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Multiple carboxylase deficiency


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Multiple carboxylase deficiency

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Multiple carboxylase deficiency

  1. 1. Multiple carboxylase deficiency Omar aljabri
  2. 2. Definition and enzymatic deficiency Multiple carboxylase deficiency is recessive inherited amino acidopathy caused by deficiency of either of two enzymes necessary for activity of several biotin containing carboxylases. enzymes:  Holocaroxylase synthetase (HCLS)  Biotinidase Prior to the advent of universal newborn screening (NBS) in the United States, age of onset was used to differentiate between HCLS deficiency and biotinidase deficiency, with biotinidase deficiency generally presenting after 3 months.
  3. 3. biotin Water-soluble essential B complex vitamin (vitamin H) Cofactor for all 4 carboxylase enzymes: 1) pyruvate caboxylase 2) acetyl-CoA carboxylase 3) propionyl-CoA carboxylase 4) methylcrotonyl-CoA carboxylase
  4. 4. Pathogenesis • Holocaroxylase synthetase (HCLS)  the HCLS is responsible for covalently linking biotin to(PCC, 3-MCC, PC, ACC) Failure to attach biotin causes reduced activity of these biotin- dependent carboxylases and results in multiple carboxylase deficiency • Biotinidase:  A major function of biotinidase is to recycle biotin liberated from biocytin and/or small biotinyl-peptides from degraded holocarboxylase.  It is also important in freeing biotin from dietary protein-bound biotin.
  5. 5. Causes • Mutations in the genes for holocarboxylase synthetase and biotinidase produce deficient or defective enzymes inhibiting the activation of the four carboxylases and limiting the recovery of protein bound biotin for reactivation of the carboxylases. • The gene for holocarboxylase synthetase is located on chromosome 21, and has 11 exons. There are at least 35 mutations known. • The gene for biotinidase is located on chromosome 3, and has 4 axons. Over 100 mutations have been reported, but 5 common mutations account for about 60% of the abnormal alleles.
  6. 6. Inheritance pattern Incidence of profound and partial deficiency is 1:60.000 in most countries
  7. 7. metabolic consequence • excessive levels of acids in the blood resulting in acidosis. • accumulations of (ketone bodies) in tissues to excessive breakdown of fats resulting in ketosis • inhibits the urea cycle resulting in hyperammonemia. • inhibits gluconeogenesis resulting in hypoglycemia • abnormal urine organic acids characteristic of ketosis increased lactic acid.  3-hydroxy isovaleric acid .  3-methylcrotonylglycine.  methylcitrate. hydroxy-propionate and propionylglycine .
  8. 8. Diagnosis and Laboratory findings the enzyme activity should be assayed in leukocytes Primary newborn screening for multiple carboxylase deficiency utilizes tandem mass spectrometry. Elevated C5-OH acylcarnitine indicates the possibility of multiple carboxylase deficiency Pathological organic acid profile in the urine propionic acid, methylcitrate, 3- methylcrotonic-, 3-hydroxyisovaleric acid, 3-methylcrotonylglycine)
  9. 9. clinical manifestations
  10. 10. clinical manifestations • Multiple carboxylase deficiency may occur early in infancy as result of holocarboxylase synthetase deficiency • Biotinidase deficiency is associated with a later and more gradual onset Symptoms if untreatedthe first signs are Hearing loss optic atrophy Skin rashes Mental retardation Coma and death possible Later-onset forms occur vomiting poor appetite Seizures hypotonia
  11. 11. TREATMENT Immediate diagnosis and treatment of multiple carboxylase deficiency is critical to normal growth and development. Treatment is usually effective if started early. Recommended treatment is daily supplementation of biotin. Biotin can prevent symptoms and may reverse some health problems.