alkaptonuria cagayan state university

8/2/2019 Alkaptonuria Cagayan State university

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3/5/12

Alkaptonuria

Presented by:CHEERAMKULANGARA, MUHAMMED SHAFIKUTTATH 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 withthe following symptoms

1. Dark urine

2. Severe chronic low back pain

3. Dark-brownish pigmentation of sclera.

4. Bluish Pigmentations of Hands


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Dark urine

pigmentation of

sclera.

Bluish Pigmentations of


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Severe chronic low back pain

X- Ray of lumbar spine of thepatient

shows

1. Narrowing of disc spaces

1. Intervertebral disc calcifications

1. loss of lumbar lordosis


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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 EXPLANATIONAlkaptonuria 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 1,2-

dioxygenase (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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Therefore in

the body of an

AKU patient


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Through a simple test with Benedict's sugar reagent, it was notedthat 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 darkenson 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 PresentationOchronotic 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 alsoincrease 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 PresentationThe 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 inchondrocytes 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 symptomsBabies 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 healthproblems caused by Alkaptonuria andochronosis 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 willhave surgery to replace affected joints. Sometimes patients end upwheelchair-bound.

In general, people start complaining of back pain in their 20s and30s, and knee pain in their 40s. However, the onset of symptomsdepends on the individual and can vary greatly. Hip and shoulder painoften occurs later, but usually by the age of 50. Many people have atleast 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 depositscan 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 tothe 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 tothe individual. Effects are most noticeable in areas where the bodyis exposed to the sun and where sweat glands are located. Skintakes on a blue-black speckled discoloration. Sweat can actuallystain clothes brown.

Pigmentation of the skin is more visible in some patients thanothers. 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 systemsThe teeth, central nervous system (brain and spinal cord), andendocrine organs (which make hormones) also may be affected.


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Pathophysiology

The defect lies in the catabolic pathway of tyrosine, whichcontains 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 themid-to-u er dermal tissues hematox lin and


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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 associatedwith 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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GENETICSThe 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 anddeposits in connective tissues causing a debilitating arthritis.


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GENETICSMore 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 familyshowing 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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EPIDEMOLOGYIn Slovakia the disease occurs in 1:19,000 people. In other ethnicgroups, 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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3/5/12 Map showing the number of AKU patients in whom HGD mutations have beenidentified thus far, by country


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TREATMENT

No treatment modality has been unequivocally demonstrated toreduce 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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TREATMENTThe insecticide nitisinone inhibits 4-hydroxyphenylpyruvatedioxygenase, the enzyme that generates homogentisic acid from 4-

hydroxyphenylpyruvic 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 theear:


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Prostate and KidneyStones

This photo shows aprostate stone which wasremoved from a 77-yearold patient. At its widest,the stone measured 1cm

Clinical images


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Clinical images

Black pigment depositionin cartilage, connectivetissue, and the main

joints (hips, shoulders,


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Clinical images

An elbow joint, again taken during joint replacement surgery.


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Referenceshttp://en.wikipedia.org/wiki/Alkaptonuri ahttp://www.alkaptonuria.info /

THE INCIDENCE OF ALKAPTONURIA: A STUDY INCHEMICAL INDIVIDUALITY BY ARCHIBALD E. GARROD
http://en.wikipedia.org/wiki/Alkaptonuriahttp://www.alkaptonuria.info/http://www.alkaptonuria.info/http://en.wikipedia.org/wiki/Alkaptonuria


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alkaptonuria cagayan state university

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