Homocysteinuria
From Iusmgenetics
Contents |
[edit] Homocysteinuria
[edit] General background information
- This disease surrounds the biochemistry of converting methionine to homocystein to cystathionnine to cysteine.
- Any defect in this pathway (which requires methionine, folate, cobalamin, and pyrodoxine) can cause homocysteinuria.
[edit] Mode of inheritance
- Autosomal recessive
[edit] Single important gene
- CBS: Cystathionine beta synthase defect is the classic case.
- There is locus heterogeneity in homocysteinuria as there are other loci that can cause the disease upon damage.
- There are 5 other known defects that can cause homocysteinuria.
- Methylene-H4-folate reductase defects
- Cytosolic cobalamin metabolism defects
- Methylcobalamin synthesis defects
- Cobalamin absorption defects
- Cobalamin transport defects
- Don't worry about all those other defects, we'll worry about the cystathionine synthase (because that one we can treat)
[edit] Etiology
- Homocysteine is the toxic substance that causes disease.
- Homocystein may impair disulphide bridges in FBN1 and thus cause a Marfan-like disorder (because of defective fibrillin).
[edit] Pathogenesis
[edit] Phenotypic information
- Like Marfans, three systems involved: skeletal, ocular, vascular:
- Long, thin bones
- Lens dislocation (Marfan dislocates upward, homocystinuria dislocates downward)
- Thromboembolism
- With potential for mental impairment secondary to embolism
- Case example: 13 yo male with history of right lens dislocation admitted with severe headache, nausea, vomitting, fever. PE reveals a Marfanoid habitus, left hemiparesis, meningeal irritation signs, mental retardation, and severe myopia. CT showed a cerebral venous infarct; MRI confirmed the infarct was secondary to thrombosis.
[edit] Diagnosis
[edit] Treatment
- The goal is to normalize the homocysteine levels as it is the toxic substance.
- Recall that cystathionine beta synthase converts homocysteine to cystathionine which can be converted to cystein and used / degraded.
- Because cystathionine beta synthase requires pyridoxine (B6 = pyridoxal phosphate) as a cofactor, we often provide B6 supplements to boost the function of endogenous (albeit damaged) cystathione beta synthase.
- Also, methionine is the aa most readily converted to homocysteine, so pts should be put on a low methionine diet.
- Finally, betaine helps convert homocysteine back to methionine (via the folate-, b12- dependent pathways).
- So betaine supplements should be given to help reduce homocysteine levels
- To summarize:
- Decrease methionine intake to decrease production of homocysteine.
- Increase pyridoxine (B6 = pyridoxal phosphate) intake to increase CBS function.
- Increase betaine intake to increase homocystein-methionine conversion.
[edit] Recent research
[edit] 5 important facts
[edit] Not to be confused with
- Marfan syndrome
- Both present with similar skeletal, ocular, and vascular symptoms.
- Excess homocysteine may inhibit the appropriate disulfide briding in FBN1 and thus cause Marfan-like symptoms, thus reducing the amount of functional fibrillin-1.
- Recall that FBN1 is important for TGF-beta signaling and therefore ECM maintenance.