Classic galactosemia (G/G) is an autosomal recessive disor- der of galactose metabolism, caused by a deficiency of galac- tose-
L-phosphate uridyl transferase. The incidence is estimated to be 1 in 30,000 births, based on the results of newborn screening programs.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal recessive
2. Cause: deficiency of galactose-
L-phosphate uridyl transferase (GALT)
3. Galactose-
L-phosphate uridyl transferase
a. The gene for GALT is mapped on chromosome 9p13 b. GALT is second enzyme in the Leloir pathway, cat- alyzing conversion of galactose-
L-phosphate and UDP glucose to UDP galactose and glucose-
L-phosphate c. Essential in human infants who consume lactose as
their primary carbohydrate source
d. Near total absence of GALT activity in infants with classical galactosemia
e. A deficiency causes elevated levels of galactose-
L
-phosphate and galactitol in body tissues
4. Endogenous production of galactose may be responsible for the long-term effects, such as cognitive dysfunction and gonadal dysfunction in female patients
5. Duarte (D) allele a. Very common
b. Defined biochemically by:
i. Reduced enzyme activity
ii. An isoform distinguishable by gel electrophoresis and isoelectric focusing
c. Heterozygous Duarte variants (D/N)
i. Observed in about 11% of Caucasian subjects ii. Have about 75% of normal GALT activity d. Homozygotes for the Duarte variant (D/D)
i. Have approximately one half (50%) of normal transferase activity
ii. Mimic carriers for galactosemia
e. Infants with a galactosemia allele and a Duarte allele (D/G)
i. Have one-quarter (25%) of normal enzyme activity ii. Have reduced capacity to metabolize galactose with abnormal accumulation of galactose-
L- phosphate in the red cells
iii. Phenotypically normal with no ill effect 6. Genotype-phenotype correlations
a. Q188R mutations (prevalent in 70% of Caucasians): a poorer outcome in homozygous state associated with essentially no enzyme activity
b. Duarte variant (N314D)
i. Homozygous state (D/D or N314D/N314D) with erythrocyte GALT enzyme activity reduced by only 50%
ii. Compound heterozygotes (D/G or N314D/Q188R) a) Relatively benign in most infants
b) May or may not require dietary intervention c. Los Angels (LA) variant with identical N314D mis- sense mutation but has normal erythrocyte GALT activity
d. S135L allele
i. Prevalent in Africa
ii. A good prognosis if therapy is initiated in the neonatal period without neonatal hepatotoxicity and chronic problems
e. K285N allele
i. Prevalent in Southern Germany, Austria, and Croatia
ii. A poor prognosis for neurological and cognitive dysfunction in either the homozygous state or compound heterozygous state with Q188R
CLINICAL FEATURES
1. Onset of symptoms
a. May present by the end of the first week of life b. May die or develop cataracts, hepatomegaly, cirrhosis,
and mental retardation in late-detected cases 2. Neonatal toxicity syndrome
a. Exposure to dietary galactose in infants with classical galactosemia results in acute deterioration of multiple organ systems, including the following:
i. Liver dysfunction a) Jaundice b) Hepatomegaly ii. Coagulopathy
iii. Poor feeding and weight loss iv. Vomiting and diarrhea
v. Lethargy and hypotonia vi. Renal tubular dysfunction vii. Cerebral edema (encephalopathy) viii. Vitreous hemorrhage
ix.
Escherichia coli sepsisb. Withdrawal of dietary galactose results in reversal of neonatal toxicity syndrome and reducing mortality and morbidity in the early weeks of life
3. Cataracts
a. Resulting from accumulation of galactitol within the lens
b. Seen in infants with classical GALT-deficient galac- tosemia (and also in galactokinase deficiency)
i. The ocular hallmark of untreated or late-detected patients
ii. Severity of lens involvement dependent on the severity of galactosemia and the age at com- mencement of therapy
437
c. Reoccur in older patients who have poor dietary compliance
d. May be prevented by dietary restriction of galactose 4. Ovarian failure
a. Hypergonadotropic hypogonadism occurring almost universally ( >90%) in females with classical GALT deficiency
b. The rapidity and severity of the ovarian failure vary widely among individuals
c. Clinical manifestations i. Delayed puberty ii. Primary amenorrhea iii. Secondary amenorrhea
iv. Oligomenorrhea 5. Chronic brain effects
a. Specific deficits
i. Developmental speech dyspraxia and tremor ii. Globally decreased IQ and/or learning disability b. Uncertainty as to:
i. Whether these deficits are initiated in early devel- opment, perhaps even prenatally, and unmasked, as more complex brain function is required ii. Whether these deficits represent true neurode-
generative processes compounded by dietary exposure and endogenous production of
“intoxicants”
6. Prognosis
a. A life-threatening disorder if untreated
b. Currently, affected infants are treated before becom- ing ill because of newborn screening in most states 7. Differential diagnosis
a. Galactokinase (GALK) deficiency i. An autosomal recessive disorder
ii. Considered in patients with cataracts and galac- tosemia but otherwise healthy
iii. Cataracts
a) The main clinical feature
b) Due to accumulation of galactitol iv. Pseudotumor cerebri
a) Described in several cases
b) Considered to be a true consequence of the disorder
v. These features resolve when a galactose-restricted diet is introduced
vi. Diagnosis made by detection of reduced galac- tokinase activity
vii. Caused by mutations in the GALK1 gene b. UDP-galactose 4-epimerase (GALE) deficiency
i. An autosomal recessive disorder
ii. Considered in patients with liver disease, sen- sorineural deafness, failure to thrive, and elevated galactose-
L-phosphate but normal GALT activity iii. Response to the removal of galactose from their
diets
iv. Diagnosis made by detection of reduced UDP- galactose 4-epimerase activity
v. Caused by mutations in the GALE gene c. Neonatal hepatotoxicity
i. Infectious diseases (sepsis) ii. Obstructive biliary disease
a) Progressive familial intrahepatic cholestasis (Byler disease)
b) Metabolic diseases such as Niemann-Pick disease, type C and Wilson disease
DIAGNOSTIC INVESTIGATIONS
1. Newborn screening programs in most states
a. An almost 100% detection of affected infants in states that include testing for galactosemia in their newborn screening programs
b. Prevention of needless deaths associated with galac- tosemia, resulting from limiting diagnostic measures to infants who develop symptoms
c. A positive (i.e., abnormal) screening, followed by a quantitative erythrocyte GALT analysis
2. Liver dysfunction
a. Bilirubin determination
i. Initial unconjugated hyperbilirubinemia ii. Later conjugated hyperbilirubinemia b. Abnormal liver function tests
c. Abnormal clotting
d. Raised plasma amino acids, particularly phenylala- nine, tyrosine, and methionine. Raised phenylalanine may result in a false positive neonatal screening test for phenylketonuria
3. Renal tubular dysfunction a. Metabolic acidosis b. Urinalysis
i. Galactosuria
a) The presence of reducing substances or galactose in the urine is neither sensitive nor specific
b) Small quantities of galactose commonly found in the urine of any patient with liver disease ii. Albuminuria
a) Present in the initial stage
b) Quick disappearance of albuminuria after eliminating lactose-containing formula from the diet
iii. Aminoaciduria in the later stage 4. Abnormal carbohydrate metabolism
a. Increased plasma galactose
b. Increased red cell galactose-
L-phosphate c. Increased urine and blood galactitol 5. Testing for hemolytic anemia
6. Study for septicemia, especially Escherichia coli 7. Slit lamp examination for cataract assessment
8. Computerized tomography and magnetic resonance imaging a. Abnormalities on brain imaging: common in classical
galactosemia
b. Patients with late neurologic disease i. Abnormal white matter ii. Ventricular enlargement
iii. Diffuse cortical atrophy with basal ganglia and brainstem involvement
iv. Cerebellar atrophy
v. Failure of normal myelination
9. Endocrine investigations for hypergonadotropic hypo-
gonadism
a. Raised follicle stimulating hormone b. Raised luteinizing hormone
c. Initially normal estradiol concentration with high gonadotropin levels, indicating continued follicular development, but fall as ovarian failure progresses 10. Increased urinary galactitol excretion
11. Beutler test
a. A fluorescent spot test for galactose-
L-phosphate uridyl transferase activity
b. Now widely used for the diagnosis of galactosemia c. False negative resulting from recent blood transfu-
sions (within 3 months)
d. False positive resulting from glucose-6-phosphate dehydrogenase deficiency
12. Red blood cell galactose-
L-phosphate
a. Concentration always raised in classical galactosemia b. Not significantly affected by blood transfusions 13. Biochemical confirmation of the diagnosis
a. Red blood cell galactose-
L-phosphate uridyl trans- ferase assay
i. A quantitative assay to confirm the diagnosis (virtual absence of the enzyme activity in classical (G/G) galactosemia)
ii. Also identifies variants with residual enzyme activity
iii. False negative results due to blood transfusion within 3 months
b. A GALT isoelectric-focusing electrophoresis test to distinguish variant forms such as the Duarte defect 14. DNA analysis: GALT genotyping for providing specific
molecular diagnosis
a. Classic (G/G) galactosemia
i. Mutation analysis for the six common GALT galactosemia (G) mutations
a) Q188R mutation: the most common GALT allele in whites
b) S135L: the most common allele in blacks c) K285N
d) L195P e) Y209C f) F171S
ii.
GALT sequence analysis to detect private muta-tions under the following two conditions:
a) Both disease-causing mutations not detected by mutation analysis
b) Diagnosis of galactosemia confirmed by biochemical testing
b. Mutation analysis for Duarte variant (D/G) galac- tosemia identified by biochemical testing of the patient and both parents
i. Identification of Duarte allele (N314D) by muta- tion analysis
ii. Identification of G allele by mutation analysis or sequence analysis
15. Carrier testing
a. Measuring GALT activity: about 50% of control values in carriers
b. Molecular genetic testing for carriers available to family members, provided GALT mutation(s) has/have been identified in the proband
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. A proband with G/G galactosemia
a) Given the parents are G/N and G/N: a 25%
chance of being affected with G/G galac- tosemia for each sib
b) Given the parents are D/G and G/N: a 25%
chance of being affected with G/G galac- tosemia and a 25% chance of being affected with D/G galactosemia for each sib
ii. A proband with D/G galactosemia, given the parents are D/N and G/N: a 25% chance of being affected with D/G galactosemia for each sib b. Patient’s offspring:
i. Patient with G/G galactosemia and the normal spouse with N/N: All offspring are carriers ii. Patient with G/G galactosemia and the carrier
spouse for a G allele (N/G): a 50% chance of having G/G galactosemia
iii. Patient with G/G galactosemia and the carrier spouse for a G allele (D/G): a 50% chance of having G/G galactosemia and a 50% chance of having D/G galactosemia
2. Prenatal diagnosis possible for fetuses at a 25% risk for classical galactosemia
a. Galactose-
L-phosphate uridyl transferase assay in cultured amniotic fluid cells or in chorionic villus biopsies
b. Galactitol estimation in amniotic fluid supernatant c. Mutation analysis of DNA extracted from chorionic
villus biopsy if the genotype of the index case has been characterized
d. Prenatal diagnosis of a treatable condition, such as classic galactosemia, may be controversial if the pre- natal testing is being considered for the purpose of pregnancy termination rather than early diagnosis 3. Management
a. Dietary intervention
i. Lactose-galactose-restricted diet
a) Restrict milk, the principal source of lactose, and products made from milk
b) Breast milk and cows’ milk contraindicated ii. Milk substitutes
a) Use a formula free of bioavailable lactose (e.g., Isomil or Prosobee)
b) Casein hydrolysate (Alimentum, Nutramigen, Pregestimil): not recommended because they contain small amounts of bioavailable lactose
iii. Difficult to totally eliminate galactose since it is present in a wide variety of food, such as infant foods, fruits, and vegetables
iv. Older patients tolerating lactose much better than children, but recommend restrict milk intake throughout life
v. Calcium supplementation
vi. May prevent cataracts, hepatomegaly, liver cir-
rhosis, mental retardation, and other symptoms
vii. Effect of dietary restrictions during pregnancy on the long-term complications of an affected fetus: unknown
viii. Management of D/G or N344D/Q188R com- pound heterozygotes
a) Decision to treat should be based on the demonstration of abnormal biochemical indices
b) No dietary therapy is instituted if the blood galactose and/or galactose-
L-phosphate do not rise above 12 mg/dL within 4 hours fol- lowing such ingestion and there are no clin- ical signs associated with galactosemia c) Dietary therapy should probably be given if
there is a greater accumulation of galactose or of galactose-
L-phosphate
d) There is possible benefit of dietary interven- tion to individuals with variant forms of galactosemia with residual GALT activity in the range of 5%–20%: for prevention of cataracts, ataxia, dyspraxic speech, and cognitive deficits
b. Vitamin K and fresh-frozen plasma to correct clotting abnormalities
c. An appropriate intravenous antibiotic for Gram- negative sepsis
d. Treat unconjugated hyperbilirubinemia with pho- totherapy or exchange transfusion to infants who may be at an increased risk of kernicterus if albu- min levels are particularly low secondary to liver disease
e. Parental feeding if the infant is too sick to tolerate enteral feeding for more than 1 or 2 days, unless there is significant liver disease or thrombocytopenia f. Treat the following long-term problems in older
children and adults with classical galactosemia, despite early and adequate therapy
i. Cataracts ii. Speech defects iii. Poor growth
iv. Poor intellectual function
v. Neurological deficits, predominantly extrapyra- midal findings with ataxia
vi. Ovarian failure
REFERENCES
Anadiotis GA, Berry GT: Galactose-1-phosphate uridyltransferase deficiency (galactosemia). http://www.emedicine.com
Beutler E: Galactosemia: screening and diagnosis. Clin Biochem 24:293–300, 1991.
Burke JP, O’Keefe M, Bowell R, et al.: Ophthalmic findings in classical galac- tosemia—a screened population. J Pediatr Ophthalmol Strabismus 26:
165–168, 1989.
Elsas LJ: Prenatal diagnosis of galactose-1-phosphate uridyltransferase (GALT)-deficient galactosemia. Prenat Diagn 21:302–303, 2001.
Elsas LJ II: Galactosemia. Gene Reviews. 2003. http://www.genetests.org Elsas LJ, Dembure PP, Langley S, et al.: A common mutation associated with
the Duarte galactosemia allele. Am J Hum Genet 54:1030–1036, 1994.
Elsas LJ II, Lai K: The molecular biology of galactosemia. Genet Med 1:40–48, 1998.
Elsas LJ, Lai K, Saunders CJ, et al.: Functional analysis of the human galactose- 1-phosphate uridyltransferase promoter in Duarte and LA variant galac- tosemia. Mol Genet Metab 72:297–305, 2001.
Holton JB: Effects of galactosemia in utero. Eur J Pediatr 154:S77–S81, 1995.
Holton JB, Walter JH, Tyfield LA: Galactosemia. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001.
Jakobs C, Kleijer WJ, Allen J, et al.: Prenatal diagnosis of galactosemia. Eur J Pediatr 154:S33–S36, 1995.
Lai K, Elsas LJ: Structure-function analyses of a common mutation in blacks with transferase-deficiency galactosemia. Mol Genet Metab 74:264–272, 2001.
Lai K, Langley SD, Singh RH, et al.: A prevalent mutation for galactosemia among black Americans. J Pediatr 128:89–95, 1996.
Langley SD, Lai K, Dembure PP, et al.: Molecular basis for Duarte and Los Angeles variant galactosemia. Am J Hum Genet 60:366–372, 1997.
Leslie ND: Insights into the pathogenesis of galactosemia. Annu Rev Nutr 23:59–80, 2003.
Levy HL, Sepe SJ, Shih VE, et al.: Sepsis due to Escherichia coli in neonates with galactosemia. N Engl J Med 297:823–825, 1977.
Nelson MD Jr, Wolff JA, Cross CA, et al.: Galactosemia: evaluation with MR imaging. Radiology 184:255–261, 1992.
Ng WG, Xu YK, Kaufman FR, et al.: Biochemical and molecular studies of 132 patients with galactosemia. Hum Genet 94:359–363, 1994.
Waggoner DD, Buist NR, Donnell GN: Long-term prognosis in galactosaemia:
results of a survey of 350 cases. J Inher Metab Dis 13:802–818, 1990.
Waisbren SE, Norman TR, Schnell RR, et al.: Speech and language deficits in early-treated children with galactosemia. J Pediatr 102:75–77, 1983.
Walter JH, Collins JE, Leonard JV: Recommendations for the management of galactosaemia. UK Galactosaemia Steering Group. Arch Dis Child 80:93–96, 1999.
Fig. 1. A 5-year-old boy with classical galactosemia. The initial clin- ical presentation was at 12 days of age with unconjugated hyperbiliru- binemia, presence of reducing substance in the urine, and E. coli sepsis.
The patient was found to have posterior stellate lens opacities OU. He was found to have deficient galactose-L-phosphate uridyltransferase activity of 0.3 (normal range: 17–37 μM/h/g Hgb). Galactokinase was within normal limits. The patient was put on galactose-free diet and has been growing well.
Fig. 2. A 2-month-old girl with D/G compound heterozygote. The new- born screening revealed total blood galactose (Gal + Gal-L-phosphate) level of 33.4 mg/dL (Normal, <15.0) and blood galactose (without Gal-L-phosphate) level of 3.7 mg/dL. Enzyme assay for uridyltrans- ferase was 41.3 μM (Normal, >40.0). DNA analysis showed one copy of the N314D (Duarte galactosemia) variant and one copy of the Q188R (classical galactosemia) mutation. The patient is currently on Isomil and growing well.
