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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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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 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/Alkaptonuria8/2/2019 Alkaptonuria Cagayan State university
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