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The Homocystinurias

Presenter Disclosure Information Harvey L. Levy, MD. The following relationships exists related to this presentation: No relationship to disclose. Methionine Metabolic Cycle. MethionineTHF SAM5-MTHF SAH5, 10-MTHFHomocysteineCystathionineCystei

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The Homocystinurias

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    1. The Homocystinurias Harvey L. Levy, MD Childrens Hospital Boston Harvard Medical School

    2. Presenter Disclosure Information Harvey L. Levy, MD The following relationships exists related to this presentation: No relationship to disclose

    3. Methionine Metabolic Cycle Methionine THF SAM 5-MTHF SAH 5, 10-MTHF Homocysteine Cystathionine Cysteine

    4. Methionine Metabolic Cycle Gene/Enzyme of Transporter MAT I/III Methionine adenosyltransferase I/III GNMT N-Glycine methyltransferase AHH Adenosylhomcysteine hydrolase CBS Cystathionine B-synthase MTHFR Methylenetetrahydrofolate reductase MMACHC Methylmalonic aciduria homocystinuria C (cblC MMADHC Methylmalonic aciduria homocystinuric D (cblD) LMBRDI cbl F transporter MSRR Methionine synthase reductase (cblE) MSR Methionine synthase (cblG)

    5. HOMOCYSTINURIA (cbs def) Mental retardation Ectopia lentis Skeletal abnormalities Thromboembolism

    6. NBS ELEVATED METHIONINE

    7. Homocystinuria B6 Challenge B6-responsive or B6-nonresponsive? Administer B6 (pyridoxine) 250 mg PO daily X3 days when on normal diet Measure plasma methionine and homocysteine daily Marked reduction indicates B6-responsive Do not give infant more than 250 mg pyridoxine

    8. Homocystinuria Therapy Methionine-restricted diet Methionine-free formula Low-protein foods (medical) B6 (?), B12 (?), folic acid (?) Betaine

    9. Homocystinuria Goal of Therapy Metabolic Reduce homocystine/homocysteine (optimal level(s) not yet known) Clinical Normality (monitor eyes, development/IQ, bone density)

    10. MAT I/III Deficiency Biochemical Increased methionine Reduced S-adenosylmethionine (SAM) Normal/slightly increase homocysteine Clinical Benign ?Mild developmental delay *Contact Dr. Harvey Mudd at NIH for analysis Tel: 301-496-0681 Email: shm@codon.nih.gov

    11. N-Glycine methyltransferase (GNMT) deficiency Biochemical Increased methionine Increased S-adenosylmethionine (SAM) Normal/slightly increased homocysteine Clinical Liver disease *Contact Dr. Harvey Mudd for analysis

    12. Adenosylhomocysteine hydrolase (AHH) deficiency Biochemical Increased methionine Increased S-adenosylmethionine (SAM) Normal/slightly increased homocysteine Clinical Myopathy Hypertonia Developmental Delay *Contact Dr. Harvey Mudd for analysis

    13. Methylenetetrahydrofolate reductase (MTHFR) deficiency Biochemical Decreased methionine Increased homocysteine No methylmalonic aciduria Clinical Developmental delay/MR Subacute combined degeneration of the spinal cord (SCD) with hypotonia and peripheral neuropathy

    14. NBS Elevated C3

    15. Cobalamin C (clbc) Defect B12 Metabolic Defect (Methylmalonic aciduria/Homocystinuria)

    16. CblC Disorder Clinical Newborn usually normal Developmental delay/MR Poor vision/blindness (retinal degeneration) Seizures Megaloblastic anemia

    17. CblC Disorder Treatment Normal diet Vitamin B12 (OHCbl) at least 1 mg IM daily Betaine ~ 200-250 mg/kg/day ?Carnitine ~ 50-100 mg/kg/day ?Supplemental methionine

    18. cblD disorder Biochemical Decreased methionine Methylmalonic aciduria only or Homocystinuria only or Both methylmalonic aciduria and homocystinuria Clinical Developmental delay/MR Seizures (eyes are normal)

    19. cblF disorder Biochemical Decreased methionine Methylmalonic aciduria (possibly increased homocysteine) Clinical Developmental delay

    20. cblE and cblG disorders Biochemical Decreased methionine Markedly increased homocysteine Methylmalonic acid absent Clinical Developmental delay Megaloblastic anemia

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