Homocysteinuria

From Iusmgenetics

Contents 1 Homocysteinuria 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

Homocysteinuria

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.
• 

Mode of inheritance

• Autosomal recessive

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)
• 

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).

Pathogenesis

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

Diagnosis

Treatment

• Because cystathionine beta synthase requires pyridoxine (B6) as a cofactor, we often provide B6 supplements to boost the function of endogenous (albeit damaged) CBS.
• Cystathionine beta synthase also requires pyridoxal phosphate as a cofactor.

Recent research

5 important facts

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.

Questions and answers