, and are able to lead independent lives
• Outcome can be based on GALT activity, genotype, age at diagnosis and compliance with lactose restriction
• Diagnosis made by measuring erythrocyte GALT activity and isoelectric focusing of GALT
  • Done for infants who have a positive newborn screening test, symptoms, or a positive clinitest reaction (copper oxidizing aldehyde) and a negative glucostix reaction (glucose oxidase impregnated strip)
  • Classic galactosemia G/G homozygote activity less than 5% of control
  • Heterozygote G/N GALT activity about 50% of control
  • Duarte variant activity between 5-20% (express stronger activity bands, which move toward the anode and lower pH)
• Mol gen testing of GALT gene (chromosome 9p13) clinically available for biochemically confirmed galactosemia and is used for:
  • prognostic information
  • heterozygote detection
  • genetic counseling,
  • prenatal diagnosis
• Biochemical assays also necessary for diagnosis and as therapeutic parameters include:
  • Erythrocyte galactose-1-phosphate -- metabolism of this precursor is blocked in the GALT reaction sequence --Concentration of erythrocyte galactose-1-phosphate exceeds 2mg/dl in untreated individuals and can be used to monitor the effectiveness of therapy.
  • Galactitol is a product of an alternate pathway for galactose metabolism and can be measured in the urine. Correlation with other measures may not be perfect.
  • Total body oxidation of 13C-galactose to 13CO 2 in breath is a good predictor of outcome and differentiates forms of galactosemia that reduce GALT activity in erythrocytes, but not liver

Variant Galactosemia

• partial impairment of GALT activity (2% to 10% residual activity)
• some aspects of classical galactosemia, such as early cataracts, mild mental retardation with ataxia, and growth retardatio
• may have dyspraxic speech, and females may have amenorrhea or early menopause

Common Long Term Problems

• memory problems
• neurological problems (tremors and trouble with balance and gait).
• Cataracts

Prevalence

• Classic galactosemia -- based on the results of newborn screening programs, is approximately 1/30,000
• Carrier rate is 1:112

Genotype-Phenotype Correlations

• Significant correlations being found
• arginine substitution for a glutamine at amino acid position 188 (Q188R) accounts for about 70% of the G alleles in the Caucasian population with northern European ethnicity. Homozygotes have no enzyme activity
• some studies found greater proportion of patients with a poor outcome were homozygous for the Q188R mutation, and a greater proportion with a good outcome were not homozygous for the Q188R
• Duarte variant is the allele in which an aspartate substituted for asparagine at position 314 (N314D) imparts bioinstability to the GALT enzyme.
• In the homozygous state (D/D or N314D/N314D), erythrocyte GALT enzyme activity is reduced by only 50%.
• Compound heterozygotes with this mutation (i.e., D/G or N314D/Q188R) have good prognoses and it is not clear whether dietary intervention is required
• The S135L allele, in which a leucine is substituted for serine at amino acid 135, is prevalent in Africa. African-Americans with galactosemia and this allele in either homozygous or compound heterozygous state have a good prognosis because of lack of neonatal hepatotoxicity and chronic problems if therapy is begun early
• An asparagine substitution for a lysine at position 285 (K285N) is prevalent in southern Germany, Austria, and Croatia and has a poor prognosis for neurological and cognitive dysfunction in either the homozygous state or compound heterozygous state with Q188R.

Differential Diagnosis

• for neonatal hepatotoxicity
  • infectious diseases
  • obstructive biliary disease
  • other metabolic diseases such as (Niemann-Pick Disease, Type C1 and Wilson disease).
• Galactokinase deficiency
  • should be considered in patients who have cataracts and galactosemia but healthy
  • have normal GALT activity
  • reduced galactokinase activity is diagnostic and is what causes cataracts
• Epimerase deficiency
  • should be considered in patients who have liver disease, sensorineural deafness, failure to thrive, and elevated galactose-1-phosphate, but normal GALT activity
  • Detection of reduced epimerase activity is diagnostic

Management

• Immediate dietary intervention is indicated in infants whose GALT activity is less than 10% of control activity
• Human milk, cow's milk and many formulas have lactose. There are currently many infant formulas that do not contain lactose, to choose from. These include soy-based formulas, such as Isomil or Prosobee, specialty formulas based on hydrolysed casein, such as Nutramigen or Alimentum and formulas based on cow's milk, in which the lactose has been removed and replaced with other sugars, including Similac Sensitive and Enfamil Lactofree. Additionally, it is important to know that Galactosemia may be less severe in some infants, allowing for partial breastfeeding.
• Ideally blood gal-1-p level below 3 to 4 mg/100 ml
• galactose-restricted diet should keep blood gal-1-p at this level, while containing enough nutrients for normal body function
• The diet allows most protein-containing foods other than milk and milk products. Fruits, vegetables, grains, breads, fats and sugars are acceptable, as long as they do not have ingredients that contain galactose
• Food labels should be read carefully
• Medicines should be checked because lactose often an inactive ingredient
• Dietary supplements only taken when recommended because inactive ingredients not listed
• people with galactosemia should have a regular daily supplement of calcium either from a soy formula or tablets
• Dietary restrictions on all lactose-containing continue throughout life
• Uridine supplements have not been of value.
• Recent research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 2.0 g per day
• The efficiency of restricting lactose in the diets of women who are at risk for having a child with galactosemia is unknown.
• Agreement has not been reached on whether individuals with variant forms of galactosemia with residual GALT activity in the range of 3% to 20% should be restricted from galactose intake during infancy and early childhood --possible that dietary restriction of galactose might prevent sequelae such as cataracts, ataxia, dyspraxic speech, and cognitive deficits.

Risk To Family Members

• Unaffected parents of an affected individual are obligate heterozygotes and carry at one disease-causing GALT allele
• Such carriers are asymptomatic and do not develop galactosemia
• Appropriate and can be important to determine the disease-causing GALT alleles in the parents of an affected child to establish the risk for galactosemia in future pregnancies
• Affected individuals have a risk for premature ovarian failure, but may have children. Children born to one parent with (G/G) galactosemia and one parent with two normal alleles (N/N) are obligate heterozygotes (N/G)
• If one parent is affected (G/G) and the other parent is a carrier for a G allele (N/G or D/G), the child has a 50% chance of being a heterozygote and a 50% chance of having G/G galactosemia

Prenatal Testing

• possible for fetuses at 25% risk for classical (G/G) galactosemia using either GALT enzyme activity or molecular genetic testing if the disease-causing GALT mutations in the family are known
• Enzyme analysis and molecular diagnosis rely upon cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks' gestation* or amniocentesis at 16-18 weeks' gestation.

Resources

• Galactosemia Support Group

31 Cotysmore

Sutton Coldfield

West Midlands, B75 6BJ, UK

Phone: 0121 378 5143

• Adult Metabolic Transition Project

depts.washington.edu/transmet/gal.html

• Children Living with Inherited Metabolic Diseases (CLIMB)

The Quadrangle, Crewe Hall

Weston Road, Crewe

Cheshire, CW1 6UR, UK

Phone: 01270 250221

Fax: 01270 250224

www.climb.org.uk

• http://www.tdh.state.tx.us/newborn/handbook.htm -- great website for parent of newly diagnosed child
• http://www.galactosemia.org/ -- website for parent support group
• http://www.galactosemiaresource.com --site providing parents with links to research, support groups and provides a matching service to other galt parents in the same state

Notes

The information in this outline was last updated in 2001.