Alkaptonuria

Click to edit Master subtitle style Presented by:

CHEERAMKULANGARA, MUHAMMED SHAFI KUTTATH KUNNUMMEL, AJITHLAL

Presented to: Dr. Pablo M. Afidchao

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CASE PRESENTATION
A 58-year-old female present to Al-karak hospital, Jordan with the following symptoms
1. 2. 3. 4.

Dark urine Severe chronic low back pain Dark-brownish pigmentation of sclera. Bluish Pigmentations of Hands

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Dark urine

pigmentation of sclera.

Bluish Pigmentations of 3/5/12

Severe chronic low back pain

X- Ray of lumbar spine of the patient shows

1.

Narrowing of disc spaces Intervertebral disc calcifications loss of lumbar lordosis

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1.

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EXAMINATION

Qualitative urine examination showed dark greenish black discoloration due to presence of homogentisic acid .

Quantitative examination of urine revealed concentration of homogentisic acid in urine was 112 mg/dl (normally HA is not present in urine).

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SCIENTIFIC EXPLANATION

Alkaptonuria was the first condition noted as following Mendelian Inheritance (by Sir Archibald Garrod in 1902). Since then, more work has been done to understand its genetic mechanism. We now know that Alkaptonuria is a recessive disorder, caused by a single gene defect, mapped to Chromosome 3, between regions 3q21-q23. The site of the homogentisate 1,2dioxygenase (HGD) gene.

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SCIENTIFIC EXPLANATION

HGD is a vital enzyme in tyrosine metabolism. The graphic below shows a general overview of this pathway. With a malfunctioning or inactive HGD enzyme, AKU patients are unable to convert Homogentisic Acid (HGA) into Maleylacetoacetic acid. Therefore instead of the natural condition of eliminating excess tyrosine from the body; AKU patients end up converting excess tyrosine ultimately to HGA.

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SCIENTIFIC EXPLANATION

Therefore in the body of an AKU patient,

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SCIENTIFIC EXPLANATION
Through a simple test with Benedict's sugar reagent, it was noted that the urine was a powerful reducing agent. Not only reducing the copper reagent to an orange precipitate, but also darkening the solution due to its alkalinity. The net effect results in orange particles suspended in a muddy-brown solution

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Clinical Presentation
AKU has several characteristic symptoms; urine that darkens on standing, ochronosis in certain tissues, and, the most severe symptom, degenerative arthropathy resulting from ochronosis in joint tissues. The joints most affected are those of the thigh, hips and knees, whereas the ankles and wrists are usually much less involved. This variability in arthropathy may be related to load bearing and it is interesting to note that pigmentation of the pinna of the ear can vary from left to right side. This has led us to speculate that mechanical loading may be an important factor in pigment deposition.

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Clinical Presentation
Ochronotic arthopathies have a large number of presentations including limitations of movement to the shoulder, hip and knee. The intervertebral discs often show degeneration and can cause pain including sciatica, lordosis and kyphosis. Cardiovascular symptoms include effects on the mitral and aortic valves, which can harden and need replacing. Ochronosis can also increase arteriosclerotic plaques. Overall, patients suffering from Alkaptonuria-induced ochronosis can experience a lot of pain, incapacity and disability The oldest recorded sufferer is 99 years of age and there have been examples of first diagnosis as late as 77 years, following bronchoscopy.

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Clinical Presentation

The ochronosis of tissues results from the deposition of oxidised and polymerised HGA in the form of benzoqinones in the extracellular matrices of connective tissues. Although there have been many publications on AKU, there is little understanding of the mechanism of ochronosis. Mammalian cartilages contain polyphenyl oxidases, which can catalyse the oxidation of HGA into pigment, and benzoquinoneacetic acid has been identified in the in vitro environment as an intermediate in the oxidation of HGA. However intracellular granules are also present in chondrocytes of patients with ochronosis and it is still not known whether the pigment deposition and binding to ECM components occurs primarily at the intracellular or extracellular level.

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Diagnosis and symptoms

Babies born with Alkaptonuria do not suffer any immediate ill effects. However, because of the presence in their urine of homogentisic acid, which turns a dark colour after several hours exposure to air, parents may notice dark staining of the babys nappies or diapers. If proper tests are then carried out, this can lead to diagnosis of the disease. Many sufferers, however, are not diagnosed with Alkaptonuria until symptoms appear later in life, after years of accumulation of homogentisic acid in their body tissues. The onset of clinical joint disease may differ from an age of six years to an age of 60 years. Generally, there is increasing joint pain and limited and painful use of the large weight-bearing joints: knees, hips, spine and shoulders.
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The main symptoms and some of the health problems causedby Alkaptonuria and ochronosis are described below.

Skeletal (bones and cartilage)

The knees, shoulders, and hips are most affected. Deposits of pigment cause cartilage to become brittle and eventually to fragment (break apart). Arthropathy (diseased joints characterised by swelling and enlarged bones) is common. Patients suffer intense joint pain and decreased mobility. Many will have surgery to replace affected joints. Sometimes patients end up wheelchair-bound. In general, people start complaining of back pain in their 20s and 30s, and knee pain in their 40s. However, the onset of symptoms depends on the individual and can vary greatly. Hip and shoulder pain often occurs later, but usually by the age of 50. Many people have at least one joint replaced by age 55.
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Cardiovascular (heart and blood vessels) Heart problems often start after age 50. These include calcification of the coronary arteries (the vessels that feed the heart). The aortic and mitral heart valves which separate chambers of the heart are most affected. The build-up of homogentisic acid can cause valves to calcify or harden, leading to narrowing of the valve causing problems with blood flow. Pigment deposits also can lead to the formation of atherosclerotic plaques (hard spots in arteries) containing cholesterol and fat.

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Genitourinary (genital and urinary systems and organs) In men, the prostate is most commonly affected. Pigment deposits can form stones in the prostate. Respiratory (organs and structures involved in breathing) Heavy pigment deposits are common in the cartilage of the larynx (voice box), the trachea (windpipe), and the bronchi (air passages to the lungs). Ocular (eyes) Vision is not usually affected, but pigmentation in the white part of the eye is evident in most patients by their early 40s.

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Cutaneous (skin) Again, the age at which this becomes noticeable varies according to the individual. Effects are most noticeable in areas where the body is exposed to the sun and where sweat glands are located. Skin takes on a blue-black speckled discoloration. Sweat can actually stain clothes brown. Pigmentation of the skin is more visible in some patients than others. It is often first seen in the ear lobe. It can also be seen in the bridge of the nose, cheeks, hands, and skin overlying tendons.

Other body systems The teeth, central nervous system (brain and spinal cord), and endocrine organs (which make hormones) also may be affected.

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Pathophysiology
The defect lies in the catabolic pathway of tyrosine, which contains a parahydroxylated ring structure. In a poorly understood complex reaction, the enzyme phenylpyruvic acid oxidase is thought simultaneously to move the pyruvic acid side chain, to decarboxylate it, and to add an additional hydroxyl group to the ring. The product, homogentisic acid, is actually ortho-meta-dihydroxyphenylacetic acid. A deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase (HGO) forces the accumulation of homogentisic acid, which is rapidly cleared in the kidney and excreted.

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Pathophysiology
Upon contact with air, homogentisic acid is oxidized to form a pigment like polymeric material responsible for the black color of standing urine. Although homogentisic acid blood levels are kept very low through rapid kidney clearance, over time homogentisic acid is deposited in cartilage throughout the body and is converted to the pigment like polymer through an enzyme-mediated reaction that occurs chiefly in collagenous tissues. As the polymer accumulates within cartilage, a process that takes many years, the normally transparent tissues become slate blue, an effect ordinarily not seen until adulthood

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Pathophysiology

The earliest sign of the disorder is the tendency for diapers to stain black. Throughout childhood and most of early adulthood, an asymptomatic, slowly progressive deposition of pigmentlike polymer material into collagenous tissues occurs. In the fourth decade of life, external signs of pigment deposition, called ochronosis, begin to appear. See the image below.

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Upon microscopic examination, amber-colored, oval-shaped structures are detected in the 3/5/12 mid-to-upper dermal tissues (hematoxylin and

Pathophysiology

The slate blue, gray, or black discoloration of sclerae and ear cartilage is indicative of widespread staining of the body tissues, particularly cartilage. The hips, knees, and intervertebral joints are affected most commonly and show clinical symptoms resembling rheumatoid arthritis. Because of calcifications that occur in these sites, however, the radiologic picture is more consistent with osteoarthritis.

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Pathophysiology

Despite many speculations that this polymer deposition is associated with cardiac pathology, no reports of mortality directly related to the homozygous state for alkaptonuria exist. Reports exist of calcification and stenosis of the aortic annulus leading to coronary artery disease, and the risk of myocardial infarction is higher than normal in older patients with ochronosis. Molecular analysis of the HGO gene shows a wide spectrum of mutation. Although no correlation has so far been made between the molecular nature of the HGO mutation and its clinical phenotype, the wide variability of mutational phenomena could certainly help explain the clinical variability in this disease. Approximately 70 separate mutations have thus far been reported.
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GENETICS

The molecular basis of alkaptonuria. Alkaptonuria (AKU) occupies a unique place in the history of

human genetics because it was the first disease to be interpreted as a mendelian recessive trait by Garrod in 1902. Alkaptonuria is a rare metabolic disorder resulting from loss of homogentisate 1,2 dioxygenase (HGO) activity. Affected individuals accumulate large quantities of homogentisic acid, an intermediary product of the catabolism of tyrosine and phenylalanine, which darkens the urine and deposits in connective tissues causing a debilitating arthritis.

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GENETICS
More than 80 mutations in the HGD gene have been identified in people with alkaptonuria. Many of these mutations change single amino acids in the homogentisate oxidase protein. A substitution of the amino acid valine for methionine at position 368 is the most common HGD mutation in European populations. Mutations in the HGD gene probably inactivate the enzyme by changing its structure

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Pedigree of family showing disease status

Father is carrier, mother is affected 8 siblings (2 males & 6 females) have the disease 5 siblings are carriers

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EPIDEMOLOGY

In Slovakia the disease occurs in 1:19,000 people. In other ethnic groups, the normal prevalence is between 1:100,000 and 1:250,000. It is reported frequently in the Dominican Republic, but exact prevalence there is not known

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Map showing the number of AKU patients in whom HGD mutations have been 3/5/12 identified thus far, by country

TREATMENT

No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Commonly recommended treatments include large doses of ascorbic acid (vitamin C)and dietary restriction of phenylalanine and tyrosine. Dietary restriction may be effective in children, but benefits in adults have not been demonstrated.

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TREATMENT

The insecticide nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that generates homogentisic acid from 4hydroxyphenylpyruvic acid. This reduces homogentisic acid. The main side-effect is irritation of the cornea, and there is a concern that it will cause the symptoms of hereditary tyrosinaemia type III because of the possible accumulation of tyrosine or other intermediaries.[7] Further studies are being conducted

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Clinical images

Narrowing and calcification of intervertebral spaces

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Clinical images

Pigmentation in the eye

Pigmentation of the ear:

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Clinical images

Prostate and Kidney Stones

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This photo shows a prostate stone which was removed from a 77-year old patient. At its widest, the stone measured 1cm

Clinical images

Black pigment deposition in cartilage, connective tissue, and the main 3/5/12 joints (hips, shoulders,

Clinical images

An elbow joint, again taken during joint replacement surgery.

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References

http://en.wikipedia.org/wiki/Alkaptonuria http://www.alkaptonuria.info/

THE INCIDENCE OF ALKAPTONURIA: A STUDY IN CHEMICAL INDIVIDUALITY BY ARCHIBALD E. GARROD

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