What is Homocystinuria?



Amino acid disorders (AAs) are a group of rare inherited conditions. They are caused by enzymes that do not work properly. Protein is made up of smaller building blocks called amino acids. A number of different enzymes are needed to process these amino acids for use by the body. Because of missing or non-working enzymes, people with amino acid disorders cannot process certain amino acids. These amino acids, along with other toxic substances, then build up in the body and cause problems.

Homocystinuria is an inherited disorder of amino acid metabolism, leading to abnormal accumulation of homocysteine and its metabolites in blood and urine”. (Wikipedia.org)

Prevalence Rate:

Guthrie testing has shown the incidence to be 1 in 344,000 worldwide.

Reference: Homocystinuria; Online Mendelian Inheritance in Man (OMIM).

  • At least 1 per 200,000 – 335,000 people is affected by homocystinuria worldwide. But there is large population difference, being highest in ethnic population where there is high level of consanguinity. In Ireland, the incidence is 1 in 65000. The difference may be under estimated due to the infrequency of newborn screening for this disorder. In Pakistan this disorder is less documented and still in study.
  • Racial predominance for Homocystinuria:More common in Ireland and Italy
  • (Genetics Home Reference website).


  • Classical homocystinuria, also known as cystathionine beta synthase deficiencyor CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase (CBS).
  • It results from reduced activity of the enzyme CBS which is involved in the conversion of methionine to cysteine. The enzyme is mapped to gene locus 21q22. Homocysteine and methionine accumulate in tissues and interfere with the cross-linking of collagen fibers.


  • This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

Signs and Symptoms:

  • While the metabolic defect is present at birth, initial symptoms of homocystinuria usually have onset later in infancy and childhood.Prompt detection and treatment of homocystinuria due to CBS deficiency is important in preventing or reducing the symptoms associated with the disorder.
  • In some cases, delays in attaining developmental milestones (developmental delays) may be the first noticeable symptom in children with homocystinuria due to CBS deficiency. Affected children may be slow in sitting, standing, walking and speaking or other milestones. Some children have normal intelligence; others develop varying degrees of mental retardation. Approximately 20 percent of children with homocystinuria due to CBS deficiency develop seizures. Some affected children also exhibit psychiatric issues including depression, anxiety, obsessive-compulsive disorder, and other behavioral or personality disorders.
  • This defect leads to a multi-systemic disorder of the connective tissuemusclescentral nervous system(CNS), and cardiovascular system. Signs and symptoms of homocystinuria that may be seen include the following:
  • Musculoskeletal Abnormalities
  • Intellectual disability
  • Psychiatric disease

  Eye anomalies:

Additional abnormalities of the eyes have been reported in individuals with homocystinuria due to CBS deficiency. These abnormalities occur less frequently than ectopia lentis and myopia. Such abnormalities include clouding of the lenses of the eyes (cataracts), degeneration of the nerve (optic nerve) that relays signals from the eye to the brain (optic atrophy), and glaucoma, a condition in which increased pressure within the eye causes characteristic damage to the optic nerve. Some individuals may have separation of the thin layer of nerve cells (retina) that lines the back of the eyes from its underlying support tissue (retinal detachment). The retina normally senses light and converts it into nerve signals, which are then relayed to the brain through the optic nerve. Retinal detachment may cause blurred vision or the appearance of “floaters” in the field of vision.

 Vascular disease:

  • A serious complication associated with homocystinuria due to CBS deficiency is an increased risk of developing clots (thrombi) in blood vessels that can break off and become lodged in another vessel (thromboembolism). Blood clots can occur at any age. Specific symptoms associated with a thromboembolic event depend on the exact site of the clot and the specific blood vessels and organs that are affected. Thromboemboli can cause serious, life-threatening complications.
  • Skeletal abnormalities are usually not present at birth and may not become detectable until later during childhood. Common findings include thinning and lengthening of the long bones (dolichostenomelia), knees that are bent inward so that they touch when the legs are straight (“knock knees” or genu valgum), a highly arched foot (pes cavus), abnormal sideways curvature of the spine (scoliosis), or an abnormally protruding chest (pectus carinatum) or an abnormally sunken chest (pectus excavatum). Many individuals with homocystinuria due to CBS deficiency are at a greater risk than the general population of developing osteoporosis. Osteoporosis is condition characterized by a general loss of bone density that can lead to an increased risk of fractures.
  • Although less common, several additional findings have been reported in individuals with homocystinuria due to CBS deficiency including extremely fine, fragile skin, discoloration of the skin (hypopigmentation), rashes on the cheeks (malar flushing) and abnormally thin skin. Some individuals may develop fatty changes in the liver, protrusion of part of the intestines through a tear in the abdominal wall (inguinal hernia) or inflammation of the pancreas (pancreatitis), a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid indigestion. Abnormal front-to-back curvature of the spine (kyphosis) and a collapsed lung (spontaneous pneumothorax) have also been reported in individuals with homocystinuria due to CBS deficiency.


  • The best option is to diagnose the disease in the newborn by extended newborn screening before the newborn leaves the hospital.
  • Newborn screening of a dried blood spot using tandem mass spectrometry reveals elevated levels of methionine (MET). Elevated methionine and homocysteine in plasma indicate CBS deficiency.
  • The presence of homocystine in the urine is a consistent finding, especially after early infanc
  • Ophthalmology tests to detect myopia and dislocated lens.
  • Imaging: X-rays; dual-energy X-ray absorptiometry (DEXA) bone scans to detect osteoporosis.
  • *Plasma and Urine analysis of Homocystinuria is available in Excel lab, Islamabad Diagnostic Centre and Agha Khan Laboratory.

Confirmatory Tests:

Blood examination: It is essential for the diagnosis of classical homocystinuria to be confirmed by determination of amino acids in fasting blood.


Analyte Specimen Expected findings in affected neonate Healthy Neonate
homocystine plasma 10-100 micromol/litre <1 micromol/litre
Total homocysteine Plasma 50-100 micromol/litre <15 micromol/litre
Methionine Plasma 200-1500 micromol/litre 10-40 micromol/litre
Homocystine Urine Detectable Undetectable

Table 1: Amino acid levels in patients and healthy neonates

Direct enzyme assays: Estimating the cystathionine beta synthase enzyme in liver biopsy specimens or cultured skin fibroblasts or cultured lymphocytes.

Molecular diagnosis: Screening for cystathionine beta synthase mutations can be done on cultured fibroblasts.

Treatment: Effective treatment requires early diagnosis and initiation of therapy.

  • Pyridoxine is the drug of choice. Patients may be divided into pyridoxine-sensitive and pyridoxine-insensitive
    Pyridoxine-sensitive: pyridoxine, folic acid, and vitamin B12 are used in combination to reduce the homocysteine levels.
  • Pyridoxine-insensitive: low-methionine diet is started at diagnosis; given along with betaine supplementation, it may help reduce homocysteine levels.
  • Methionine restriction has been shown to prevent general learning disability and reduce the rate of lens dislocation and seizure activity.


  • Homocystinuria; Online Mendelian Inheritance in Man (OMIM)
  • Picker JD, Levy HL; Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency.
  • Walter JH, Jahnke N, Remmington T; Newborn screening for homocystinuria. Cochrane Database Syst Rev. 2013 Aug 1 8:CD00 doi: 10.1002/14651858.CD008840.pub3
  • https://ghr.nlm.nih.gov/



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