In homocystinuria, “homocysteine” is a metabolite of the amino acid methionine, and “uria” means, a substance present in urine.

So people with homocystinuria have large amounts of homocysteine in their urine, as well as other problems in the connective tissue, muscles, brain, heart, and blood vessels.

Now, amino acids are the basic building blocks that make up proteins.

There are 20 amino acids used in the human body and they all contain a carboxyl (-COOH) group and an amine (-NH2) group.

Methionine is one of the essential amino acids, meaning our bodies can't create it, but they must be acquired through food that’s rich in protein like meat, eggs, dairy, avocados, beans, etc.

So the proteins you eat are broken down into amino acids in the gastrointestinal tract by gastric acid and digestive enzymes.

The amino acids are then absorbed by the small intestine into the bloodstream, and then travel to the cells of the body, where they are used for protein synthesis.

Since the body can’t store these amino acids, any excess amino acids are converted into glucose or ketones and used for energy.

Now methionine is also used to synthesize another amino acid, cysteine.

First, methionine is converted into the amino acid homocysteine through multiple steps.

Next, the enzyme cystathionine beta- synthase, which requires vitamin B6 as a substrate, combines homocysteine and serine to create cystathionine.

Finally, the enzyme cystathionase converts cystathionine into cysteine.

Any homocysteine that does not undergo this process can be converted back into methionine by methionine synthase, which requires vitamin B12, or cobalamin, and folate as substrates.

There are two types of homocystinuria: familial and acquired.

Familial homocystinuria is an autosomal recessive genetic disorder that first manifests early in life.

It’s usually caused by cystathionine beta-synthase deficiency, but it can also be caused by decreased B12 affinity in cystathionine beta- synthase, or methionine synthase deficiency.

Now, when there’s a problem with cystathionine beta- synthase, homocysteine cannot be combined with serine, so less cysteine is produced, and homocysteine builds up in the body.

If methionine synthase is defective, homocysteine can be converted into cysteine, but it can’t be converted back into methionine, which also leads to its accumulation.

Acquired homocystinuria happens later in life and is often caused by poor diet, where there are deficiencies in vitamin B6, B12, or folate.

B12 and folate deficiency decreases the activity of methionine synthase, while B6 deficiency does the same to cystathionine beta-synthase, both leading to the build up of homocysteine in the body.

Whatever the cause, when homocysteine builds up in the body, some of it is excreted in the urine leading to homocystinuria.

They also build up in the blood, where they bind to the endothelial cells lining blood vessels, causing them to secrete molecules called proinflammatory cytokines.

These attract immune cells like leukocytes to the area and cause inflammation, which leads to atherosclerosis, or plaque build up inside the arteries.

This narrows the arteries and could lead to ischemia of the tissue supplied by these arteries.

Furthermore, homocysteine also binds to platelets and cause them to stick to one another to make blood clots.

In the bones, homocysteine binds to fibrillin-1 proteins that normally provide structural support.

Video - Homocystinuria

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