Lesch-Nyhan syndrome
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.
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.
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.
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.
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