Galactosemia

Classic galactosemia (G/G) is an autosomal recessive disor- ii. Compound heterozygotes (D/G or N314D/Q188R) der of galactose metabolism, caused by a deficiency of galac- a) Relatively benign in most infants tose-L-phosphate uridyl transferase. The incidence is estimated b) May or may not require dietary intervention to be 1 in 30,000 births, based on the results of newborn c. Los Angels (LA) variant with identical N314D mis- screening programs. sense mutation but has normal erythrocyte GALT activity GENETICS/BASIC DEFECTS d. S135L allele 1. Inheritance: autosomal recessive i. Prevalent in Africa 2. Cause: deficiency of galactose-L-phosphate uridyl ii. A good prognosis if therapy is initiated in the transferase (GALT) neonatal period without neonatal hepatotoxicity 3. Galactose-L-phosphate uridyl transferase and chronic problems a. The gene for GALT is mapped on chromosome 9p13 e. K285N allele b. GALT is second enzyme in the Leloir pathway, cat- i. Prevalent in Southern Germany, Austria, and alyzing conversion of galactose-L-phosphate and UDP Croatia glucose to UDP galactose and glucose-L-phosphate ii. A poor prognosis for neurological and cognitive c. Essential in human infants who consume lactose as dysfunction in either the homozygous state or their primary carbohydrate source compound heterozygous state with Q188R d. Near total absence of GALT activity in infants with classical galactosemia CLINICAL FEATURES e. A deficiency causes elevated levels of galactose- L-phosphate and galactitol in body tissues 1. Onset of symptoms 4. Endogenous production of galactose may be responsible a. May present by the end of the first week of life for the long-term effects, such as cognitive dysfunction b. May die or develop cataracts, hepatomegaly, cirrhosis, and gonadal dysfunction in female patients and mental retardation in late-detected cases 5. Duarte (D) allele 2. Neonatal toxicity syndrome a. Very common a. Exposure to dietary galactose in infants with classical b. Defined biochemically by: galactosemia results in acute deterioration of multiple i. Reduced enzyme activity organ systems, including the following: ii. An isoform distinguishable by gel electrophoresis i. Liver dysfunction and isoelectric focusing a) Jaundice c. Heterozygous Duarte variants (D/N) b) Hepatomegaly i. Observed in about 11% of Caucasian subjects ii. Coagulopathy ii. Have about 75% of normal GALT activity iii. Poor feeding and weight loss d. Homozygotes for the Duarte variant (D/D) iv. Vomiting and diarrhea i. Have approximately one half (50%) of normal v. Lethargy and hypotonia transferase activity vi. Renal tubular dysfunction ii. Mimic carriers for galactosemia vii. Cerebral edema (encephalopathy) e. Infants with a galactosemia allele and a Duarte allele viii. Vitreous hemorrhage (D/G) ix. Escherichia coli sepsis i. Have one-quarter (25%) of normal enzyme activity b. Withdrawal of dietary galactose results in reversal of ii. Have reduced capacity to metabolize galactose neonatal toxicity syndrome and reducing mortality with abnormal accumulation of galactose-L- and morbidity in the early weeks of life phosphate in the red cells 3. Cataracts iii. Phenotypically normal with no ill effect a. Resulting from accumulation of galactitol within the 6. Genotype-phenotype correlations lens a. Q188R mutations (prevalent in 70% of Caucasians): a b. Seen in infants with classical GALT-deficient galac- poorer outcome in homozygous state associated with tosemia (and also in galactokinase deficiency) essentially no enzyme activity i. The ocular hallmark of untreated or late-detected b. Duarte variant (N314D) patients i. Homozygous state (D/D or N314D/N314D) with ii. Severity of lens involvement dependent on the erythrocyte GALT enzyme activity reduced by severity of galactosemia and the age at com- only 50% mencement of therapy

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c. Reoccur in older patients who have poor dietary a) Progressive familial intrahepatic cholestasis compliance (Byler disease) d. May be prevented by dietary restriction of galactose b) Metabolic diseases such as Niemann-Pick 4. Ovarian failure disease, type C and Wilson disease a. Hypergonadotropic hypogonadism occurring almost universally (>90%) in females with classical GALT deficiency DIAGNOSTIC INVESTIGATIONS b. The rapidity and severity of the ovarian failure vary 1. Newborn screening programs in most states widely among individuals a. An almost 100% detection of affected infants in states c. Clinical manifestations that include testing for galactosemia in their newborn i. Delayed puberty screening programs ii. Primary amenorrhea b. Prevention of needless deaths associated with galac- iii. Secondary amenorrhea tosemia, resulting from limiting diagnostic measures iv. Oligomenorrhea to infants who develop symptoms 5. Chronic brain effects c. A positive (i.e., abnormal) screening, followed by a a. Specific deficits quantitative erythrocyte GALT analysis i. Developmental speech dyspraxia and tremor 2. Liver dysfunction ii. Globally decreased IQ and/or learning disability a. Bilirubin determination b. Uncertainty as to: i. Initial unconjugated hyperbilirubinemia i. Whether these deficits are initiated in early devel- ii. Later conjugated hyperbilirubinemia opment, perhaps even prenatally, and unmasked, b. Abnormal liver function tests as more complex brain function is required c. Abnormal clotting ii. Whether these deficits represent true neurode- d. Raised plasma amino acids, particularly phenylala- generative processes compounded by dietary nine, tyrosine, and methionine. Raised phenylalanine exposure and endogenous production of may result in a false positive neonatal screening test “intoxicants” for phenylketonuria 6. Prognosis 3. Renal tubular dysfunction a. A life-threatening disorder if untreated a. Metabolic acidosis b. Currently, affected infants are treated before becom- b. Urinalysis ing ill because of newborn screening in most states i. Galactosuria 7. Differential diagnosis a) The presence of reducing substances or a. Galactokinase (GALK) deficiency galactose in the urine is neither sensitive nor i. An autosomal recessive disorder specific ii. Considered in patients with cataracts and galac- b) Small quantities of galactose commonly found tosemia but otherwise healthy in the urine of any patient with liver disease iii. Cataracts ii. Albuminuria a) The main clinical feature a) Present in the initial stage b) Due to accumulation of galactitol b) Quick disappearance of albuminuria after iv. Pseudotumor cerebri eliminating lactose-containing formula from a) Described in several cases the diet b) Considered to be a true consequence of the iii. Aminoaciduria in the later stage disorder 4. Abnormal carbohydrate metabolism v. These features resolve when a galactose-restricted a. Increased plasma galactose diet is introduced b. Increased red cell galactose-L-phosphate vi. Diagnosis made by detection of reduced galac- c. Increased urine and blood galactitol tokinase activity 5. Testing for hemolytic anemia vii. Caused by mutations in the GALK1 gene 6. Study for septicemia, especially Escherichia coli b. UDP-galactose 4-epimerase (GALE) deficiency 7. Slit lamp examination for cataract assessment i. An autosomal recessive disorder 8. Computerized tomography and magnetic resonance imaging ii. Considered in patients with liver disease, sen- a. Abnormalities on brain imaging: common in classical sorineural deafness, failure to thrive, and elevated galactosemia galactose-L-phosphate but normal GALT activity b. Patients with late neurologic disease iii. Response to the removal of galactose from their i. Abnormal white matter diets ii. Ventricular enlargement iv. Diagnosis made by detection of reduced UDP- iii. Diffuse cortical atrophy with basal ganglia and galactose 4-epimerase activity brainstem involvement v. Caused by mutations in the GALE gene iv. Cerebellar atrophy c. Neonatal hepatotoxicity v. Failure of normal myelination i. Infectious diseases (sepsis) 9. Endocrine investigations for hypergonadotropic hypo- ii. Obstructive biliary disease gonadism GALACTOSEMIA 439

a. Raised follicle stimulating hormone GENETIC COUNSELING b. Raised luteinizing hormone c. Initially normal estradiol concentration with high 1. Recurrence risk gonadotropin levels, indicating continued follicular a. Patient’s sib development, but fall as ovarian failure progresses i. A proband with G/G galactosemia 10. Increased urinary galactitol excretion a) Given the parents are G/N and G/N: a 25% 11. Beutler test chance of being affected with G/G galactosemia for each sib a. A fluorescent spot test for galactose-L-phosphate uridyl transferase activity b) Given the parents are D/G and G/N: a 25% b. Now widely used for the diagnosis of galactosemia chance of being affected with G/G galac- c. False negative resulting from recent blood transfu- tosemia and a 25% chance of being affected sions (within 3 months) with D/G galactosemia for each sib d. False positive resulting from glucose-6-phosphate ii. A proband with D/G galactosemia, given the dehydrogenase deficiency parents are D/N and G/N: a 25% chance of being affected with D/G galactosemia for each sib 12. Red blood cell galactose-L-phosphate a. Concentration always raised in classical galactosemia b. Patient’s offspring: b. Not significantly affected by blood transfusions i. Patient with G/G galactosemia and the normal 13. Biochemical confirmation of the diagnosis spouse with N/N: All offspring are carriers ii. Patient with G/G galactosemia and the carrier a. Red blood cell galactose-L-phosphate uridyl transferase assay spouse for a G allele (N/G): a 50% chance of i. A quantitative assay to confirm the diagnosis having G/G galactosemia (virtual absence of the enzyme activity in classical iii. Patient with G/G galactosemia and the carrier (G/G) galactosemia) spouse for a G allele (D/G): a 50% chance of ii. Also identifies variants with residual enzyme having G/G galactosemia and a 50% chance of activity having D/G galactosemia iii. False negative results due to blood transfusion 2. Prenatal diagnosis possible for fetuses at a 25% risk for within 3 months classical galactosemia b. A GALT isoelectric-focusing electrophoresis test to a. Galactose-L-phosphate uridyl transferase assay in distinguish variant forms such as the Duarte defect cultured amniotic fluid cells or in chorionic villus 14. DNA analysis: GALT genotyping for providing specific biopsies molecular diagnosis b. Galactitol estimation in amniotic fluid supernatant a. Classic (G/G) galactosemia c. Mutation analysis of DNA extracted from chorionic i. Mutation analysis for the six common GALT villus biopsy if the genotype of the index case has galactosemia (G) mutations been characterized a) Q188R mutation: the most common GALT d. Prenatal diagnosis of a treatable condition, such as allele in whites classic galactosemia, may be controversial if the pre- b) S135L: the most common allele in blacks natal testing is being considered for the purpose of c) K285N pregnancy termination rather than early diagnosis d) L195P 3. Management e) Y209C a. Dietary intervention f) F171S i. Lactose-galactose-restricted diet ii. GALT sequence analysis to detect private muta- a) Restrict milk, the principal source of lactose, tions under the following two conditions: and products made from milk a) Both disease-causing mutations not detected b) Breast milk and cows’ milk contraindicated by mutation analysis ii. Milk substitutes b) Diagnosis of galactosemia confirmed by a) Use a formula free of bioavailable lactose biochemical testing (e.g., Isomil or Prosobee) b. Mutation analysis for Duarte variant (D/G) galac- b) Casein hydrolysate (Alimentum, Nutramigen, tosemia identified by biochemical testing of the Pregestimil): not recommended because patient and both parents they contain small amounts of bioavailable i. Identification of Duarte allele (N314D) by muta- lactose tion analysis iii. Difficult to totally eliminate galactose since it is ii. Identification of G allele by mutation analysis or present in a wide variety of food, such as infant sequence analysis foods, fruits, and vegetables 15. Carrier testing iv. Older patients tolerating lactose much better than a. Measuring GALT activity: about 50% of control values children, but recommend restrict milk intake in carriers throughout life b. Molecular genetic testing for carriers available to v. Calcium supplementation family members, provided GALT mutation(s) has/have vi. May prevent cataracts, hepatomegaly, liver cir- been identified in the proband rhosis, mental retardation, and other symptoms 440 GALACTOSEMIA

vii. Effect of dietary restrictions during pregnancy v. Neurological deficits, predominantly extrapyra- on the long-term complications of an affected midal findings with ataxia fetus: unknown vi. Ovarian failure viii. Management of D/G or N344D/Q188R compound heterozygotes REFERENCES a) Decision to treat should be based on the Anadiotis GA, Berry GT: Galactose-1-phosphate uridyltransferase deficiency demonstration of abnormal biochemical (galactosemia). http://www.emedicine.com indices Beutler E: Galactosemia: screening and diagnosis. Clin Biochem 24:293–300, 1991. b) No dietary therapy is instituted if the blood Burke JP, O’Keefe M, Bowell R, et al.: Ophthalmic findings in classical galactosemia—a screened population. J Pediatr Ophthalmol Strabismus 26: galactose and/or galactose-L-phosphate do 165–168, 1989. not rise above 12 mg/dL within 4 hours fol- Elsas LJ: Prenatal diagnosis of galactose-1-phosphate uridyltransferase lowing such ingestion and there are no clin- (GALT)-deficient galactosemia. Prenat Diagn 21:302–303, 2001. ical signs associated with galactosemia Elsas LJ II: Galactosemia. Gene Reviews. 2003. http://www.genetests.org c) Dietary therapy should probably be given if Elsas LJ, Dembure PP, Langley S, et al.: A common mutation associated with there is a greater accumulation of galactose the Duarte galactosemia allele. Am J Hum Genet 54:1030–1036, 1994. Elsas LJ II, Lai K: The molecular biology of galactosemia. Genet Med or of galactose-L-phosphate 1:40–48, 1998. d) There is possible benefit of dietary interven- Elsas LJ, Lai K, Saunders CJ, et al.: Functional analysis of the human galactose- tion to individuals with variant forms of 1-phosphate uridyltransferase promoter in Duarte and LA variant galac- galactosemia with residual GALT activity tosemia. Mol Genet Metab 72:297–305, 2001. Holton JB: Effects of galactosemia in utero. Eur J Pediatr 154:S77–S81, 1995. in the range of 5%–20%: for prevention of Holton JB, Walter JH, Tyfield LA: Galactosemia. In Scriver CR, Beaudet AL, cataracts, ataxia, dyspraxic speech, and Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited cognitive deficits Disease. 8th ed. New York: McGraw-Hill, 2001. b. Vitamin K and fresh-frozen plasma to correct clotting Jakobs C, Kleijer WJ, Allen J, et al.: Prenatal diagnosis of galactosemia. Eur J abnormalities Pediatr 154:S33–S36, 1995. Lai K, Elsas LJ: Structure-function analyses of a common mutation in blacks with c. An appropriate intravenous antibiotic for Gram- transferase-deficiency galactosemia. Mol Genet Metab 74:264–272, 2001. negative sepsis Lai K, Langley SD, Singh RH, et al.: A prevalent mutation for galactosemia d. Treat unconjugated hyperbilirubinemia with pho- among black Americans. J Pediatr 128:89–95, 1996. totherapy or exchange transfusion to infants who Langley SD, Lai K, Dembure PP, et al.: Molecular basis for Duarte and Los may be at an increased risk of kernicterus if albu- Angeles variant galactosemia. Am J Hum Genet 60:366–372, 1997. Leslie ND: Insights into the pathogenesis of galactosemia. Annu Rev Nutr min levels are particularly low secondary to liver 23:59–80, 2003. disease Levy HL, Sepe SJ, Shih VE, et al.: Sepsis due to Escherichia coli in neonates e. Parental feeding if the infant is too sick to tolerate with galactosemia. N Engl J Med 297:823–825, 1977. enteral feeding for more than 1 or 2 days, unless there Nelson MD Jr, Wolff JA, Cross CA, et al.: Galactosemia: evaluation with MR imaging. Radiology 184:255–261, 1992. is significant liver disease or thrombocytopenia Ng WG, Xu YK, Kaufman FR, et al.: Biochemical and molecular studies of 132 f. Treat the following long-term problems in older patients with galactosemia. Hum Genet 94:359–363, 1994. children and adults with classical galactosemia, despite Waggoner DD, Buist NR, Donnell GN: Long-term prognosis in galactosaemia: early and adequate therapy results of a survey of 350 cases. J Inher Metab Dis 13:802–818, 1990. i. Cataracts Waisbren SE, Norman TR, Schnell RR, et al.: Speech and language deficits in early-treated children with galactosemia. J Pediatr 102:75–77, 1983. ii. Speech defects Walter JH, Collins JE, Leonard JV: Recommendations for the management of iii. Poor growth galactosaemia. UK Galactosaemia Steering Group. Arch Dis Child iv. Poor intellectual function 80:93–96, 1999. GALACTOSEMIA 441

Fig. 1. A 5-year-old boy with classical galactosemia. The initial clinical presentation was at 12 days of age with unconjugated hyperbilirubinemia, 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 newborn 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 uridyltransferase 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.