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Galactosemia

Galactosemia. Galactose. Six carbon aldose carbohydrate Major dietary source is lactose from milk and milk products Epimer of glucose Differs from glucose at carbon 4. Lactose. Galactose Metabolism. Patients with galactosemia lack activity of uridyltransferase. Clinical Features.

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Galactosemia

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  1. Galactosemia

  2. Galactose • Six carbon aldose carbohydrate • Major dietary source is lactose • from milk and milk products • Epimer of glucose • Differs from glucose at carbon 4 Lactose

  3. Galactose Metabolism Patients with galactosemia lack activity of uridyltransferase

  4. Clinical Features Short Term (within 1-2 days after birth) • Failure to Thrive • Vomiting • Diarrhea • Jaundice • Cataracts • Infection and Sepsis POTENTIALLY LETHAL IF UNDIAGNOSED/UNTREATED

  5. Inheritance • 1 in ~40,000 live births (7-8K patients in US) • The gene for GALT is located on chromosome 9p13 • Classic galactosemia and the other disorders of galactose metabolism are all transmitted by autosomal recessive inheritance and the vast majority of patients are compound heterozygotes

  6. Cause of Symptoms? • aldose reductase?? • Buildup of galactitol causes ???? • Mental retardation • Cataracts • Buildup of galactose-1-phosphate ???? • Liver and renal damage • Severe mental retardation Aldose Reductase Galactose Galactitol NADPH + H+ NADP+

  7. The GALT Gene • Located at 9p13 • 4.3 kb in DNA length • 11 exons • 379 amino acids

  8. Missense mutations within the GALT gene • S135L = Leu for Ser • Almost exclusively in individuals of African decent • 50% of African American mutations • Q188R = Arg for Gln • Classic galactosemia • 60-70% of mutated chromosomes  5  6 • K285N = Asn for Lys • 2nd most common disease-causing mutation  9 • N314D = Asp for Asn • Duarte alleles • 2 variations: D1 & D2  10

  9. Q188R • Most deleterious mutation on GALT gene • Ireland and British (highest frequency) • Close proximity to His-186, the putative catalytic site • Homozygous individuals show no activity (in vitro)

  10. Etiology GALT Mutations: • 61% missense mutations • 10% small deletions or insertions • 9% non-sense mutations (towards C-term) • 5% splice-site mutations

  11. Diagnosis Newborn screening 48 states including Florida Assays either: detects level of blood galactose or measures GALT activity

  12. Diagnosis • If you have the misfortune of being born in Washington or Louisiana… • Present with symptoms • Test for reducing substance in urine • Confirm via enzymatic assay

  13. Dietary Management Initial management that continues throughout life • Eliminate galactose from the diet • Lactose* • Galactose* • Life-long diet • Calcium supplements • Avoid some pharmaceuticals • Endogenous galactose • Vitamin K JH Walter, JE Collins & JV Leonard, 1999.

  14. LK Mahan & S Escott-Stump, 1996.

  15. Manifestations Notes amenorrhea male gonad not affected ovary failure language problems mental retardation especially females Clinical Features Long Term (puberty)

  16. Long Term Management • Outpatient review throughout life • Dietary compliance • Growth • Biochemical Analysis • Red Cell Galactose-1-Phosphate • Urinary Galactitol • Development • Speech • Cognition • Motor skills • Opthalmology JH Walter, et al., 1999.

  17. An attempt to begin building genotype/ phenotype correlations for various GALT missense mutations in the hopes of identifying predictive factors for outcome

  18. Background

  19. Steady-State Levels 0.2X

  20. Activity Wild Type 100± 6 N314D 103 ± 33 E291K 63 ± 10 R201H 63 ± 10 P183T 45 ± 7 T350A 10 ± 1 Y323D 10 ± 1 V151A 5 ± 1 S135L 2.7 ± .4 R67C 2.3 ± .4 L139P 1.9 ± .6 F171S <0.2 Q188R <0.2 R231H <0.2 R259W <0.2 K285N <0.2 R333W <0.2

  21. Growth in Glycerol/Ethanol with 0.05% Gal All strains grew equally well in Glc Growth in Gal Correlates Well With Activity!!

  22. Gal-1-P Accumulation >Gal-1-P correlates with < Activity, Note lag in intermediate growth correlates With presence of gal-1-p

  23. UDP-Gal is Depleted in Nulls Arrow Indicates Addition of Gal Open circle with Gal Black circle w/out Gal UDP-Gal levels are depleted in Nulls (this is true for yeast and humans but NOT mice???)

  24. Conclusions • Enzy Act Negatively Correlates with growth in low gal and gal-1-p accumulation • Depletion of UDP-Gal in the presence of gal in Nulls (same as humans but NOT mice--see next paper)--how? • How do Gal-1-P levels go back down in nulls?

  25. Goal: To generate a mouse-KO of GALT in Order to study galactosemia

  26. Successful KO (Mendelian #s) No GALT Act and Mice Accumulate Gal-1-P

  27. So Far So Good Nulls have elevated gal, galactitol, gal-1-P (later studies show normal UDP-Gal in KO)

  28. Uh Oh Develop to breeding age fine! Females are fertile! No cataracts, no liver damage, no phenotype!!!

  29. What? • How toxic is gal-1-p? • Is UDP-Gal depletion the culprit? • What about pyrophosphorylase activity? • Aldose Reductase Activity (human>>>mouse) -is galactitol culprit? • Examples of other diseases which often time biochemically reproduce but do not “clinically” reproduce phenotype • Tay-Sachs, Glycogen Storage Disease TypeII, Lowe and Lesch-Nyhan Syndromes, X-linked adrenoleukodystrophy, alpha-galactosidase deficiency (Fabry disease), and metachromatic leukodystrophy

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