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In a 39-year-old woman who just gave birth, chorionic villus sampling was performed, and a battery of genetic panels was assessed on the new born. One marker indicated a defective Cystathionine -β- Synthase. Which of the following compounds you most likely expect to be elevated in the blood of the infant at birth if the mother was not treated properly?

A) Valine

B) Methionine

C) Threonine

D) Glutamine

E) Cysteine

The correct answer is- B) – Methionine.

This seems to be a case of” Classical homocystinuria”, that occurs due to defective Cystathionine-β- Synthase activity.

Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine.

Basic Concept-

Most homocysteine, an intermediate compound of Methionine degradation, is normally remethylated to Methionine. This Methionine-sparing reaction is catalyzed by the enzyme Methionine Synthase, which requires a metabolite of folic acid (5-methyltetrahydrofolate) as a methyl donor and a metabolite of vitamin B12 (Methylcobalamin) as a cofactor .Only 20–30% of total homocysteine (and its dimer homocystine) is in free form in the plasma of normal individuals. The rest is bound to protein.

The accumulation of homocysteine and its metabolites is caused by disruption of any of the 3 interrelated pathways of methionine metabolism—

1) Deficiency in the Cystathionine β-synthase (CBS) enzyme (Type I/Classical Homocystinuria)

2) Defective methyl cobalamin synthesis -Type II

3) Abnormality in Methylene tetrahydrofolate reductase (MTHFR) – Type III

Three different cofactors/vitamins—pyridoxal 5-phosphate, methylcobalamin, and folate—are necessary for the 3 different metabolic paths.

The pathway, starting at methionine, progressing through homocysteine, and onward to cysteine, is termed the trans- sulfuration pathway. Conversion of homocysteine back to methionine, catalyzed by MTHFR and methylcobalamin, is termed the remethylation pathway. (Figure-1).

 methionine metab


Figure-1- Remethylation and Transsulfuration pathway of methionine metabolism

Defective Cystathionine beta Synthase

 (Classical Homocystinuria)


Homocystinuria is inherited in families as an autosomal recessive trait.

Clinical Manifestations

Infants with this disorder are normal at birth.

  • Clinical manifestations during infancy are nonspecific and may include failure to thrive and developmental delay.
  • The diagnosis is usually made after 3 yr of age, when subluxation of the ocular lens (ectopia lentis) occurs (figure-2). This causes severe myopia and iridodonesis (quivering of the iris), astigmatism, glaucoma, cataract, retinal detachment, and optic atrophy may develop later in life.

Dislocated lens

Figure-2- Dislocated lens

  • Progressive mental retardation is common. Normal intelligence, however, has been reported.
  • Affected individuals with homocystinuria manifest skeletal abnormalities resembling those of Marfan syndrome; they are usually tall and thin with elongated limbs and arachnodactyly (figure-3), scoliosis (figure-4), pectus excavatum, genu valgum, pes cavus, high arched palate, and crowding of the teeth are common.


Figure-3- Arachnodactyly


Figure-4- Scoliosis

  • Patients usually have fair complexions, blue eyes, and a peculiar malar flush.
  • Thromboembolic episodes involving both large and small vessels, especially those of the brain, are common and may occur at any age.

Laboratory findings

  • Amino acid screen of blood and urine – Elevations of both Methionine and homocystine in body fluids are the diagnostic laboratory findings, as in the given case.
  • Total plasma homocysteine is extremely elevated (usually >100μ M).
  • Cystine is low or absent in plasma.
  • The urine screening test for sulfur-containing amino acids, called the cyanide nitroprusside test, can be undertaken;
  • Liver biopsy and enzyme assay are diagnostic
  • Skeletal x-ray reveals generalized osteoporotic changes
  • Skin biopsy with a fibroblast culture (The diagnosis may be established by assay of the enzyme in liver biopsy specimens, cultured fibroblasts)
  • Standard ophthalmic examination is diagnostic for various eye changes
  • Genetic testing can be helpful.


  • A high dose of vitamin B6 causes dramatic improvement in patients who are responsive to this therapy.
  • The cysteine deficiency must be made up from dietary sources.
  • Supplementation with pyridoxine, folic acid, B12 or trimethyl glycine (Betaine) reduces the concentration of homocysteine considerably in the bloodstream.
  • A low Methionine diet is also recommended.
  • Existing mental retardation can be improved by symptomatic treatment

As regards other options,

The amino acids such as

Valine, Threonine, Glutamine, or Cysteine are not found in high concentration in blood in conditions of defective Cystathionine-β-synthase activity. Cysteine concentration is rather decreased in such defect.








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