Lesch-Nyhan syndrome

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much more. Try it free today! Lesch-Nyhan syndrome is a rare genetic condition
which leads to excess uric acid in the blood, and it causes kidney, joint, neurological,
and behavioral problems. Normally, each cell contains both DNA and
RNA, and diving deeper, each nucleotide can be broken down into a sugar, a deoxyribose
in DNA or a ribose in RNA, one to three phosphate groups, and a nucleobase, which can be either
a pyrimidine or a purine. There are three pyrimidine bases– cytosine,
thymine and uracil and two purine bases, adenine and guanine. So, the name of a ribose-containing, monophosphatic
nucleotide, based on guanine, would be guanosine monophosphate, or GMP for short, whereas one
based on adenine, would be adenosine monophosphate, or AMP, for short. Now, there are two ways our cells can make
nucleotides – one is to make from scratch, also known as de novo synthesis, and the other
is the salvage pathway, which recycles nucleotides that are already semi-degraded. Let’s focus on the purine salvage pathway. In the case of GMP, the enzyme purine nucleoside
phosphorylase, first removes the ribose and the phosphate from it, turning it into guanine. Next, another enzyme called guanase removes
an amine group turning guanine into xanthine. Finally, xanthine is oxidized into uric acid
by the enzyme xanthine oxidase. On the other hand, for AMP to become uric
acid, first the enzyme AMP deaminase removes an amine group from it, turning it into IMP. Then purine nucleoside phosphorylase comes
in and removes the phosphate and the ribose from IMP, making hypoxanthine. Hypoxanthine is then oxidized twice by xanthine
oxidase – first to become xanthine, and then finally, to uric acid. Uric acid can then be filtered out of the
blood and excreted in the urine. Now those intermediate molecules in purine
degradation, guanine and hypoxanthine, can be restored into fresh new nucleic acids,
through what is known as a salvage pathway. There’s an enzyme called hypoxanthine-guanine
phosphoribosyl transferase, or HGPRT for short, which returns ribose and phosphate back to
guanine to form GMP, and to hypoxanthine to form IMP. From there, IMP can become AMP again. Now, in Lesch-Nyhan syndrome, there’s a
mutation in HGPRT gene which is on the X chromosome. So, Lesch- Nyhan syndrome is an X-linked recessive
condition, and it almost exclusively occurs in males, because if they get one mutation
they get the disease. In females, a single mutation makes them a
carrier, and two mutations are needed to have the disease. Finally, the mutation sometimes arises sporadically
rather than being inherited from a parent. Now, a mutation in the HGRPT gene means that
there’s less of the functional enzyme and as a result, purine bases cannot get recycled
and instead they get degraded into uric acid. At the same time, to make up for the lack
of recycling, the de novo purine synthesis pathway ramps up, which results in even more
purines getting broken down to uric acid. All that uric acid builds up in the blood,
causing hyperuricemia. At first, the kidneys try to compensate by
increasing the uric acid excretion into the urine and this is called hyperuricosuria. As the disease progresses, uric acid precipitates
and crystallizes, forming urate stones that can get lodged in the urinary tract, obstructing
the flow in the ureters, bladder or urethra. Soon, though, kidneys can’t keep up anymore
so the excess uric acid begins getting stored up in tissues, in the form of urate crystals. The urate crystals can particularly effect
the interstitium of the kidney, causing urate nephropathy, or deposit in areas of slow blood
flow around the body- for example just beneath the skin along the bones, or within the joint
space. For unknown reasons, the elevated levels of
uric acid seems to cause a drop in the levels and activity of dopamine, a neurotransmitter
in the brain, and that can affect a person’s emotions and behavior. Symptoms of Lesch-Nyhan syndrome typically
present during the first year of life. Sometimes the uric acid forms small orange
sand-like urate crystals that can go through the urinary tract and end up in an infant’s
diaper. Other times, the uric acid forms larger urate
crystals that get stuck in the urinary tract and cause intense pain, fussiness, and hematuria,
or blood in the urine, as well as recurrent urinary tract infections. In older children and adults, the urate crystals
deposit all over the body- in the kidneys, slowly leading to kidney failure, and under
the skin of the elbows, earlobes, fingers and knees, appearing as chalky lumps or nodules,
called tophi. They can also collect within joints, particularly
within the first metatarsal joint of the foot – or the base of the big toe, causing a form
of inflammatory arthritis, called gout. Classically, gout presents as attacks of severe
joint pain, swelling, warmth and redness that can last for days or weeks. Individuals with Lesch-Nyhan syndrome also
have neurologic problems like hypotonia, or decreased muscle tone and have a delay in
reaching childhood milestones – like walking and talking. Neuromuscular problems are also common like
having involuntary muscle movements, dystonia, chorea which is characterized by brief, jerky
movements, and ballismus which is characterized by flinging of the limbs. Finally, these individuals usually have aggressive,
compulsive behavior, often resorting to self-injury, such as nail or finger biting and head banging. The diagnosis usually begins with detecting
increased uric acid levels in the blood and urine and is confirmed by identifying a gene
mutation and a decrease in the activity of the enzyme HGPRT. Treatment of Lesch-Nyhan syndrome involves
reducing uric acid levels with allopurinol, a drug which blocks the enzyme xanthine oxidase,
inhibiting the metabolism of hypoxanthine and xanthine to uric acid. Kidney stones can be treated with shockwave
lithotripsy, which uses high-intensity acoustic pulses that travel through the body to break
up the stones. Neurological and behavioral issues are difficult
to control, but medications that alleviate anxiety, such as benzodiazepines, combined
with behavioral-modification techniques can help. All right, as a quick recap, Lesch-Nyhan syndrome
is an X-linked recessive disorder caused by a deficiency or absence of the enzyme Hypoxanthine
Guanine Phosphoribosyl Transferase, or HGPRT for short, which takes part in the purine
salvage pathway. The result is hyperuricemia and hyperuricosuria,
which leads to kidney stones, gouty arthritis, neurological dysfunction, like movement disorders
and behavioral disturbances, including self-injury.


  1. I like the new voice for this video, a fresh voice, not to say the other regular voice bad or what not, it's just that something new and variable is good sometimes. A bit bored with the regular voice tbh. Keep up the good content!

  2. Earlier videos was like a short note , but from now onwards your almost explaining everything including how those symptoms appears, which in turn, making osmosis much better place for medicos and help in making concepts to learn the things in a easier way. Keep up the Good work !!

  3. Seems like alot of talking not a lot of info. Blah blah bad piss, then somehow they turn evil? Ok. I read strange things like a little boy that swears and attacks people before 1 year old. How the hell does a 1 year old know how to swear and how the hell are they gonna 'attack' people? So got gout naturally start acting like a crazy old man? Pretty sure thats why we used to smack kids. Teach them hitting results in pain. Maybe get them on dialysis and some gene therapy and stop letting them be an evil shit. We all have kids that get labelled with aspergers ADD depression etc but if you accept that then you are a mug. It is normally found AFTER vaccination JUST LIKE THIS ONE. So after inserting foreign matter and DNA into a developing biological creature you expect it not to have development issues? Thats a form of insanity? You cant corrupt DNA and claim it is hereditary until they dont find the marker. They want so say it is a new mutation that just so happens to be exactly the same as the last kid with the so called hereditary gene. That's nonsense.

  4. you are making medicine learning more simple , enjoyable and attractable . i really appreciate your great efforts for delivering such extraordinary useful videos , love you guys

  5. I am really enjoying the videos. Thanks osmosis. The lectures have been made very precise and to the point.

  6. Very good explanation in short time 😊😊😊good job and give us more & more vedios 😊😊😊

  7. I'm in med school and that you all for your help. I will contribute as soon as I get some extra income…… thank you so much.

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