Genetic counseling: Galactosemia

Galactosemia

Introduction

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

Diagnosis
Variant Galactosemia
 * 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
 * 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
Genotype-Phenotype Correlations
 * Classic galactosemia -- based on the results of newborn screening programs, is approximately 1/30,000
 * Carrier rate is 1:112
 * 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
Risk To Family Members
 * 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 so all of these milk products must be replaced by a formula such as Isomil or Prosobee
 * 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.
 * 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