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ARTICLES

We plan to regularly publish articles from experts in the field of alkaptonuria and related conditions here - as new articles appear previous articles will be archived so they will always be available.

Management and Therapy of Alkaptonuria
Attempts to treat alkaptonuria involve correcting the underlying metabolic defect and preventing or reversing the pigmentation and arthritic changes. However, no proven preventative or curative treatment is currently available. Dietary restriction of the amino acid precursors, phenylalanine and tyrosine, has no proven efficacy in improving symptoms. The long-term restriction of these amino acids is also extremely difficult to maintain. In guinea pigs induced to have alkaptonuria by being fed large amounts of tyrosine, the anti-oxidant vitamin C apparently prevents alkaptonuria. Unfortunately, vitamin C does not improve the hereditary type of alkaptonuria in humans. Therefore, early detection and symptomatic treatments are recommended.

Ochronosis There is no clinically proven treatment available to prevent or reverse the pigmentary changes seen in alkaptonuria.

Joint management Close attention to control of joint pain is critically important for patients with alkaptonuria. Inadequate pain control may lead to limited use of the affected joint, further reducing range of motion in that joint. In our experience, the use of a long-acting non-steroidal anti-inflammatory medication on a regular basis in combination with a more potent short-acting medication for breakthrough periods of increased pain can be beneficial. Physical and occupational therapy are important to maintain muscle strength and flexibility. A program involving swimming or pool physical therapy is ideal, since this puts less stress on the joints. Avoiding manual labour or high-impact sports, which can stress the spine and large joints, may help delay the progression of arthritis. Joint replacement surgery is an option available for significant arthritis, and is generally performed with the goal of pain relief rather than increased mobility.

Other organs After age 40, evaluation is recommended for possible heart complications related to alkaptonuria. An echocardiogram can detect aortic or mitral valve calcification and a computed tomography, or CT scan, of the chest can detect coronary artery calcification. Kidney and prostate stones can also occur in individuals with alkaptonuria and may require surgery.

Potential treatment A potential treatment directed toward the primary defect in alkaptonuria has been proposed. Nitisinone, or NTBC, is an herbicide which causes plants to bleach. It is an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), which produces homogentisic acid, the compound considered to cause the signs and symptoms of alkaptonuria. Nitisinone has been shown to reduce urinary homogentisic acid in patients with alkaptonuria. Nitisinone is currently approved for use in tyrosinemia type I, a severe liver disease in infants and children, but not for alkaptonuria. The possible side effects are related to the elevated tyrosine levels that occur with the use of nitisinone. This could lead to eye complications, such as sensitivity to light and crystal formation in the cornea. There have been no reports of permanent eye damage. Further studies evaluating the treatment of alkaptonuria with nitisinone are needed to identify its appropriate dosage, benefits, safety, and possible side effects.

Low protein diet for alkaptonuria.

The main cause of disability in patients with alkaptonuria (AKU) is arthritis. A low protein diet is sometimes prescribed to help reduce the joint pain associated with AKU. If you have AKU, a low protein diet (LPD) may be worth considering. This article will attempt to:

1. explain why LPD may work,

2. tell you whether it works,

3. what it involves and

4. what you should do if you think it may help you.

1. Why should LPD work in AKU?

There are very good reasons a low protein diet may help reduce joint pain in AKU. Protein, present in foods, is broken down into smaller components called amino acids in the intestine. Amino acids can be transported around the body and used for growth, maintenance and repair of all parts of the body. People with AKU lack an enzyme. This means that two amino acids called phenylalanine and tyrosine cannot be broken down by the body. As a result a by-product called homogentisic acid (HGA) accumulates in the joints and causes pain (and arthritis). If less protein is eaten, the less HGA will be made from phenylalanine and tyrosine. This could therefore reduce joint pain and arthritis.

2. Does LPD work in AKU?

Some small studies published in reputable medical journals have shown that LPD reduces pain and arthritis. At present there are more studies showing a benefit in children – possibly because some adults find it very hard to comply with the diet.

3. What is a low protein diet for AKU?

The main sources of protein in the diet are meat, fish, dairy products, eggs, nuts, beans and pulses. Smaller amounts of protein are also found in cereal products such as bread, pasta, cakes, breakfast cereals and biscuits. It is not possible to cut out all protein foods from the diet – we cannot live without some protein. These foods are also important sources of vitamins and minerals. The aim of the diet is therefore to reduce protein foods to the minimum safe level – this can be calculated by a dietician on the basis of your age weight and gender.

4. What you should do if you want to begin LPD?

It is very important the diet is only followed under strict medical supervision. Without the input of a state registered dietician the diet could lead to dangerous deficiencies of protein, vitamins and minerals. If you feel you would like to try the diet to reduce your joint pain you should ask your GP to refer you to a state registered dietician. Correctly supervised the diet could be a safe way to reduce pain. The need for pain killing drugs may be reduced by the LPD. The benefits only last as long as protein is restricted.

Alkaptonuria

Biochemical background

Alkaptonuria (AKU; McKusick 203500), the first inborn error of metabolism described by Garrod in 1902, is an inborn error of metabolism caused by deficiency of the enzyme homogentisic acid oxidase (HGO). Homogentisic acid (HGA) is a metabolite in the metabolism of phenylalanine and tyrosine. HGO catalyses the conversion of HGA to maleylacetoacetate. As a consequence of the enzymatic block, HGA accumulates in body fluids and tissues and excess HGA is also excreted in large amounts in the urine. This HGA, HGA-polymers and other related compounds cause the characteristic dark coloration of the urine after voiding in patients with alkaptonuria.

Clinical background

The clinical abnormalities of alkaptonuria are related to HGA-excess. In some cases, alkaptonuria is detected soon after birth because of the dark urine or dark staining of some kinds of diapers. There are no other clinical symptoms early after birth. In the following months to years, HGA-excess causes dark coloration of the cartilage and some soft tissue leading to discoloration of the auricles, sclera and sometimes a dark hue of the skin.

In the later years (already beginning in the pre-pubertal and teen-period) joint problems can appear. There is progressive destruction of cartilage over time with increasing signs and symptoms of joint disease. The onset of clinical joint disease may differ from an age of 6 years to an age of 60 years. The speed of development may also differ from patient to patient. Generally, there is increasing joint pain and limited and painful use of the large weight-bearing joints: knees, hips, spine and shoulders. The small joints of the hand and feet are generally not affected and there is no major inflammatory component (arthritis).

The progressive nature of the disease leads to increasing problems and incapacity, leading to the indication for joint replacement with sometimes patients ending up wheelchair-bound. Major joint problems can make it necessary for patients to stop working and to rely on social security. There is no indication that life expectancy is significantly shortened.

HGA-excess and discoloration can be seen in other tissues as well. Endothelium is also affected, but a link with premature atherosclerotic disease is uncertain. The cardiac valves, most notably the aortic valve, are affected. In many patients, there is a degree of aortic valve calcification as a consequence of HGA-excess-related valvular damage. Valvular damage can lead to aortic valve stenosis and/or insufficiency. This aortic valve stenosis and/or insufficiency is an indication for valve replacement.

Finally, an association has been described between alkaptonuria and liability to develop renal and prostate calculi, related to excess urinary HGA-excretion. Also, a number of patients with defects of conduction in the auricular chain or hearing loss have been described, presumably related to HGA-linked problems with the small joints in the auricular chain.

Biochemical pathophysiology

The organ damage associated with alkaptonuria is caused by excess HGA, HGA-polymers and related compounds. The main damaged organ is cartilage and the musculo-skeletal system as well as vascular endothelium. From a pathophysiologic point of view, HGA is a necessary compound to cause alkaptonuria. It may be HGA itself, HGA-polymers and/or HGA-metabolites (benzoquinone acetate).

The mechanism of damage of HGA can involve different pathways. HGA (or related compounds) can have a direct toxic effect on cartilage compounds, involving cells (chondrocytes) as well as macromolecules (proteoglycans). This toxic effect may be mediated by the generation of oxygen radicals (linked to benzoquinone acetate) but may also involve other pathways. The effect of HGA may also be linked to effects of the HGA-polymers. There is some evidence that HGA-related damaged involves specifically lysine-residue in cartilage proteins. Finally, in vitro studies have indicated that high HGA levels impair the production of proteoglycans by chondrocytes and impair cross-linking of collagen fibrils in cartilage.

The mechanism of damage to the vascular endothelium can conceivably involve similar mechanisms; the same is true for stiffening of the auricular conduction chain. Urinary tract stones are formed because of the high concentration of HGA in the urinary tract, sometimes in combination with an anatomic of physiologic abnormality providing a nidus for stone formation.

Treatment

Until now there is no satisfactory treatment. Protein restriction to diminish the supply of substrate to the deficient enzyme is difficult to implement and of unproven value. Vitamin C as an anti-oxidant to prevent HGA-related damage to cartilage has not been shown to be effective. From a pathophysiological point of view, inhibiting the supply of substrate to the deficient enzyme HGO would prevent excess production and accumulation of HGA and thus of HGA-related end-organ damage. The new drug NTBC inhibits the enzyme 4-hydroxy-phenylpyruvate dioxygenase (HPPD) that converts 4-hydroxy-phenylpyruvate to HGA; thus, little HGA is generated preventing the accumulation of HGA.

Barrientos ZM, de Valk HW. Clinical outcome in adult patients with alkaptonuria. J Inherit Metab Dis 2002; 25 (suppl 1): 61.

Low Protein Diet in Islam

For many practising Muslims religion has a much more comprehensive role in life than is often typical in Europe or the Americas. Islam has a profound influence on dietary practices, therefore following a low protein diet (LPD) needs to be medically supervised.

Arabic word Halal means lawful, Halal foods are foods that one is allowed to eat. Halal foods include all foods of plant origin and some animal origin only if they conform to the religious method of slaughtering.

“Haram” are forbidden foods or drinks, including pork, blood, animals not slaughtered by Islamic methods, alcohol, drugs and foods containing ingredients obtained from other haram foods.

Practising Muslims with AKU wishing to follow LPD should, like other AKU patients, seek medical advice preferably from a dietician to ensure they are meeting their nutritional requirements. In addition a LPD may affect practising Muslims because there may also be changes to commonly consumed foods and cooking methods, which may be of benefit on a LPD. During the holy month of Ramadan where fasting is practised, dietary intake is often reduced. LPD may need to be customised to the individual needs of the patient therefore dietetic input may be very valuable to overcome any concerns of both the patients and providers. In general the approach to advising a LPD is the same for all AKU patients.

Nirouz Zarroug SRD, Dietitian. Royal Liverpool Hospital UK