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Understanding Galactosemia: Symptoms, Diagnosis, and Management

Galactosemia is a rare genetic disorder impacting galactose metabolism. Learn about clinical features, genetic inheritance, diagnosis methods, dietary management, and long-term care for affected individuals.

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Understanding Galactosemia: Symptoms, Diagnosis, and Management

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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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