Homocystinuria

Homocystinuria is an inherited genetic disorder that prevents the body from properly processing certain protein building blocks, leading to skeletal abnormalities, vision issues, and an increased risk of blood clotting.

Overview

Homocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins properly. The signs and symptoms of the condition typically develop during childhood, although some mildly affected individuals may not show signs and symptoms until adulthood.

Symptoms

The symptoms of this condition vary depending on the specific form of the disorder:

Classic Homocystinuria

The most common form of the disorder, known as classic homocystinuria, is characterized by the following features:

• Tall stature
• Nearsightedness
• Dislocation of the lens at the front of the eye
• A higher risk of blood clotting disorders
• Brittle bones that are prone to fracture or other skeletal abnormalities
• Developmental delay and learning problems in some affected individuals

Less Common Forms

Rarer forms of the condition can present with a different set of symptoms, including:

• Intellectual disability
• Slower growth and weight gain (failure to thrive)
• Seizures
• Problems with movement
• A blood disorder called megaloblastic anemia, which occurs when a person has a low number of red blood cells and the remaining red blood cells are larger than normal

Frequency

Classic homocystinuria affects at least 1 in 200,000 to 335,000 people worldwide. The disorder appears to be more common in certain countries, including:

• Ireland (1 in 65,000)
• Germany (1 in 17,800)
• Norway (1 in 6,400)
• Qatar (1 in 1,800)

The rarer forms of the condition have only a small number of cases reported in the scientific literature.

Causes

Variants (also called mutations) in the CBS, MTHFR, MTR, MTRR, and MMADHC genes cause this condition.

Variants in the CBS gene cause classic homocystinuria. The CBS gene provides instructions for making an enzyme called cystathionine beta-synthase. This enzyme helps break down the amino acid methionine by converting homocysteine to a molecule called cystathionine. Variants in this gene disrupt the enzyme's function, preventing homocysteine from being used properly. As a result, homocysteine and methionine build up in the blood, and some excess homocysteine is excreted in the urine.

Rarely, variants in the MTHFR, MTR, MTRR, and MMADHC genes cause the condition. The enzymes produced by these genes play roles in converting homocysteine back to methionine. Variants in these genes prevent the enzymes from functioning properly, leading to a buildup of homocysteine in the body. Researchers have not yet determined exactly how excess homocysteine and related compounds lead to the specific signs and symptoms of the disorder.

Associated Genes

• CBS
• MMADHC
• MTHFR
• MTR
• MTRR

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Although people who carry only one altered copy and one normal copy of the CBS gene do not develop the disorder, they are more likely than people without a CBS variant to experience shortages (deficiencies) of vitamin B12 and folic acid.

Other Names for This Condition

• Cystathionine beta synthase deficiency
• Homocysteinemia