Homocystinuria – causes, symptoms, diagnosis, treatment, pathology

Learning medicine is hard work! Osmosis makes it easy. It takes your lectures and notes to create
a personalized study plan with exclusive videos, practice questions and flashcards, and so
much more. Try it free today! 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 B6 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. Once homocysteine binds to these proteins,
they can’t bind to each other or other proteins, so the bones become weaker or deformed. These deformities are also found in another
connective tissue disorder called Marfan syndrome, where there’s a mutation in the fibrillin-1
gene. Homocysteine can also build up in the eye. The lens of the eye is held in place by a
ring of cysteine rich fibers, called zonular fibers. When cystine can’t be synthesized, homocysteine
get incorporated into these fibers instead, and cause them to degenerate, which leads
to ectopia lentis, or the downward dislocation of the lens. Finally, when homocysteine builds up in the
brain, it causes neurons to undergo apoptosis or programed cell death. This could lead to developmental delay or
neurodegeneration. Symptoms of familial homocystinuria can manifest
during infancy since homocysteine disrupts the development of many organ systems. People with this disorder can have marfanoid
habitus, where they are unusually tall and thin, with long arms and legs. Other features include pectus excavatum or
caved in sternum, pectus carinatum or protruding sternum, genu valgum, where the knees angle
towards each other, and problems with the spine like kyphosis or an abnormally convexed
spine. Next, ectopia lentis can cause nearsightedness,
blurred vision, and neurological problems like intellectual disabilities, and seizures
can also occur. Finally, the combination of atherosclerosis
and thrombosis can cause transient ischemic attacks or strokes even in childhood. Symptoms of acquired homocystinuria are related
to atherosclerosis and thrombosis since they don’t affect the development of the individual. These include hypertension and increased risk
of strokes and myocardial infarctions. Diagnosis of homocystinuria is based on the
presence of clinical symptoms and a positive family history of the disease. The diagnosis can be confirmed by elevated
levels of homocysteine in the urine. A blood test will show elevated methionine
and homocysteine levels and decreased cysteine levels. Finally, a blood test for vitamin B6, B12,
and folate levels should be done. The main treatment for homocystinuria is a
diet high in vitamin B6, B12, folate, and cystine, and betaine if needed, which will
all help decrease homocysteine levels and reduce the risk of strokes. All right, as a quick recap, homocystinuria
is a disorder where there’s a defect in methionine metabolism. It could be familial, where there’s a genetic
defect in the genes coding for cystathionine beta- synthase or methionine synthase, or
it could be acquired, due to deficiencies in vitamin B6, B12, and folate. Symptoms of the familial form of this disorder
include connective tissue abnormalities like marfanoid habitus, as well as ectopia lentis,
intellectual disability, seizures, atherosclerosis, and thrombosis. The acquired form usually has symptoms related
to atherosclerosis and thrombosis like strokes and myocardial infarctions. It is usually diagnosed by the presence of
high levels of homocysteine in the urine, elevated methionine and homocysteine, and
decreased cysteine in the blood. It’s treated with proper diet and betaine
if needed.


  1. Thanks and excellent but :

    Please more stress on (without time extensions) :
    Differential diagnosis
    Treatment !!!!!!!! e.g Betaine is available or no and what about updates

    Allah bless you all

  2. Great video, very informative. I love the way you setup those videos adressing all the important topics.

  3. Osmosis i just cant tell how happy i m by finding this channel ,i m a first year medical student ,and sometimes i feel that i m just cramming ,but HOLLA,i dont need to as diagrams are just,just beautiful,rather i can go on writing a para on this..

Leave a Reply

(*) Required, Your email will not be published