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In general, cystine stones constitute 1-2% of urinary calculi. Studies have shown that the peak age of onset is in the third decade although they can occur at any time. Cystine stones are generally yellowish with a waxy appearance. Under a microscope they consist of hexagonal crystals (as shown in the image).
What are amino acids.. and why are they relevant?
Amino acids are the building blocks of proteins in the body. They are known as amino acids because they contain certain chemical groups. Methionine, cysteine and cystine are all different amino acids although the terminology can be confusing:
Methionine is an essential amino acid. It is 'essential' because it cannot be made by the body and has to be ingested in the diet. Methionine can be converted to cysteine in the body. (Cysteine is therefore known as a non-essential amino acid because it is produced by the body). Two cysteine molecules combine together to form one cystine molecule. Note: cystine is a dimeric amino acid - this means it is made up of two other molecules. You may also see it referred to as dibasic - this just means that it has two hydrogen (H) atoms. 
Cystine is both absorbed in the diet and also converted from methionine. Cystine is absorbed in the intestine from dietary sources and is also converted from methionine (another amino acid). Usually most cystine is reabsorbed by the kidney (back into the body meaning it cannot form stones) and excretion in the urine is usually only 20mg per day. In cystinuria there is failure of the kidney to reabsorb cystine leading to a build up of levels in the urine - People with cystinuria have excretion levels of over 250mg/day.

The actual structure of cystine is shown. It is a combination of 2 cysteine molecules linked by a bond between two sulphur (S) molecules (a disulphide bond) which gives cystine its strength. It also explains why, when cystine stones are broken with a laser they give off a characteristic odour - because the disulphide bond is broken - and sulphur (or rotten eggs) can be smelt.

Cystinuria is caused by a defect in both the intestinal and renal (kidney) tubular transport of dibasic amino acids. However only the renal defect is clinically important and results in excessive urinary excretion of cystine. The other amino acids affected are ornithine, arginine and lysine (remembered by the word COAL or COLA).

Solubility and saturation

Ornithine, arginine and lysine are completely soluble in urine and therefore do not form crystals and stones even though the levels in the urine are high. Unfortunately, the poor solubility of cystine in urine leads to stone formation. The accumulation of cystine causes crystals to form when the concentration of cystine rises above a certain 'saturation point'. This explains why drinking plenty of fluid helps to reduce the incidence of stones as it makes the urine more dilute.
The autosomal recessive pattern of inheritance was described in the 1950's. Initially three types of cystinuria were described (Types I, II and III) although this is less commonly used now as it has not proved useful and types II and III are difficult to differentiate. Two genes have (so far) been associated with type I (SLC3A1) and types II/III (SLC7A9). Multiple mutations of these genes have been identified. The type II/III form has a more complex mode of inheritance - described as autosomal dominant with incomplete penetrance. Occasionally even carriers of cystinuria may get stones if they have type II/III. The better understanding of the genetics of cystinuria may in the future influence the type and timing of treatment given.

Although the genes for cystinuria are known, there is no routine genetic testing to diagnose the condition. This is not necessary as the diagnosis can often be made on a simple urine test or by analysing a stone that has been passed. For monitoring of the impact of treatment a 24 hour urine test may be required - although we often find a single 'spot' urine sample sufficient. We are the first group to study the genetics of a UK population with cystinuria and offer this test in our lab. However this is analysed from a research perspective but not used to influence treatment (at present).This may be interesting from a research perspective but unlikely to be used in routine practice at present. So in summary if you are concerned that either you or a member of your family has cystinuria ask your doctor to send your urine for testing.

Our Genetics Research

In an effort to understand the genetics behind what causes cystinuria in a UK population, we have been offering all patients genetic testing on blood samples taken in our clinic at Guy's and St. Thomas'. Working closely with our geneticists, we have found  several genetic mutations in the genes that cause cystinuria (25 different mutations in gene SLC3A1 and 17 different mutations in gene SLC7A9). Interestingly, we have found 9 new mutations not previously described in the literature. This has led to fascinatingly new insights into the disease.

We found that in patients who have one specific type of change (missense mutations in the SLC3A1 gene mutation), have lower levels of urinary lysine, ornithine and arginine compared with all other the types of mutations.

This work has been presented internationally at the American Urological Association Annual Meeting and won First Prize at the Royal Society of Medicine Urology Section Meeting and Best Paper prize at the British Association of Urological Surgeons Annual Meeting.

We are now working to model the proteins encoded by the two genes and to identify where on the protein the mutations may affect and suggest how it may affect protein function. This work is still in early stages, but we hope in the future, this may enable us to understand which patients are at high risk of forming stones and so may benefit from drug treatment and more regular observation in clinic.

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