Dr. Kakul Husain Page 1

Diseases related to amino acids and nucleic acid metabolism

1 Synthesis of nucleic acids

1.1 Purine Synthesis

1.2 Pyrimidine synthesis

1.3 Converting nucleotides to deoxynucleotides

2 Degradation of nucleic acids

2.1 Pyrimidine catabolism

2.2 Purine catabolism

3 Interconversion of nucleotides

Etiology and clinical manifestation of phenylketonuria,

cystinuria,

Alkaptonuria,

Fanconi's syndrome,

albinism and tyrosinemia,

hypo and hyperuricemia,

Gout.

Nucleic acid metabolism

Nucleic acid metabolism is the process by which nucleic

acids (DNA and RNA) are synthesized and degraded.

Nucleic acids are polymers of nucleotides. Nucleotide synthesis is

an anabolic mechanism generally involving the chemical reaction

of phosphate, pentose sugar, and a nitrogenous base.

Destruction of nucleic acid is a catabolic reaction.

Additionally, parts of the nucleotides or nucleobases can be salvaged to

recreate new nucleotides.

Both synthesis and degradation reactions require enzymes to facilitate the

event. Defects or deficiencies in these enzymes can lead to a variety of

diseases.

Fig: Composition of nucleotides, which make up nucleic acids.

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Synthesis of nucleic acids

Nucleotides can be separated into purines and pyrimidines.

They both contain a sugar and a phosphate, but have nitrogenous

bases that are different sizes.

Because of this, the two different groups are synthesized in

different ways.

However, all nucleotide synthesis requires the use

of phosphoribosyl pyrophosphate (PRPP) which donates the ribose

and phosphate necessary to create a nucleotide.

Purine Synthesis

The origin of atoms that make up purine bases.

Adenine and guanine are the two nucleotides classified as purines.

In purine synthesis, PRPP is turned into inosine monophosphate, or IMP.*

Production of IMP from PRPP requires glutamine, glycine, aspartate, and

6 ATP, among other things.

IMP is then converted to AMP (adenosine monophosphate) using GTP and

aspartate, which is converted into fumarate.

While IMP can be directly converted to AMP, synthesis of GMP (guanosine

monophosphate) requires an intermediate step, in which NAD+ is used to

form the intermediate xanthosine monophosphate, or XMP. XMP is then

converted into GMP by using the hydrolysis of 1 ATP and the conversion of

glutamine to glutamate.

AMP and GMP can then be converted into ATP and GTP, respectively,

by kinases that add additional phosphates.

ATP stimulates production of GTP, while GTP stimulates production of ATP.

This cross regulation keeps the relative amounts of ATP and GTP the same.

Excess of either nucleotide could increase the likelihood of DNA mutations,

where the wrong purine nucleotide is inserted.

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Lesch-Nyhan syndrome is caused by a deficiency in hypoxanthine-

guanine phosphoribosyltransferase or HGPRT, the enzyme that

catalyzes the reversible reaction of producing guanine from GMP

(Guanine mono phosphate). write

This is a sex-linked congenital defect that causes overproduction of

uric acid along with mental retardation, spasticity, and an urge to

self-mutilate.

Pyrimidine synthesis

Uridine-triphosphate (UTP), at left, reacts with glutamine and other chemicals to form cytidine-triphosphate

(CTP), on the right.

Pyrimidine nucleotides include cytidine, uridine, and thymidine.

The synthesis of any pyrimidine nucleotide begins with the formation of

uridine.

This reaction requires aspartate, glutamine, bicarbonate, and 2 ATP molecules

(to provide energy), as well as PRPP which provides the ribose-

monophosphate.

Unlike in purine synthesis, the sugar/phosphate group from PRPP is not added

to the nitrogenous base until towards the end of the process.

After uridine-monophosphate is synthesized, it can react with 2 ATP to form

uridine-triphosphate or UTP. UTP can be converted to CTP (cytidine-

triphosphate) in a reaction catalyzed by CTP synthetase. Thymidine synthesis

first requires reduction of the uridine to deoxyuridine, before the base can be

methylated to produce thymidine.

ATP, a purine nucleotide, is an activator of pyrimidine synthesis, while CTP, a

pyrimidine nucleotide, is an inhibitor of pyrimidine synthesis. **

This regulation helps to keep the purine/pyrimidine amounts similar, which is

beneficial because equal amounts of purines and pyrimidines are required for

DNA synthesis.

Deficiencies of enzymes involved in pyrimidine synthesis can lead to the

genetic disease Orotic aciduria which causes excessive excretion of orotic acid

in the urine.

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Converting nucleotides to deoxynucleotides

Nucleotides are initially made with ribose as the sugar component, which is a

feature of RNA. DNA, however, requires deoxyribose, which is missing the 2'-

hydroxyl (-OH group) on the ribose.

The reaction to remove the -OH [RNA] is catalyzed by ribonucleotide

reductase. This enzyme converts NDPs (nucleoside-diphosphate) to dNDPs

(deoxynucleoside-diphosphate). **

The nucleotides must be in the diphosphate form for the reaction to occur. [1]

In order to synthesize thymidine, a component of DNA which only exists in

the deoxy form, uridine is converted to deoxyuridine (by ribonucleotide

reductase), and then is methylated by thymidylate synthase to create

thymidine.

Degradation of nucleic acids

General outline of nucleic acid degradation for purines.

The breakdown of DNA and RNA is occurring continuously in the cell.

Purine and pyrimidine nucleosides can either be degraded to waste products

and excreted or can be salvaged as nucleotide components.

Pyrimidine catabolism

Cytosine and uracil are converted into beta-alanine and later

to malonyl-CoA which is needed for fatty acid synthesis, among

other things.

Thymine, on the other hand, is converted into β-aminoisobutyric

acid which is then used to form methylmalonyl-CoA.

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The leftover carbon skeletons such as acetyl-CoA and Succinyl-

CoA can then by oxidized by the citric acid cycle.

Pyrimidine degradation ultimately ends in the formation

of ammonium, water, and carbon dioxide.

The ammonium can then enter the urea cycle which occurs in the

cytosol and the mitochondria of cells.

Pyrimidine bases can also be salvaged. For example, the uracil base can

be combined with ribose-1-phosphate to create uridine monophosphate or

UMP.

A similar reaction can also be done with thymine and deoxyribose-

1-phosphate.

Deficiencies in enzymes involved in pyrimidine catabolism can

lead to diseases such as Dihydropyrimidine dehydrogenase

deficiency which has negative neurological effects. [8]

Purine catabolism

Purine degradation takes place mainly in the liver of humans and

requires an assortment of enzymes to degrade purines to uric acid.

First, the nucleotide will lose its phosphate through 5'-nucleotidase.

The nucleoside, adenosine, is then deaminated and hydrolyzed to

form hypoxanthine via adenosine deaminase and nucleosidase

respectively.

Hypoxanthine is then oxidized to form xanthine and then uric acid

through the action of xanthine oxidase.

The other purine nucleoside, guanosine, is cleaved to form

guanine.

Guanine is then deaminated via guanine deaminase to form

xanthine which is then converted to uric acid.

Oxygen is the final electron acceptor in the degradation of both

purines.

Uric acid is then excreted from the body in different forms

depending on the animal.

Free purine and pyrimidine bases that are released into the cell are

typically transported intercellularly across membranes and salvaged to

create more nucleotides via nucleotide salvage.

For example, adenine + PRPP --> AMP + PPi. This reaction requires the

enzyme adenine phosphoribosyltransferase.

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Free guanine is salvaged in the same way except it

requires hypoxanthine-guanine phosphoribosyltransferase.

Defects in purine catabolism can result in a variety of diseases

including gout, which stems from an accumulation of uric acid

crystals in various joints, and adenosine deaminase deficiency,

which causes immunodeficiency. **write

Interconversion of nucleotides

Once the nucleotides are synthesized they can exchange

phosphates among one another in order to create mono-, di-, and

tri-phosphate molecules.

The conversion of a nucleoside-diphosphate (NDP) to a

nucleoside-triphosphate (NTP) is catalyzed by nucleoside

diphosphate kinase, which uses ATP as the phosphate donor.

Similarly, nucleoside-monophosphate kinase carries out the

phosphorylation of nucleside-monophosphates.

Adenylate kinase is a specific nucleoside-monophosphate kinase

that functions only on adenosine-monophosphate

Phenylketonuria

Phenylketonuria

Phenylalanine

Specialty Medical genetics, pediatrics

Phenylketonuria (PKU) (phenyl + ketone + -

uria; /ˌfinəlˌkitɵnˈjʊəriə/) is an inborn error of

metabolism involving impaired metabolism

of phenylalanine, one of the amino acids.

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Phenylketonuria is caused by absent or virtually absent phenylalanine

hydroxylase (PAH)enzyme activity. The condition is also known as

"phenylalanine hydroxylase deficiency."

Untreated PKU can lead to intellectual disability, seizures, and other serious

medical problems.[2] The best proven treatment for classical PKU patients is a

strict phenylalanine-restricted diet supplemented by a medical formula

containing amino acids and other nutrients.

Patients who are diagnosed early and maintain a strict diet can have a normal

life span with normal mental development.

PKU is an inherited disease.

When an infant is diagnosed with PKU, it is never the result of any action of

the parents or any environmental factor. Rather, for a child to inherit PKU,

both of his or her parents must have at least one mutated allele of the PAH

gene.*

Most parents who are carriers of PKU genes are not aware that they have this

mutation because being a carrier causes no medical problems.

To be affected by PKU, a child must inherit two mutated alleles, one from

each parent.

Signs and symptoms

Blood is taken from a two-week-old infant to test for phenylketonuria

PKU is commonly included in the newborn screening panel of most countries, with

varied detection techniques.

Most babies in developed countries are screened for PKU soon after birth.

Screening for PKU is done with bacterial inhibition assay (Guthrie test),

immunoassays using fluorometric or photometric detection, or amino acid

measurement using tandem mass spectrometry (MS/MS).

Measurements done using MS/MS determine the concentration of Phe and the ratio of

Phe to tyrosine, the ratio will be elevated in PKU.

Because the mother's body is able to break down phenylalanine during pregnancy,

infants with PKU are normal at birth.

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The disease is not detectable by physical examination at that time, because no

damage has yet been done.

However, a blood test can reveal elevated phenylalanine levels after one or two days

of normal infant feeding. This is the purpose of newborn screening, to detect the

disease with a blood test before any damage is done, so that treatment can prevent the

damage from happening.

Genetics

Phenylketonuria is inherited in an autosomal recessive fashion

PKU is an autosomal recessive metabolic genetic disorder. As an autosomal recessive

disorder, two PKU alleles are required for an individual to exhibit symptoms of the

disease. If both parents are carriers for PKU, there is a 25% chance any child they

have will be born with the disorder, a 50% chance the child will be a carrier, and a

25% chance the child will neither develop nor be a carrier for the disease.

Pathophysiology

Classical

Classical PKU, and its less severe forms "mild PKU" and "mild

hyperphenylalaninemia" are caused by a mutated gene for

the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid

phenylalanine ("Phe") to other essential compounds in the body, in particular

tyrosine.

Tyrosine is a conditionally essential Amino acid for PKU patients because

without PAH it cannot be produced in the body through the breakdown of

phenylalanine.

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Tyrosine is necessary for the production of neurotransmitters like epinephrine,

norepinephrine, and dopamine.[15]

Treatment

PKU is not curable.

However, if PKU is diagnosed early enough, an affected newborn can grow up

with normal brain development by managing and controlling phenylalanine

("Phe") levels through diet, or a combination of diet and medication.

When Phe cannot be metabolized by the body, a typical diet that would be

healthy for people without PKU causes abnormally high levels of Phe to

accumulate in the blood, which is toxic to the brain.

If left untreated, complications of PKU include severe intellectual disability,

brain function abnormalities, microcephaly, mood disorders, irregular motor

functioning, and behavioral problems such as attention deficit hyperactivity

disorder, as well as physical symptoms such as a "musty" odor, eczema, and

unusually light skin and hair coloration.

In contrast, PKU patients who follow the prescribed dietary treatment from

birth, may have no symptoms at all. Their PKU would be detectable only by a

blood test.

To achieve these good outcomes, all PKU patients must adhere to a special

diet low in Phe for optimal brain development.

Since Phe is necessary for the synthesis of many proteins, it is required for

appropriate growth, but levels must be strictly controlled in PKU patients.

Cystinuria

Cystinuria is an inherited autosomal recessive disease that is characterized by the

formation of cystine stones in the kidneys, ureter, and bladder.

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Genetics

Figure: Cystinuria has an autosomal recessive pattern of inheritance.

Cystinuria is an autosomal recessive disease, which means that the defective

gene responsible for the disease is located on an autosome, and two copies of

the defective gene (one inherited from each parent) are required in order to be

born with the disease.

The parents of an individual with an autosomal recessive disease

both carry one copy of the defective gene, but usually do not experience any

signs or symptoms of the disease.

Cause

Cystinuria is caused by mutations in the SLC3A1 and SLC7A9 genes.

These defects prevent proper reabsorption of basic, or positively charged,

amino acids:Cystine, lysine, ornithine,arginine.

Under normal circumstances, this protein allows certain amino acids,

including cysteine, to be reabsorbed into the blood from the filtered fluid that

will become urine.

Mutations in either of these genes disrupt the ability of this transporter protein

to reabsorb these amino acids, allowing them to become concentrated in the

urine.

As the levels of cystine in the urine increase, the crystals typical of cystinuria

are able to form, resulting in kidney stones.

Cystine crystals form hexagonal-shaped crystals that can be viewed upon

microscopic analysis of the urine.

The other amino acids that are not reabsorbed do not create crystals in urine.

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Pathophysiology

Cystinuria is characterized by the inadequate reabsorption of cystine in the

proximal convoluted tubules after the filtering of the amino acids by the

kidney's glomeruli, thus resulting in an excessive concentration of this amino

acid in the urine.

Cystine may precipitate out of the urine, if the urine is neutral or acidic, and

form crystals or stones in the kidneys, ureters, or bladder.

It is one of several inborn errors of metabolism included in the Garrod's tetrad.

CYSTINE disease is attributed to deficiency in transport and metabolism of

amino acids.

Clinical Features

Cystinuria is a cause of persistent kidney stones.

It is a disease involving the defective transepithelial transport of cystine and dibasic

amino acids in the kidney and intestine, and is one of many causes of kidney stones.

If not treated properly, the disease could cause serious damage to the kidneys and

surrounding organs, and in some rare cases death.

The stones may be identified by a positive nitroprusside cyanide test.

The crystals are usually hexagonal, translucent, white.

Upon removal, the stones may be pink or yellow in color, but later they turn to

greenish due to exposure to air.

Cystinuria is usually asymptomatic when no stone is formed. However,

once a stone is formed, or if stone production is severe or frequent,

symptoms may be present:

Nausea/Vomiting

Dull ache or "colicky" pain

Chronic pain

Hematuria

Obstructive syndromes like hydronephrosis

Cystinurics can also experience chronic pain in one, or both,

kidneys due to the scars that the jagged edges of the stones can

leave or damage from multiple stone removal surgeries.

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Urine odor in cystinuria has a smell of rotten eggs due to the

increase in cystine.

Investigations

1. Blood: Routine hemogram along with blood sugar, urea, and creatinine.

2. Urine: For cystine crystals, and casts. The most specific test is the cyanide–

nitroprusside test

3. Ultrasound/CT scan to reveal if a stone is present.

4. Genetic analysis to determine which mutation associated with the disease may be

present. Currently genotyping is not available in the United States but might be

available in Spain and Italy.

Regular X-rays often fail to show the cystine stones, however they can be visualized

in the diagnostic procedure that is called intravenous pyelogram (or IVP for short).

Stones may show up on XR with a fuzzy gray appearance. They are radioopaque due

to sulfur content, though more difficult to visualize than calcium oxalate stones.

Treatment

Initial treatment is with adequate hydration, alkalization of the urine with

citrate supplementation or acetazolamide, and dietary modification to reduce

salt and protein intake (especially methionine).

If this fails then patients are usually started on chelation therapy with an agent

such as penicillamine.

Once renal stones have formed, however, the first-line treatment is ESWL

(Extracorporeal shock wave lithotripsy). If ESWL do not work efficiently

surgery can be necessary.

Both endoscopic surgery and conventional open-abdominal surgery have

proven to be effective treatment modalities for patients with more advanced

disease.

Alkaptonuria

Alkaptonuria

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Pigmentation of the face in alkaptonuria

Specialty endocrinology

Alkaptonuria (black urine disease, black bone disease, or alcaptonuria) is

a rare inherited genetic disorder in which the body cannot process the amino

acids phenylalanine and tyrosine, which occur in protein.**** WRITE

It is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-

dioxygenase (EC 1.13.11.5); if a person inherits abnormal copies from each

parent (it is a recessive condition) the body accumulates an intermediate

substance called homogentisic acid in the blood and tissues.

Homogentisic acid and its oxidated form alkapton are excreted in the urine,

giving it an unusually dark color. The accumulating homogentisic acid causes

damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as

well as precipitating as kidney stones and stones in other organs.

Symptoms usually develop in people over thirty years old, although the dark

discoloration of the urine is present from birth.

Apart from treatment of the complications (such as pain relief and joint

replacement for the cartilage damage), vitamin C has been used to reduce the

ochronosis and lowering of the homogentisic acid levels may be attempted

with a low-protein diet.

Recently the drug nitisinone has been found to suppresses homogentisic acid

production, and research is ongoing as to whether it can improve symptoms.

Alkaptonuria is a rare disease; it occurs in one in 250,000 people, but is more

common in Slovakia and the Dominican Republic.

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Signs and symptoms

Intervertebral discs calcification due to ochronosis

Patients with alkaptonuria are asymptomatic as children or young adults, but

their urine may turn brown or even inky black if collected and left exposed to

open air.

Pigmentation may be noted in the cartilage of the ear as well as other

cartilage, and the sclera and corneal limbus of the eye.

After the age of thirty people begin to develop pain in the weight-bearing

joints of the spine, hips and knees.

The pain can be severe to the point that interferes with activities of daily living

and may affect ability to work. Joint replacement surgery (hip and shoulder) is

often necessary at a relatively young age.

In the longer term, the involvement of the spinal joints leads to reduced

movement of the rib cage and can affect breathing.

Bone mineral density may be affected, increasing the risk of bone fractures,

and rupture of tendons and muscles may occur.

Pathophysiology

Chemical skeletal formula of homogentisic acid, which accumulates in the body fluids of people

with alkaptonuria.

Every person carries in their DNA two copies (one received from each parent)

of the gene HGD, which contains the genetic information to produce the

enzyme homogentisate 1,2-dioxygenase (HGD) which can normally be found

Dr. Kakul Husain Page 15

in numerous tissues in the body (liver, kidney, small intestine, colon and

prostate).

In people with alkaptonuria, both copies of the gene contain abnormalities that

mean that the body cannot produce an adequately functioning enzyme.

HGD mutations are generally found in certain parts (exons 6, 8, 10 and 13) but

a total of over 100 abnormalities have been described throughout the gene.

The normal HGD enzyme is a hexamer (it has six subunits) that are organized

in two groups of three (two trimers) and contains an iron atom.

Different mutations may affect the structure, function or solubility of the

enzyme.

Very occasionally the disease appears to be transmitted in an autosomal

dominant fashion, where a single abnormal copy of HGD from a single parent

is associated with alkaptonuria; it is possible that other mechanisms or defects

in other genes are responsible in those cases.

Diagnosis

Urine of a four-month-old baby with dark urine (on the left) after 10%

ammonia and 3% silver nitrate were added.

The tube in the middle is a normal control.

Color change on alkalinization is not a specific test, and confirmatory

investigations are needed.

Treatment

No treatment modality has been unequivocally demonstrated to reduce the

complications of alkaptonuria.

Main treatment attempts have focused on preventing ochronosis through the

reduction of accumulating homogentisic acid.

Such commonly recommended treatments include large doses of ascorbic

acid (vitamin C) or dietary restriction of amino

acids phenylalanine and tyrosine.

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However, vitamin C treatment has not shown to be effective, and protein

restriction (which can be difficult to adhere to) has not shown to be effective

in clinical studies.

FANCONI SYNDROME

Fanconi syndrome (also known as Fanconi's syndrome) is a disease of

the proximal renal tubules of the kidney in which glucose, amino acids, uric

acid, phosphate and bicarbonate are passed into the urine, instead of being

reabsorbed.

Fanconi syndrome affects the proximal tubule, which is the first part of the

tubule to process fluid after it is filtered through the glomerulus. It may be

inherited, or caused by drugs or heavy metals.

Different forms of Fanconi syndrome can affect different functions of the

proximal tubule, and result in different complications.

*The loss of bicarbonate results in type 2 or proximal renal tubular acidosis.

The loss of phosphate results in the bone disease rickets(even with adequate

vitamin D and calcium), because phosphate is necessary for bone

development.

Clinical features

The clinical features of proximal renal tubular acidosis are:

Polyuria,

polydipsia and dehydration

Hypophosphatemic rickets (in children) and osteomalacia (in adults)

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Growth failure

Acidosis

Hypokalemia

Hyperchloremia

Other features of the generalized proximal tubular dysfunction of the Fanconi

syndrome are:

Hypophosphatemia/phosphaturia

Glycosuria

Proteinuria/aminoaciduria

Hyperuricosuria

Causes

In contrast to Hartnup disease and related tubular conditions, Fanconi

syndrome affects the transport of many different substances, so is not

considered to be a defect in a specific channel, but a more general defect in the

function of the proximal tubules.

Different diseases underlie Fanconi syndrome; they can

be inherited, congenital, or acquired.

Inherited

Cystinosis is the most common cause of Fanconi syndrome in children.

Other recognised causes are Wilson's disease (a genetically inherited

condition of copper metabolism), Lowe syndrome, tyrosinemia

(type-I), galactosemia, glycogen storage diseases, and hereditary

fructose intolerance.

Two forms, Dent's disease and Lowe syndrome, are X linked.

Acquired

It is possible to acquire this disease later in life.

Causes include ingesting expired tetracyclines, and as a side effect

of tenofovir in cases of pre-existing renal impairment.

In the HIV population, Fanconi syndrome can develop secondary to the use of

an antiretroviral regimen containing tenofovir and didanosine.

Lead poisoning also leads to Fanconi syndrome.

Treatment

Treatment of children with Fanconi syndrome mainly consists of replacement

of substances lost in the urine (mainly fluid and bicarbonate).

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Tyrosinemia (or "Tyrosinaemia") is an error of metabolism, usually

inborn, in which the body cannot effectively break down the amino

acid tyrosine. *

Symptoms include liver and kidney disturbances and mental retardation.

Untreated, tyrosinemia can be fatal.

Most inborn forms of tyrosinemia produce hypertyrosinemia (high levels of

tyrosine).

Types

Tyrosinemia is inherited in an autosomal recessive pattern.

There are three types of tyrosinemia, each with distinctive symptoms and caused by

the deficiency of a different enzyme.

Type I tyrosinemia

Type II tyrosinemia

Type III tyrosinemia

Treatment

Treatment varies depending on the specific type.

A low protein diet may be required in the management of tyrosinemia.

Recent experience with NTBC has shown to be very effective.

The most effective treatment in patients with tyrosinemia type I seems to be

full or partial liver transplant.

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Albinism

"Albino" redirects here. For an overview, see Albinism in biology.

Albinism

An albino boy of Black ethnicity

Specialty Dermatology

Albinism in humans (from the Latin albus,

"white"; see extended etymology, also

called achromia, achromasia, or achromatosis) is

a congenital disorder characterized by the complete or

partial absence of pigment in the skin, hair and eyes due to

absence or defect of tyrosinase, a copper-containing

enzyme involved in the production of melanin.

It is the opposite of melanism.

Unlike humans, other animals have multiple pigments and for

these, albinism is considered to be a hereditary condition characterised by the

absence of melanin in particular, in the eyes, skin, hair, scales, feathers or

cuticle.

Albinism results from inheritance of recessive gene alleles and is known

to affect all vertebrates, including humans.

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While an organism with complete absence of melanin is called an albino, an

organism with only a diminished amount of melanin is described

as leucistic or albinoid.***

Albinism is associated with a number of vision defects, such

as photophobia, nystagmus and amblyopia.

Signs and symptoms

Girl with albinism from Papua New Guinea

In humans, there are two principal types of albinism: oculocutaneous,

affecting the eyes, skin and hair, and ocular affecting the eyes only.

Most people with oculocutaneous albinism appear white or very pale, as the

melanin pigments responsible for brown, black, and some yellow colorations

are not present.

Ocular albinism results in light blue eyes, and may require genetic testing to

diagnose.

Visual problems

Development of the optical system is highly dependent on the presence of melanin,

and the reduction or absence of this pigment in sufferers of albinism may lead to:

Photophobia and decreased visual acuity due to light scattering within the eye

(ocular straylight)

Reduced visual acuity due to foveal hypoplasia and possibly light-

induced retinal damage.

Eye conditions common in albinism include:

Nystagmus, irregular rapid movement of the eyes back and forth, or in circular

motion.[7]

Amblyopia, decrease in acuity of one or both eyes due to poor transmission to the

brain, often due to other conditions such as strabismus.[7]

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Enzyme

The enzyme defect responsible for albinism is tyrosine 3-monooxegenase

(tyrosinase), which synthesizes melanin from the amino acid tyrosine.

Diagnosis

Genetic testing can confirm albinism and what variety it is, but offers no

medical benefits except in the cases of non-OCA disorders that cause

albinism along withother medical problems which may be treatable.

There is no 'cure' for Albinism.

Treatment

As there is no cure for albinism, it is managed through lifestyle adjustments.

People with Albinism need to take care not to sun-burn and should have

regular healthy skin checks by a dermatologist.

For the most part, treatment of the eye conditions consists of visual

rehabilitation.

Surgery is possible on the extra-ocular muscles to decrease strabismus.

Hypouricemia

Hypouricemia

Uric acid

Specialty endocrinology

Hypouricemia is a level of uric acid in blood serum that is below normal.

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In humans, the normal range of this blood component has a lower threshold set

variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530

micromol/L (6 mg/dL) for women and 619 micromol/L (7 mg/dL) for men.

Hypouricemia usually is benign and sometimes is a sign of a medical

condition.

Causes

Hypouricemia is not a medical condition itself (i.e., it is benign), but it is a

useful medical sign.

Usually hypouricemia is due to drugs and toxic agents, sometimes it is due to

diet or genetics, and rarely it is due to an underlying medical condition.

When one of these causal medical conditions is present, hypouricemia is a

common sign.

Medication

The majority of drugs that contribute to hypouricemia are uricosurics (drugs that

increase the excretion of uric acid from the blood into the urine).

Others include drugs that reduce the production of uric acid: xanthine oxidase

inhibitors, urate oxidase (rasburicase), and sevelamer.

Diet

Hypouricemia is common in vegetarians due to the low purine content of most

vegetarian diets.[4]

Vegetarian diet has been found to result in mean serum uric

acid values as low as 239 µmol/L (2.7 mg/dL).

While a vegetarian diet is typically seen as beneficial with respect to

conditions such as gout,[5]

care should be taken to avoid associated health

conditions.

Transient hypouricemia sometimes is produced by total parenteral nutrition.

Medical conditions

Medical conditions that can cause hypouricemia include:

Fanconi syndrome

Hyperthyroidism

Multiple Sclerosis[13]

Myeloma

Nephritis

Dr. Kakul Husain Page 23

Wilson's disease

Prevalence

In one study, hypouricemia was found in 4.8% of hospitalized women and 6.5% of

hospitalized men. (The definition was less than 0.14 mmol l-1 for women and less

than 0.20 mmol l-1 in men.)

Diagnosis[

Uric acid clearance should also be performed, increase in clearance points to

proximal tubular defects in the kidney, normal or reduced clearance points to a

defect in xanthine oxidase.

Treatment

Idiopathic hypouricemia usually requires no treatment. In some cases,

hypouricemia is a medical sign of an underlying condition that does require

treatment.

For example, if hypouricemia reflects high excretion of uric acid into the urine

(hyperuricosuria) with its risk of uric acid nephrolithiasis, the hyperuricosuria

may require treatment.[15]

Drugs and dietary supplements that may be helpful

Inositol

Antiuricosurics

Complications

Although normally benign, idiopathic renal hypouricemia may increase the risk of

exercise-induced acute renal failure.

Hyperuricemia

Asymptomatic hyperuricemia

Dr. Kakul Husain Page 24

Uric acid

Specialty endocrinology

Hyperuricemia is an abnormally high level of uric acid in the blood. In the

pH conditions of body fluid, uric acid exists largely as urate, the ion form.

The amount of urate in the body depends on the balance between the amount

of purines eaten in food, the amount of urate synthesised within the body (e.g.,

through cell turnover), and the amount of urate that is excreted in urine or

through the gastrointestinal tract.

In humans, the upper end of the normal range is 360 µmol/L (6 mg/dL) for

women and 400 µmol/L (6.8 mg/dL) for men.[3]

Causes WRITE 4

Many factors contribute to hyperuricemia, including: genetics,

insulin resistance, hypertension, renal insufficiency, obesity, diet, use

of diuretics, and consumption of alcoholic beverages.

Of these, alcohol consumption is the most important.

Causes of hyperuricemia can be classified into three functional types:

1. increased production of uric acid,

2. decreased excretion of uric acid, and

3. mixed type.

Causes of increased production include high levels of purine in the diet and

increased purine metabolism.

Causes of decreased excretion include kidney disease, certain drugs, and

competition for excretion between uric acid and other molecules.

Mixed causes include high levels of alcohol and/or fructose in the diet, and

starvation.

Treatment

Precipitation of uric acid crystals, and conversely their dissolution, is known to be

dependent on the concentration of uric acid in solution, pH, sodium concentration,

and temperature. Established treatments address these parameters.

Dr. Kakul Husain Page 25

Concentration

Following Le Chatelier's principle, lowering the blood concentration of uric

acid may permit any existing crystals of uric acid to be gradually dissolved

into the blood, from whence the dissolved uric acid can be excreted.

Maintaining a lower blood concentration of uric acid similarly should reduce

the formation of new crystals.

pH

Serum pH is neither safely nor easily altered.

Therapies that alter pH principally alter the pH of urine, to discourage a

possible complication of uricosuric therapy: formation of uric acid kidney

stones due to increased uric acid in the urine.

Dietary supplements that can be used to make the urine

more alkaline include sodium bicarbonate, potassium citrate, magnesium

citrate, and Shohl's Solution (now replaced by Bicitra).

Temperature

Low temperature is a commonly reported trigger of acute gout: an example

would be a day spent standing in cold water, followed by an attack of gout the

next morning.

This is believed to be due to temperature-dependent precipitation of uric acid

crystals in tissues at below normal temperature.

Thus, one aim of prevention is to keep the hands and feet warm, and soaking

in hot water may be therapeutic.

Prognosis

Increased levels predispose for gout and, if very high, kidney failure.

The metabolic syndrome often presents with hyperuricemia.

People with gout, and by inference hyperuricemia, are significantly less likely

to develop Parkinson's disease, unless they also require diuretics.

Gout

Gout

Dr. Kakul Husain Page 26

The Gout (James Gillray, 1799) depicts the pain of the artist's gout as

a demon ordragon.[1][2]

Specialty Rheumatology

Gout (also known as podagra when it involves the big toe) is a medical

condition usually characterized by recurrent attacks of acute inflammatory

arthritis—a red, tender, hot, swollen joint.

The metatarsal-phalangeal joint at the base of the big toe is the most

commonly affected (approximately 50% of cases).

It may also present as tophi, kidney stones, or urate nephropathy. It is caused

by elevated levels of uric acid in the blood.

The uric acid crystallizes, and the crystals deposit in joints, tendons, and

surrounding tissues.

Signs and symptoms

Gout presenting in the metatarsal-phalangeal joint of the big toe: Note the slight redness of the

skin overlying the joint.

Gout can present in a number of ways, although the most usual is a recurrent

attack of acute inflammatory arthritis (a red, tender, hot, swollen joint).

Other joints, such as the heels, knees, wrists, and fingers, may also be

affected.

Joint pain usually begins over 2–4 hours and during the night.

Dr. Kakul Husain Page 27

The reason for onset at night is due to the lower body temperature then.

Other symptoms may rarely occur along with the joint pain,

including fatigue and a high fever.

Cause

The crystallization of uric acid, often related to relatively high levels in the

blood, is the underlying cause of gout.

This can occur for a number of reasons, including diet, genetic predisposition,

or under-excretion of urate, the salts of uric acid.

Medical conditions

Gout frequently occurs in combination with other medical problems.

Metabolic syndrome, a combination of abdominal

obesity, hypertension, insulin resistance, and abnormal lipid levels, occurs in

nearly 75% of cases.

Medication

Diuretics have been associated with attacks of gout.

However, a low dose of hydrochlorothiazide does not seem to increase the

risk.

Other medicines that increase the risk

include niacin and aspirin (acetylsalicylic acid).

Pathophysiology

Uric acid

Gout is a disorder of purine metabolism, and occurs when its final

metabolite, uric acid, crystallizes in the form of monosodium

urate, precipitating and forming deposits (tophi) in joints, on tendons, and in

the surrounding tissues.

Microscopic tophi may be walled off by a ring of proteins, which blocks

interaction of the crystals with cells, and therefore avoids inflammation.

Dr. Kakul Husain Page 28

Diagnosis

Gout on X-rays of a left foot. The typical location is the big toe joint. Note also the soft tissue

swelling at the lateral border of the foot.

Spiked rods of uric acid crystals from a synovial fluidsample photographed under a microscope

withpolarized light. Formation of uric acid crystals in the joints is associated with gout.

Gout may be diagnosed and treated without further investigations in someone

with hyperuricemia and the classic podagra.

Synovial fluid analysis should be done, however, if the diagnosis is in doubt.

X-rays, while useful for identifying chronic gout, have little utility in acute

attacks.

A definitive diagnosis of gout is based upon the identification of monosodium

urate crystals in synovial fluid or a tophus.

Blood tests: the diagnostic utility of measuring uric acid level is

limited.[5]Hyperuricemia is defined as a plasma urate level greater than 420

μmol/l (7.0 mg/dl) in males and 360 μmol/l (6.0 mg/dl) in females.

Prevention

Both lifestyle changes and medications can decrease uric acid levels.

Dietary and lifestyle choices that are effective include reducing intake of food

such as meat and seafood, consuming adequate vitamin C,

limiting alcohol and fructoseconsumption, and avoiding obesity.

Dr. Kakul Husain Page 29

A low-calorie diet in obese men decreased uric acid levels by 100 µmol/l

(1.7 mg/dl).

Vitamin C intake of 1,500 mg per day decreases the risk of gout by 45%.

Coffee, but not tea, consumption is associated with a lower risk of gout.

Gout may be secondary to sleep apnea via the release of purines from oxygen-

starved cells.

Treatment of apnea can lessen the occurrence of attacks.

Treatment

The initial aim of treatment is to settle the symptoms of an acute

attack.[39]

Repeated attacks can be prevented by different drugs used to reduce

the serum uric acid levels.

Tentative evidence supports the application of ice for 20 to 30 minutes several

times a day to decrease pain.