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Galactosemia

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Galactosemia 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 437 438 GALACTOSEMIA 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 galac- tosemia 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
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