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Case Details- An adolescent girl develops hemiballismus (repetitive throwing motions of the arm) after anesthesia for a routine operation. She is tall and lanky, and it is noted that she and her sister both had previous operations for dislocated lenses of the eyes.

The symptoms are suspicious for the disease homocystinuria.

What is the nature of disease, how can this be treated?

Case discussion

Homocystinuria (Homocysteinemia) 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.

Homocystinuria is an autosomal recessively inherited defect in the transsulfuration pathway (homocystinuria I) or methylation pathway (homocystinuria II and III).


Homocysteinemia, a separate but related entity, is defined as elevation of the homocysteine level in blood. This condition has also been referred to as homocyst(e)inemia to reflect metabolites that may accumulate. A mild elevation of plasma homocysteine may exist without homocystinuria.

Homocysteinemia may be due to a genetic predisposition to abnormal activity in the same pathways as homocystinuria. Nutritional and environmental factors, as well as specific medications, may worsen this abnormality and provoke symptoms.

Basic Concept-

The pathway, starting at methionine, progressing through homocysteine, and onward to cysteine, is termed the transsulfuration pathway. Conversion of homocysteine back to methionine, catalyzed by MTHFR and methylcobalamin, is termed the remethylation pathway. A minor amount of remethylation takes place via an alternative route using betaine as the methyl donor (Figure-1)

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—deficiency in the cystathionine B-synthase (CBS) enzyme, defective methylcobalamin synthesis, or abnormality in methylene tetrahydrofolate reductase (MTHFR).

Clinical syndromes resulting from each of these metabolic abnormalities have been termed homocystinuria I, II, and III. Three different cofactors/vitamins—pyridoxal 5-phosphate, methylcobalamin, and folate—are necessary for the 3 different metabolic paths.






















Figure-1- showing metabolism of Methionine. Homoserine and  cysteine are produced by cleavage of cystothionine, homoserine is further metabolized to form propionyl co A , that gains entry in TCA cycle as succinyl co A


Three major forms of homocysteinemia and homocystinuria have been identified

1) Homocystinuria due to Cystathionine beta Synthetase deficiency

(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. This causes severe myopia and iridodonesis (quivering of the iris), astigmatism, glaucoma, cataract, retinal detachment, and optic atrophy may develop later in life.
  • 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. Scoliosis, pectus excavatum genu valgum, pes cavus, high arched palate, and crowding of the teeth are common.
  •  Patients usually have fair complexions, blue eyes, and a peculiar malar flush. Generalized osteoporosis, especially of the spine, is the main radiographic finding.
  • 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.

  • 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


  • High doses 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 not be improved by symptomatic treatment

 2) Other form of homocystinuria

They are the result of impaired remethylation of homocysteine to Methionine.

This can be caused by defective Methionine synthase or reduced availability of two essential cofactors, 5-methyltetrahydrofolate and methylcobalamin (methyl-vitamin B12).

Affected children present with vomiting, poor feeding, lethargy, hypotonia and developmental delay.

Laboratory diagnosis reveals megaloblastic anemia, Hyperhomocysteinemia and low Methionine levels in blood.

Diagnosis is confirmed by enzyme assay in cultured fibroblasts.

Treatment – supplementation  with vitamin B12.

3) MTHFR (Methylene tetra hydro folate reductase) DNA Gene mutation has been associated with an increased risk for Hyperhomocysteinemia. MTHFR is involved in the methylation of homocysteine to Methionine. The enzyme causes reduction of N5 N10 Methylene tetrahydrofolate to N5 Methyl tetra hydro folate. Individuals with MTHFR gene mutations that reduce enzyme activity may develop hyperhomocysteinemia and thus be at risk for vascular disease.

Complete absence of enzyme causes convulsions, coma and death in untreated cases.Partial deficiency causes mental retardation, microcephaly and convulsions.


In the absence of significant homocystinuria, it is found in some heterozygotes for the genetic defects noted above or in homozygotes for milder variants. Changes of homocysteine levels are also observed with increasing age; with smoking; in postmenopausal women; in patients with renal failure, hypothyroidism, leukemias, inflammatory bowel disease, or psoriasis; and during therapy with drugs such as methotrexate, nitrous oxide, isoniazid, and some antiepileptic agents. 

Consequences of Hyperhomocysteinemia:  Homocysteine acts as an atherogenic agent. An increase in total plasma homocysteine represents an independent risk factor for coronary, cerebrovascular, and peripheral arterial disease as well as for deep-vein thrombosis. Homocysteine is synergistic with hypertension and smoking, and it is additive with other risk factors that predispose to peripheral arterial disease. In addition, hyperhomocysteinemia and folate and vitamin B12 deficiency have been associated with an increased risk of neural tube defects in pregnant women. Vitamin supplements are effective in reducing plasma homocysteine levels in these cases.


Although no cure exists for homocystinuria, vitamin B6 therapy can help about half of people affected by the condition.

If the diagnosis is made while a patient is young, starting a low Methionine diet quickly can prevent some mental retardation and other complications of the disease. For this reason, some states screen for homocystinuria in all newborns.

Patients with persistent rises in blood homocysteine levels are at increased risk for Thromboembolic episodes which can cause significant medical problems and shorten lifespan.


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