This document discusses four disorders of amino acid metabolism: 1. Tyrosinemia is caused by a defect in the breakdown of tyrosine, leading to its buildup. There are three types caused by different enzyme deficiencies. Symptoms vary but can include liver and kidney failure. 2. Maple syrup urine disease results from a defect in breaking down branched chain amino acids. Affected individuals cannot metabolize certain amino acids, causing neurologic issues and a maple syrup smelling urine. 3. Homocystinuria is caused by the inability to metabolize the amino acid homocysteine. It can cause skeletal abnormalities and intellectual disabilities if left untreated. 4. Albinism is caused by a lack

1. DISORDERS OF AMINO-ACID
1. TYROSINEMIA
Tyrosinemia is a genetic disorder characterized by disruptions in the multistep
process that breaks down the amino acid tyrosine, a building block of most
proteins. If untreated, tyrosine and its byproducts build up in tissues and organs,
which can lead to serious health problems.
There are three types of tyrosinemia, which are each distinguished by their
symptoms and caused by the deficiency of a different enzyme. Namely:
Type I tyrosinemia
Type II tyrosinemia
Type III tyrosinemia
1.1 Defective Enzyme
Type I tyrosinemia - Fumarylacetoacetate hydroxylase and/or
maleylacetoacetatei
someraseT- The fumarylacetoacetate hydrolase enzyme catalyzes
the hydrolysis of 4-fumarylacetoacetate into fumarate andacetoacetate.
Type II tyrosinemia - Tyrosine transaminase- the first in a series of
five enzymes that converts tyrosine to smaller molecules, which are excreted by
the kidneys or used in reactions that produce energy.
Type III tyrosinemia- 4-hydroxyphenylpyruvate dioxygenase-
This enzyme is abundant in the liver, and smaller amounts are found in the
kidneys. It is one of a series of enzymes needed to break down tyrosine.
Specifically, 4-hydroxyphenylpyruvate dioxygenase converts a tyrosine
byproduct called 4-hydroxyphenylpyruvate to homogentisic acid.
1.2 Sign & Symtopms
Type I- Tyrosinemia type I, the most severe form of this disorder, is
characterized by signs and symptoms that begin in the first few months of life.
Affected infants fail to gain weight and grow at the expected rate (failure to
thrive) due to poor food tolerance because high-protein foods lead to diarrhea
and vomiting. Affected infants may also have yellowing of the skin and whites of
the eyes (jaundice), a cabbage-like odor, and an increased tendency to bleed
(particularly nosebleeds). Tyrosinemia type I can lead to liver and kidney failure,
softening and weakening of the bones (rickets), and an increased risk of liver
cancer (hepatocellular carcinoma). Some affected children have repeated
neurologic crises that consist of changes in mental state, reduced sensation in
the arms and legs (peripheral neuropathy), abdominal pain, and respiratory
failure. These crises can last from 1 to 7 days. Untreated, children with
tyrosinemia type I often do not survive past the age of 10
Type II- Tyrosinemia type II can affect the eyes, skin, and mental development.
Signs and symptoms often begin in early childhood and include eye pain and
redness, excessive tearing, abnormal sensitivity to light (photophobia), and thick,

2. painful skin on the palms of their hands and soles of their feet (palmoplantar
hyperkeratosis). About 50 percent of individuals with tyrosinemia type II have
some degree of intellectual disability.
Type III- Tyrosinemia type III is the rarest of the three types. The characteristic
features of this type include intellectual disability, seizures, and periodic loss of
balance and coordination (intermittent ataxia).
1.3 Investigation
Type I-
Increased succinylacetone concentration in the blood and excretion in the
urine.
Elevated plasma concentration of tyrosine, methionine, and
phenylalanine Elevated urinary concentration of tyrosine metabolites
Increased urinary excretion of the compound δ-ALA
Decreased fumarylaceteoacetic acid hydrolase (FAH) enzyme activity.
Type-II
Plasma tyrosine concentration typically greater than 500 µmol/L that
may exceed 1000 µmol/L (The concentration of other amino acids is
normal.)
Increased excretion of p-hydroxyphenylpyruvate, p-
hydroxyphenyllactate, and p-hydroxyphenylacetate and presence of small
quantities of N-acetyltyrosine and 4-tyramine on urine organic acid
analysis
Type-III
Plasma concentration of tyrosine ranges from 350 to 650 µmol/L.
Excretion of 4-hydroxyphenylpyruvic acid, 4-hydroxyphenyllactate, and
4-hydroxyphenylacetate is increased. The precise quantities vary with
protein intake.
1.4 Treatment
Nitisinone (Orfadin®), 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3
cyclohexanedione (NTBC), which blocks parahydroxyphenylpyruvic acid
dioxygenase (p-HPPD), the second step in the tyrosine degradation
pathway, prevents the accumulation of fumarylacetoacetate and its
conversion to succinylacetone. Nitisinone treatment should begin as soon
as the diagnosis of tyrosinemia type I is confirmed. Because nitisinone
increases the blood concentration of tyrosine, dietary management with
controlled intake of phenylalanine and tyrosine should be started
immediately after diagnosis to prevent tyrosine crystals from forming in
the cornea. If the blood concentration of phenylalanine becomes too low
(<20 μmol/L), additional natural protein should be added to the diet.
Prior to the availability of nitisinone, the only definitive therapy for
tyrosinemia type I was liver transplantation, which now should be
reserved for those children who have severe liver failure at presentation
and fail to respond to nitisinone therapy or have documented evidence of
malignant changes in hepatic tissue.

3. 1.5 Amino-Acid Responsible
Tyrosine
2. Maple Syrup Disease
This is a metabolic disorder of branched chain amino acids. It is caused by lack of
the enzyme needed to metabolize amino acids. By-products of these amino acids
cause the urine to smell like maple syrup. Children with maple syrup urine
disease are unable to metabolize certain amino acids. By-products of these
amino acids build up, causing neurologic changes, including seizures and
intellectual disability. These by-products also cause body fluids, such as urine
and sweat, to smell like maple syrup. This disease is most common among
Mennonite families. There are many forms of maple syrup urine disease.
2.1 Defective Enzyme
Maple syrup urine disease is due to a defect in the enzvme branched chain a-keto
acid dehydrogenase. This causes a blockade in the conversion of a-keto acids to
the respective acyl CoA thioesters.
2.2 Sign & Symptoms
In the most severe form, infants develop neurologic abnormalities, including
seizures and coma, during the first week of life and can die within days to weeks.
In the milder forms, children initially appear normal but during infection,
surgery, or other physical stress, they can develop vomiting, staggering,
confusion, and coma.
2.3 Investigation
An early diagnosis by enzyme analysis-preferably within the first week of life-is
ideal. Estimation of urinary branched amino acids and keto acids will also help in

4. diagnosis.
2.4 Treatment
The treatment is to feed a diet with low (or no) content of branched amino acids.
The plasma levels of branched amino acids should be constantly monitored for
adjusting their dietary intake.
2.5 Amino-Acid Responsible
Leucine
Isoleucine and
Valine.
3. HOMOCYSTINURIA
Homocystinuria is caused by lack of the enzyme needed to metabolize
homocysteine. This disorder can cause a number of symptoms, including
decreased vision and skeletal abnormalities.
Children with homocystinuria are unable to metabolize the amino acid
homocysteine, which, along with certain toxic by-products, builds up to cause a
variety of symptoms. Symptoms may be mild or severe, depending on the
particular enzyme defect. Infants with this disorder are normal at birth.
3.1 Defective Enzyme
Cystathionine-β-synthase, also known as CBS, It catalyzes the first step of
the transsulfuration pathway, from homocysteine to cystathionine
L-serine + L-homocysteine L-cystathionine + H2O
3.2 Sign & Symptoms
The first symptoms, including dislocation of the lens of the eye, causing severely
decreased vision, usually begin after 3 years of age. Most children have skeletal
abnormalities, including osteoporosis. Children are usually tall and thin with a
curved spine, chest deformities, elongated limbs, and long, spiderlike fingers.
Without early diagnosis and treatment, mental (psychiatric) and behavioral
disorders and intellectual disability are common. Homocystinuria makes the
blood more likely to clot spontaneously, resulting in strokes, high blood
pressure, and many other serious problems.
3.3 Investigating
The term homocystinuria describes an increased excretion of the thiol amino
acid homocysteine in urine (and incidentally, also an increased concentration
in plasma). The source of this increase may be one of many metabolic factors,
only one of which is CBS deficiency. Others include the re-methylation defects
(cobalamin defects,methionine sythase deficiency, MTHFR) and vitamin
deficiencies (cobalamin (vitamin B12) deficiency, folate (vitamin B9)
deficiency, riboflavin deficiency (vitamin B2),pyridoxal phosphate deficiency
(vitamin B6)). In light of this information, a combined approach to laboratory
diagnosis is required to reach a differential diagnosis.

5. CBS deficiency may be diagnosed by routine metabolic biochemistry. In the first
instance, plasma or urine amino acid analysis will frequently show an elevation
of methionine and the presence of homocysteine. Many neonatal screening
programs include methionine as a metabolite. The disorder may be distinguished
from the re-methylation defects (e.g., MTHFR, methionine synthase deficiency
and the cobalamin defects) in lieu of the elevated methionine concentration.
Additionally, organic acid analysis or quantitative determination of
methylmalonic acid should help to exclude cobalamin (vitamin B12) defects and
vitamin B12 deficiency giving a differential diagnosis.
3.4 Treatment
No specific cure has been discovered for homocystinuria; however, many people
are treated using high doses of vitamin B6 (also known as pyridoxine).[8] Slightly
less than 50% respond to this treatment and need to take supplemental vitamin
B6 for the rest of their lives. Those who do not respond require a Low-sulfur
diet (especially monitoring methionine), and most will need treatment
with trimethylglycine. A normal dose of folic acid supplement and occasionally
adding cysteine to the diet can be helpful, as glutathione is synthesized from
cysteine (so adding cysteine can be important to reduce oxidative stress).
3.5 Aminu-Acid Responsible
Homocysteine - is a non-protein α-amino acid. It is a homologue of the amino
acid cysteine, differing by an additional methylene bridge (-CH2-). It is
biosynthesized from methionine by the removal of its terminal Cε methyl group.
Homocysteine can be recycled into methionine or converted into cysteine with
the aid of certain B-vitamins.
4. ALBINISM
Albinism (Greek: albino-white) is an inborn error, due to the lack of synthesis of
the pigment melanin. It is an autosomal recessive disorder with a frequency of 1
in 20,000.
Albinism occurs when one of several genetic defects makes the body unable to
produce or distribute melanin, a natural substance that gives color to your hair,
skin, and iris of the eye. The defects may be passed down through families.
Many possible causes (rather explanations) for albinism have been identified
1. Deficiency or lack of the enzyme tyrosinase.
2. Decrease in melanosomes of melanocytes.
3. Impairment in melanin polymerization.

6. 4. Lack of protein matrix in melanosomes.
5. Limitation of substrate (tyrosine) availability.
6. Presence of inhibitors of tyrosinase.
The most common cause of albinism is a defect in tyrosinase the enzyme most
responsible for the synthesis of melanin in the figure below
4.1 Defective Enzyme
Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the
production of melanin

7. 4.2 Sign & Symptoms
A person with albinism will have one of the following symptoms:
Absence of color in the hair, skin, or iris of the eye
Lighter than normal skin and hair
Patchy, missing skin color
Many forms of albinism are associated with the following symptoms:
Crossed eyes (strabismus)
Light sensitivity (photophobia)
Rapid eye movements (nystagmus)
Vision problems, or functional blindness
4.3 Investigation
Genetic testing offers the most accurate way to diagnose albinism. Such testing is
helpful if you have a family history of albinism. It is also useful for certain groups
of people who are known to get the disease. Doctor may also diagnose the
condition based on the appearance of your skin, hair, and eyes. An
ophthalmologist may perform an electroretinogram, which is a test that can
reveal vision problems related to albinism. A visual evoked potentials test can be
very useful when the diagnosis is uncertain.
4.4 Treatment
The goal of treatment is to relieve symptoms. Treatment depends on the severity
of the disorder. Treatment involves protecting the skin and eyes from the sun:
Reduce sunburn risk by avoiding the sun, using sunscreen, and covering up
completely with clothing when exposed to the sun.
Sunscreen should have a high sun protection factor (SPF).
Sunglasses (UV protected) may relieve light sensitivity.

8. Glasses are often prescribed to correct vision problems and eye position. Eye
muscle surgery is sometimes recommended to correct abnormal eye movements
(nystagmus).
4.5 Amino-Acid Responsible
Tyrosine