This document discusses several inherited metabolic disorders involving amino acid metabolism. Phenylketonuria is described as the most common disorder, caused by a deficiency of the enzyme phenylalanine hydroxylase, leading to toxic accumulation of phenylalanine. Maple syrup urine disease results from a defect in the enzyme branched-chain keto acid dehydrogenase, causing a buildup of leucine, isoleucine, and valine breakdown products. Homocystinuria is caused by a cystathionine beta-synthase deficiency, preventing the breakdown of homocysteine. These disorders are typically detected via newborn screening and require dietary modifications and supplements to prevent associated complications.
Protein which are major component of our diet have amino acid as their precursor and also act as important energy source. Any imbalance in the metabolism of these amino acid cause disorders
AMINO ACID METABOLISM DISORDERS Twenty amino acids, including nine that cannot be synthesized in humans and must be obtained through food, are involved in metabolism. Amino acids are the building blocks of proteins; some also function as or are synthesized into important molecules in the body such as neurotransmitters, hormones, pigments and oxygen-carrying molecules.
Inborn errors of metabolism
Definition:- Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally.
These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components.
Protein which are major component of our diet have amino acid as their precursor and also act as important energy source. Any imbalance in the metabolism of these amino acid cause disorders
AMINO ACID METABOLISM DISORDERS Twenty amino acids, including nine that cannot be synthesized in humans and must be obtained through food, are involved in metabolism. Amino acids are the building blocks of proteins; some also function as or are synthesized into important molecules in the body such as neurotransmitters, hormones, pigments and oxygen-carrying molecules.
Inborn errors of metabolism
Definition:- Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally.
These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components.
A presentation on aminoaciduria as inborn errors of metabolism, with emphasis on the screening test ...had some animations which enhanced the presentation...but slideshare does not allow animations... so maybe dull and boring for some...
Amino acid metabolism disorders are hereditary metabolic disorders. Hereditary disorders occur when parents pass the defective genes that cause these disorders on to their children. Amino acids are the building blocks of proteins and have many functions in the body. Hereditary disorders of amino acid processing (metabolism) can result from defects either in the breakdown of amino acids or in the body’s ability to get amino acids into cells.
Inborn errors of metabolism
Definition:- These are a group of rare genetic disorders in which the body cannot metabolize food components normally.
These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down very essential biochemical components.
Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine.
Hartnup disease is caused by mutations in the SLC6A19 gene. This gene provides instructions for making a protein called B0AT1, which is primarily found embedded in the membrane of the intestine and kidney cells
Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air.
Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. A birth defect that causes an amino acid called phenylalanine to build up in the body.
Newborns should be screened for PKU.
Untreated phenylketonuria can lead to brain damage, intellectual disabilities, behavioural symptoms or seizures.
Treatment includes a strict diet with limited protein.
A presentation on aminoaciduria as inborn errors of metabolism, with emphasis on the screening test ...had some animations which enhanced the presentation...but slideshare does not allow animations... so maybe dull and boring for some...
Amino acid metabolism disorders are hereditary metabolic disorders. Hereditary disorders occur when parents pass the defective genes that cause these disorders on to their children. Amino acids are the building blocks of proteins and have many functions in the body. Hereditary disorders of amino acid processing (metabolism) can result from defects either in the breakdown of amino acids or in the body’s ability to get amino acids into cells.
Inborn errors of metabolism
Definition:- These are a group of rare genetic disorders in which the body cannot metabolize food components normally.
These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down very essential biochemical components.
Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine.
Hartnup disease is caused by mutations in the SLC6A19 gene. This gene provides instructions for making a protein called B0AT1, which is primarily found embedded in the membrane of the intestine and kidney cells
Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air.
Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. A birth defect that causes an amino acid called phenylalanine to build up in the body.
Newborns should be screened for PKU.
Untreated phenylketonuria can lead to brain damage, intellectual disabilities, behavioural symptoms or seizures.
Treatment includes a strict diet with limited protein.
inborn errors of metabolism. Inborn errors of metabolism are rare genetic (inherited) disorders in which the body cannot properly turn food into energy. The disorders are usually caused by defects in specific proteins (enzymes) that help break down (metabolize) parts of food
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RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
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The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
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Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
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Disorders amino acids
1. METABOLIC DEFECTS IN AMINO ACID
METABOLISM
• Amino acids are the building blocks of proteins
and have many functions in the body.
• Hereditary disorders of amino acid metabolism
can be the result of defects either in the
breakdown of amino acids or in the body's
ability to get the amino acids into cells.
• Because these disorders produce symptoms
early in life, newborns are routinely screened
for several common ones.
2. • Newborns are screened for:
– Phenylketonuria
– Maple syrup urine disease
– Homocystinuria
– Albinism
– Alkaptonuria
– Tyrosinemia, and
– a number of other inherited disorders, although
screening varies from country to country.
3. PHENYLKETONURIA
• Phenylketonuria (PKU) is caused by a deficiency of
Phenylanine Hydroxylase
• It is the most common clinically encountered inborn
error of amino acid metabolism (prevalence is 1 in
15,000)
• Biochemically it is characterized by an accumulation of
the amino acid phenylalanine, and sometimes a
deficiency of Tyrosine
• Hyper Phenylalaninemia may also be caused by
deficiencies in any of the several enzymes required to
synthesize BH4, or in dihropteridine (BH2) reductase,
which regenerates BH4 from BH2
4.
5.
6.
7.
8.
9. Synthesis of catecholamines
• The catecholamines are synthesized from
tyrosine
• Tyrosine is first hydroxylated by tyrosine
hydroxylase to form 3,4-
dihydroxyphenylalanine (DOPA)
• The tetrahydrobiopterin-requiring enzyme
is abundant in the central nervous system,
the sympathetic ganglia, and the adrenal
10. • DOPA is decarboxylated (decarboxylase)
in a reaction requiring pyridoxal phosphate
to form dopamine
• which is hydroxylated by the copper-
containing dopamine β-hydroxylase to
yield norepinephrine.
• Epinephrine is formed from
norepinephrine by an N-methylation
reaction using S-adenosylmethionine
as the methyl donor
• In Parkinson disease --- deficiency of
neurotransmitter DOPAMINE
11. • Such deficiencies indirectly raise phenylanine
concentrations, because phenyalanine
hydroxylase requires BH4 as a coenzyme
• BH4 is also required for Tyrosine hydroxylase
and Tryptophan hydroxylase,
• which catalyze reactions leading to the
synthesis of neurotransmitters, such as
serotonin and catecholamines.
• Simply restricting dietary phenylanine doesnot
reverse the central nervous symptoms effects
12. • Replacement therapy with BH4 improves the
clinical outcome in these variant forms of
hyperphenylalaninemia,
• although the response is unpredictable
• Phenylanine is an essential amino acid that
cannot be synthesized in the body but is
present in food.
13. • Excess phenylalanine is normally converted to
tyrosine, and eliminated from the body.
• Without the enzyme that converts it to tyrosine,
phenylalanine accumulates in the blood and is toxic to
the brain, causing mental retardation.
• PKU occurs in most ethnic groups.
• If PKU runs in the family and DNA is available from an
affected family member,
• amniocentesis or chorionic villus sampling with DNA
analysis can be performed to determine whether a
fetus has the disorder.
14. • Most affected newborns are detected during
routine screening tests.
• Newborns with PKU rarely have symptoms
right away, although sometimes an infant is
sleepy or eats poorly.
• If not treated, affected infants progressively
develop mental retardation over the first few
years of life, which eventually becomes severe.
15. • Other symptoms include failure to walk or talk,
seizures, tremor, microcephaly, nausea and
vomiting, an eczema-like rash,
• Lighter skin and hair than their family members,
aggressive or self-injurious behavior,
hyperactivity, and sometimes psychiatric
symptoms.
• Untreated children often give off a "mousy"
body and urine odor as a result of a by-product
of phenylalanine (Phenyllactate, Phenylacetate
and Phenylpyruvate) in their urine and sweat.
16. • To prevent mental retardation, phenylalanine
intake must be restricted (but not eliminated
altogether as people need some phenylalanine
to live) beginning in the first few weeks of life.
• Because all natural sources of protein contain
too much phenylalanine for children with PKU,
• affected children cannot have meat, milk, or
other common foods that contain protein.
• Instead, they must eat a variety of
phenylalanine-free processed foods, which are
specially manufactured.
• Low-protein natural foods, such as fruits, vegetables,
and restricted amounts of certain grain cereals, can be
17. MAPLE SYRUP URINE DISEASE
• Rare 1 in 185,000
• Autosomal recessive disorder in which there is
a partial or complete deficiency in Branched-
chain α-keto acid dehyrogenase
• The enzyme complex that decarboxylate
Leucine, Isoleucine and Valine
• Children with maple syrup urine disease are
unable to metabolize branched amino acids.
18.
19. • These amino acids and their by-products (α-
keto acids) accumulate in the blood,
• causing a toxic effect that interferes with
neurologic changes and brain functions,
including seizures and mental retardation.
• The disease is characterized by Feeding
problems, Vomiting, Dehydration, Severe
metabolic acidocis and characteristic maple
syrup odor to the urine.
• If untreated the disease leads to mental
retardation, physical disabilities and even death
20. • These by-products also cause body fluids, such as
urine and sweat, to smell like maple syrup.
• There are many forms of maple syrup urine disease;
symptoms vary in severity.
• 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
develop vomiting, staggering, confusion, coma, and
the odor of maple syrup particularly during physical
stress, such as infection or surgery.
21. • In some countries, newborns are routinely
screened for this disease with a blood test.
• Infants with severe disease are treated with
dialysis.
• Some children with mild disease benefit from
injections of the vitamin B1 (thiamin).
• After the disease has been brought under
control, children must always consume a
special artificial diet that is low in branched
chain amino acids that are affected by the
missing enzyme.
22. ALBINISM
• It is the result of a problem in the biochemical
pathway that converts phenylalanine to
melanin.
• It is usually characterized by eye problems;
however, people affected by albinism are
expected to fulfill a normal lifespan.
• Albinism is a heterogeneous condition inherited
through either autosomal recessive or sex-linked
recessive genes that affects approximately 1 in 17,000
people.
• It is characterized by a lack of the pigment melanin
due to an error in the biochemical pathway that
converts phenyalanine to melanin
23. • Depending on the severity of the break, a
person with albinism may not always have a
pale complexion, white hair and pink eyes.
• They can sometimes vary from other family
members by having a lighter skin tone.
• People with albinism may be affected by a lack
of melanin in their hair, skin, and eyes, while
others may only have problems with their eyes.
24. • There are two main types of albinism that are
characterized by the areas affected by the
abnormality:
• Oculotaneous albinism and Ocular albinism.
• Oculotaneous albinism describes a phenotype that
lacks pigment in the skin, hair, and eyes.
• Ocular albinism occurs when the phenotype only lacks
pigment from the eyes, the hair and skin appear
normal in these individuals.
• Of the two types, oculotaneous albinism is typically
more prominent.
25.
26. • Due to the lack of pigment, people with
albinism may also suffer from various eye
problems.
• During retina development, the fovea does not
develop correctly, and the nerve connections
between the retina and the brain become
connected abnormally
•
27. • Affected individuals can suffer from any of the
following:
– Nearsightedness
– Farsightedness
– Astigmatism(distorted images)
– Nystagmus(rapid involuntary mov of the eye)
– Strabismus(partially closed eyes)
– Photosensitivity
28. • The eye problems may become so severe as to
cause the person to be declared legally blind.
• Due to the consistent phenotype of eye
problems, the main way to test for albinism is
by completing an eye exam.
29. • Another phenotype of people with albinism is
sensitivity to the sun ultra violate rays.
• It is strongly urged that Albinos wear sunscreen
at all times because of their high risk of getting
sunburn.
• The lack of melanin makes them more
susceptible to skin cancer (Melanoma).
• Even though people with albinism may have
various medical problems, most fulfill a normal
lifespan.
30. • Some may suffer from various social problems
because of their physical appearance.
• In communities of color, one might face
discrimination due to people questioning his or
her race or paternity.
• Most people with albinism maintain a normal
lifestyle.
31. ALKAPTONURIA
• Alkaptonuria is 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
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.
32.
33. • Alkaptonuria is a rare autosomal recessive inherited
disorder caused by defects in the gene encoding an
enzyme, homogentisic acid oxidase, involved in the
catabolism of Phenylalanine and Tyrosine.
• As a consequence of this gene defect the catabolism
of these two amino acids is inhibited and the
intermediate homogentisic acid is excreted in the
urine.
• If the urine of an individual with alkaptonuria is allowed
to stand exposed to the air it will gradually turn dark
brown-black as a result of the conversion of
homogentisic acid to a melanin-like compound.
34. • This striking visual sign of alkaptonuria was key to the
initial recognition of the disorder which was first
described in detail in 1859.
• Garrod, in his seminal 1909 publication (Inborn Errors
of Metabolism), described the inherited nature of
alkaptonuria.
• In fact, alkaptonuria was not only the first
characterized inborn error of metabolism but the first
ever disease identified as being inherited.
35. • Alkaptonuria is characterized by:
– Homogentisic aciduria
– Ochronosis (a bluish-black discoloration of tissues)
and
– Arthritis.
• The exact mechanisms by which alkaptonuria
results in ochronosis and arthritis are still not
fully understood.
36. • The homogentisic acid oxidase gene (HGO) is
found on chromosome 3q21-q23 spanning 60
kb and encompassing 14 exons.
• A number of single nucleotide changes,
insertions, deletions, and mutations in introns
have been identified in alkaptonuric patients.
• In all, mutations have been found in 11 of the
14 exons of the HGO gene.
37.
38. Metabolism of sulfur-
containing AAs
Methionine cysteine cystine
CH2SH
CHNH2
COOH
CH2SH
CHNH2
COOH
CH2
CHNH2
COOH
CH2
CHNH2
COOH
S SCH2
CHNH2
COOH
CH2
CHNH2
COOH
S S
S CH3
CH2
CHNH2
COOH
CH2
S CH3
CH2
CHNH2
COOH
CH2
39. • Methionine condenses with adenosine triphosphate
(ATP), forming SAM—a high-energy compound that is
unusual in that it contains no phosphate.
• The methyl group attached to the tertiary sulfur in SAM
is “activated,” and can be transferred to a variety of
acceptor molecules, such as norepinephrine in the
synthesis of epinephrine
• After donation of the methyl group, S-
adenosylhomocysteine is hydrolyzed to homocysteine
and adenosine.
• Homocysteine has two fates. If there is a deficiency of
methionine, homocysteine may be remethylated to
methionine .
• If methionine stores are adequate, homocysteine may
enter the transsulfuration pathway, where it is converted
to cysteine.
43. Trans-Sulfuration PathwayTrans-Sulfuration Pathway
Trans - Sulfuration pathway is
analagous to transamination for AA
(i) Major degradation pathway for MET
in mammals
(ii) End Product is CYS
(iii) Two RXNs, both use pyridoxal
phosphate as a cofactor (as with
transamination)
45. HOMOCYSTINURIA
• Children with homocystinuria are unable to metabolize
the amino acid Homocysteine due to the defect in the
enzyme Cystathionine β–synthase which converts
Homocysteine to Cystathionine
• The diseases are inherited as autosomal recessive
illness, characterized by:
– High plasma and urinary levels of Homocysteine and
methionine and
– Low levels of cysteine.
• Symptoms may be mild or severe, depending on the
particular enzyme defect.
46.
47.
48. • Infants with this disorder are normal at birth.
• The first symptoms, including dislocation of the
lens of the eye (Ectopia Lentis), causing
severely decreased vision, usually begin after 3
years of age.
• Most children have skeletal abnormalities,
including osteoporosis; the child is usually tall
and thin with a curved spine, elongated limbs,
and long, spiderlike fingers, pre mature arterial
disease,
49. • Psychiatric and behavioral disorders and
mental retardation are common.
• Homocystinuria makes the blood more likely to
spontaneously clot, resulting in strokes, high
blood pressure, and many other serious
problems.
• The diagnosis is confirmed by a test measuring
enzyme function in liver.
• Some children with homocystinuria improve
when given vitamin B6 (pyridoxine) a
Coenzyme of Cystathionine β–synthase or
vitamin B12 (cobalamin
50. Hartnup disease-defect transport in
intestine& kidney of large neutral aa(Trp)
• Loss of AA in urine
• Pellagra like symptoms,diarhoea
dermatitis, dementia
Cystinuria-1 in 7,000
Defect transport in intestine and kidney of
basic AA.
• In kidney cys not reabsorbed forms
cystine-disulfide dimer(insoluble) in urine
and cause UTIs and renal stones
• Treatment –Acetazolamide-raise the ph