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Genetic counseling: Galactosemia

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Galactosemia

IntroductionEdit

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

DiagnosisEdit

  • 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 ProblemsEdit

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

PrevalenceEdit

  • 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 DiagnosisEdit

  • 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

ManagementEdit

  • 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.

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 TestingEdit

  • 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.

ResourcesEdit

  • 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

NotesEdit

The information in this outline was last updated in 2001.


This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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