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Classic Homocystinuria - An Overview

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Classical homocystinuria is caused due to a deficiency in the cystathionine beta-synthase (CBS) enzyme. Read this article for more information.

Medically reviewed by

Dr. Arpit Varshney

Published At February 24, 2023
Reviewed AtFebruary 24, 2023


Homocystinuria is a rare inherited disorder caused by the increased concentration of homocysteine, a sulfur-containing amino acid in blood and urine. This is a hereditary condition having an autosomal recessive trait, meaning that a child can get a copy of a defective gene from both affected parents. These patients have a deficiency of cystathionine beta-synthase (CBS). Patients affected by this condition usually appear normal at birth but can develop serious complications with time.

What Is Cystathionine Beta-Synthase (CBS)?

Cystathionine beta-synthase is an enzyme encoded by the gene CBS in humans. This gene provides the instructions for making the enzyme cystathionine beta-synthase. The cystathionine beta-synthase acts in a chemical pathway that helps convert the building blocks of proteins (amino acids) called homocysteine and serine to cystathionine by using vitamin B6 (pyridoxine). After that, the cystathionine gets converted into another amino acid called cysteine which is used to build proteins or is broken down and excreted in the urine.

What Is the Pathophysiology of Homocystinuria?

Classic homocystinuria is caused by the reduced activity of the enzyme CBS (cystathionine beta-synthase). This enzyme is present in gene 21q22 and helps convert methionine to cysteine. The enzymes homocysteine and methionine accumulate in tissues and interfere with the cross-linking of collagen fibers.

What Is the Epidemiology of Classic Homocystinuria?

Classic homocystinuria is the most common type and usually affects people of Celtic origin. It has been seen in 1 of 344,000 people worldwide. However, it is more commonly seen in some countries such as Ireland (1 in 65000), Germany (1 in 17,800), Norway (1 in 6,400), and Qatar (1 in 1,800). All these cases have autosomal recessive patterns, and 50 % are responsive to pyridoxine (vitamin B6).

What Is the Etiology of Classic Homocystinuria?

There are both genetic and non-genetic causes that can lead to homocystinuria.

Genetic Causes -

Genetic mutations can impact the functioning of enzymes essential for breaking amino acids. For example, as already mentioned, classic homocystinuria is caused by mutations in the gene that produces the cystathionine beta-synthase (CBS) enzyme. The abnormal functioning of CBS can lead to the build-up of homocysteine in blood and urine.

Non-genetic Causes -

Other non-genetic causes of high homocysteine in the blood and urine are more common than genetic causes. These cause different signs and symptoms, which include -

  • Vitamin deficiencies, especially vitamin B6 or B12 deficiencies.

  • Diabetes.

  • Low thyroid hormone levels (hypothyroidism).

  • High cholesterol.

  • Smoking.

  • High blood pressure.

  • Medications such as Carbamazepine, Phenytoin, Atorvastatin, and Methotrexate.

What Are the Signs and Symptoms of Classic Homocystinuria?

Homocystinuria involves different body parts, including the eyes and vascular, skeletal, and central nervous systems. However, in some cases, only one system can be involved or all of them.

1. Eyes - Myopia (common vision condition in which far objects appear blurry) and ectopia lentis (dislocation or displacement of the natural crystalline lens) can be seen after the age of one year. However, in the majority of cases, ectopia lentis occurs by age eight years. Glaucoma may also be seen in some cases.

2. Skeletal System - Some of the following skeletal characteristics can be seen in patients with classic homocystinuria such as

  • Marfanoid habitus with normal to tall stature (occasionally failure to thrive in infancy).

  • Brittle hair.

  • Hypopigmentation.

  • High-arched palate.

  • Arachnodactyly (long, slender, and curved fingers).

  • Limited joint mobility.

  • Kyphoscoliosis (abnormal curve of spine).

  • Pectus excavatum (protrusion of the breast - pigeon breast).

3. Vascular System - Thromboembolism (obstruction in a blood vessel due to a blood clot) is one of the primary causes of early death in these patients. Cerebral venous sinus thrombosis can also be seen in early childhood.

4. CNS (Central Nervous System) -

  • The delayed development of the child is the first abnormal sign of homocystinuria.

  • Low IQ ranges from 10 to 138.

  • Many patients have psychiatric problems, including personality disorders, depression, anxiety, seizures, and obsessive-compulsive behavior. Dystonia (involuntary muscle contractions) can also be seen.

How Is Classic Homocystinuria Diagnosed?

Various laboratory tests are conducted to confirm the diagnosis of homocystinuria, which include-

  • Cyanide-Nitroprusside Test - This test is done to detect the presence of sulfhydryl-containing compounds in the urine.

  • Urine Amino Acids - Urine tests can be done to check the levels of homocysteine and methionine.

  • Ophthalmology Test - The eye can be examined to detect myopia, dislocated lenses, or other eye conditions.

  • Imaging Tests - Such as X-rays and dual-energy X-ray absorptiometry (DEXA) bone scans can be done to detect osteoporosis.

  • Genetic Testing - This can be done to identify the specific disease-causing variants in the CBS gene.

  • Biopsy - Liver and skin biopsies can be done to measure the CBS activity in tissues.

What Is the Management of Classic Homocystinuria?

The management of classic homocystinuria depends on the early diagnosis and starting the treatment as soon as possible. The treatment aims to prevent complications and ensure the development of normal intelligence. If the diagnosis is made late, the aim is to prevent life-threatening thromboembolic events and prevent complications from worsening. The treatment includes -

  • Pyridoxine is the drug of choice, and in patients who are pyridoxine sensitive folic acid and vitamin B12 are used to reduce the homocysteine levels.

  • Methionine-restricted diet and a cysteine-rich diet are recommended to treat this condition. The diet consisting of methionine restriction and cysteine supplementation is of paramount importance. Non-recommended food includes the following:

    • Meat, chicken, fish, and eggs.

    • Milk, cheese, curd, ice cream, and chocolates.

    • Wheat flour, maize, barley, oatmeal, bread, cakes, biscuits, and pastries.

    • Rice and pulses.

  • Foods that can be consumed in moderate amounts include the following:

    • Fruits include bananas, grapes, mango, guava, papaya, and apple.

    • Vegetables include beans, beetroot, cauliflower, cabbage, carrot, onion, radish, sweet potato, brinjal, pumpkin, or tomatoes.

  • Unrestricted foods are the following:

    • Honey, jam, and jellies.

    • Butter, cooking fat, and oil.

    • Tea or coffee.

What Are the Complications of Classic Homocystinuria?

The complications involved with this condition are:

  • Thromboembolism (an obstruction in the blood vessel due to a blood clot).

  • Coronary artery disease such as myocardial infarction.

  • Mitral valve prolapse (a condition in which there is Improper closure of the valve between the upper and lower-left chambers of the heart).

  • Osteoporosis in two-thirds of patients by the age of 15.

  • Fatty infiltration of the liver.

  • Pancreatitis.

What Are the Risk Factors for Classic Homocystinuria?

The following conditions can lead to the elevation of urinary cystine levels, which include -

  • Older people.

  • Renal failure.

  • Postmenopausal.

  • Hypothyroidism.

  • Leukemia.

  • Psoriasis.


Classic homocystinuria is a rare inherited condition. Early diagnosis and medical and dietary care are essential to stop or even reverse some of the complications involved in this condition. However, patients who get the treatment at an early age have very little chance of developing any complications and have normal development and growth.

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Dr. Arpit Varshney
Dr. Arpit Varshney

General Medicine


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