Inborn errors of metabolism are genetic disorders caused by defects in metabolic pathways. There are approximately 500 known inherited metabolic disorders. Some major categories include disorders of carbohydrate metabolism like glycogen storage disease, disorders of amino acid metabolism like phenylketonuria, disorders of lipid metabolism like Tay-Sachs disease, lysosomal storage disorders like Gaucher's disease, and mitochondrial disorders like Kearns-Sayre syndrome. Treatment depends on the specific disorder but may include dietary modifications, enzyme replacement therapy, or symptom management. Diagnosis is important for guiding treatment and genetic counseling.
MSUD is metabolic genetic error . It happens due to lack of an enzyem that degrades specific amino acids
Homocystinuria is also a metbolic genetic error due to an enzyme defficiency it leads to an accumulation of homocystein and related chemical in the blood
An inherited enzyme deficiency leading to the disruption of normal bodily metabolism.
Accumulation of a toxic substrate.
Impaired formation of a product normally produced by the deficient enzyme.
Definition:
Many childhood conditions are caused by gene mutations that encode specific proteins. These mutations can result in the alteration of primary protein structure or the amount of protein synthesized.
The functional ability of protein, whether it is an enzyme, receptors, transport vehicle, membrane, or structural element, may be relatively or seriously compromised.
These hereditary biochemical disorders are collectively termed as ‘’Inborn errors of metabolism’’
MSUD is metabolic genetic error . It happens due to lack of an enzyem that degrades specific amino acids
Homocystinuria is also a metbolic genetic error due to an enzyme defficiency it leads to an accumulation of homocystein and related chemical in the blood
An inherited enzyme deficiency leading to the disruption of normal bodily metabolism.
Accumulation of a toxic substrate.
Impaired formation of a product normally produced by the deficient enzyme.
Definition:
Many childhood conditions are caused by gene mutations that encode specific proteins. These mutations can result in the alteration of primary protein structure or the amount of protein synthesized.
The functional ability of protein, whether it is an enzyme, receptors, transport vehicle, membrane, or structural element, may be relatively or seriously compromised.
These hereditary biochemical disorders are collectively termed as ‘’Inborn errors of metabolism’’
Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body's ability to convert galactose (a sugar contained in milk, including human mother's milk) to glucose (a different type of sugar).
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.
s an inherited autosomal recessive disease that is characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureter, and bladder.
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.
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.
IEM comprise a group of disorders in which a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product.
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.
Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body's ability to convert galactose (a sugar contained in milk, including human mother's milk) to glucose (a different type of sugar).
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.
s an inherited autosomal recessive disease that is characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureter, and bladder.
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.
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.
IEM comprise a group of disorders in which a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product.
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. 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
designed for undergraduate level teaching of nitrogen metabolism focusing on amino acid metabolism in biochemistry. this is second in the series of three lectures. ideal for MBBS level teaching
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.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
2. METABOLISM.
It is the sum total of all the
chemical reactions takes place
inside an organism.
It is of two types
• Catabolism
• Anabolism
Catabolism- breakdown of
molecules into smaller units.
Energy is released.
Anabolism- formation of
molecules from smaller units.
Energy is used in this process
3. INBORN ERROR OF METABOLISM.
Inborn error of metabolism are the disorders caused due to the blockage
at certain point in normal metabolic pathway.
As the name suggest in inborn error of metabolism there is an error in
metabolic pathways since from birth.
Inborn error of metabolism are often referred as congenital metabolic
disorders or inherited metabolic disorders .
Enzymes play an important role in facilitating the process by serving
as catalysts in the conversion of one chemical (metabolite) to another.
4. GARROD’S HYPOTHESIS
In early 20th century Garrod studied the disease Alkaptonuria and
hypothesized that a defective enzyme cause an inborn error of
metabolism along a reaction pathway.
There are approximately 500 diseases due to inherited point defects
in metabolism.
Diagnosis is important for treatment and genetic counselling.
12. DISORDERS OF AMINO ACID
METABOLISM.
Amino acids are the building block of proteins and have many
functions in the body.
Hereditary disorders of amino acids 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.
symptoms are produced in early life, newborns are screened for
several common ones.
13. Examples of amino acids metabolism disorder
1:- Phenylketonuria -
Autosomal recessive .disorder
caused by the deficiency of Phenylalanine hydroxylase.
phenylalanine hydroxylase break Phenylalanine into Tyrosine.
Deficiency of this enzyme result into accumulation of phenylalanine and sometimes deficiency of Tyrosine.
Accumulation of phenylalanine led to seizures , brain damage and mental retardation.
TREATMENT :- The Food and Drug Administration (FDA) has approved the drug Sapropterin (Kuvan) for
the treatment of PKU. It works by increasing your tolerance to phenylalanine. The drug is for use in
combination with a PKU diet.
Special diet that limits foods containing phenylalanine. Infants with PKU may be fed breast milk. They
usually also need to consume a special formula known as Lofenalac. When your baby is old enough to eat
solid foods, you need to avoid letting them eat foods high in protein.
14. ….
2:- Maple syrup urine disease –
Caused by the partial or complete deficiency in Branched- chain alpha keto acid dehydrogenase.
Rare, Autosomal recessive Disorder.
The enzyme complex that decarboxylate Leucine , Isoleucine and Valine.
Children with this disease unable to metabolize branched chain amino acids , so amino acids and their by products
accumulates in blood.
Seizures ,mental retardation , neurological changes , urine and sweat smells like maple syrup.
TREATMENT :- The two main approaches to the treatment of maple syrup urine disease
(MSUD) are
(1) long-term daily dietary management .
(2) treatment of episodes of acute metabolic decompensation.
The mainstay in the treatment of maple syrup urine disease is dietary restriction of branched-
chain amino acids (BCAAs).
16. ….
3) Alkaptonuria :-
Rare, Autosomal recessive disorder.
Caused by the loss of Homogentisic acid oxidase activity.
Affected individual accumulates 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.
Alkaptonuria was not only the first characterized inborn error of metabolism but the first ever disease identified as
being inherited.
TREATMENT :-Alkaptonuria is a lifelong condition .
there's currently no specific treatment or cure. However, a medicine called nitisinone is given to the
patients, and painkillers and lifestyle changes may help you cope with the symptoms.
management of joint pain, physical and occupational therapy, joint replacements and surgery when
needed
18. DISORDERS OF LIPID METABOLISM.
1) Tay- Sachs disease :-
Rare , Autosomal recessive disorder.
caused due to the deficiency of an enzyme hexosaminidase A.
Result in excessive accumulation of certain fats ( lipids) known as gangliosides in brain and nerve cells.
Neurodegenerative disorder.
Affected infants loose motor skills such as turning over, sitting and crawling , seizers vision and hearing loss ,
paralysis, startle reactions to loud sounds.
TREATMENT :- There is no cure for Tay-Sachs.
Treatment typically consists of keeping the child comfortable. This is called “palliative care.”
Palliative care may include medication for pain, anti-epileptics to control seizures, physical
therapy, feeding tubes, and respiratory care to reduce mucus buildup in the lungs.
20. LYSOSOMAL STORAGE DISORDER.
1) Gaucher’s disease type 3 :-
Autosomal recessive disorder.
Caused due to the mutation in GBA gene that codes for the lysosomal enzyme glucocerebrosidase.
Symptoms are Avascular necrosis , Bone pain , Encephalopathy , Fatigue , Hepatomegaly, Brain is
affected.
TREATMENT :- Gaucher disease has no cure.
Patients with Gaucher disease type 3 can receive enzyme replacement therapy (ERT) to
address symptoms not involving the brain, like organ enlargement and bone issues.
ERT works well to control complications that most commonly occur in patients with Gaucher
disease type 1.
There is no good treatment for the brain damage of types 2 and 3.
21. ….
2) Niemann Pick Disease :-
Autosomal recessive disorder
caused by mutations in the SMPD1 gene.
This gene provide instructions for producing an enzyme called acid sphingomyelinase found in lysosome.
Symptoms are walking problems, enlarged spleen and liver , seizures, jaundice after birth, loss of muscle
tone, irregular speech.
TREATMENT :- No cure exists.
No effective treatment is available to people with type A or B.
For people with mild to moderate type C, a drug called miglustat (Zavesca) may be
an option.
Physical therapy is an important part of treatment to help maintain mobility as long as
possible.
22. ….
3) Fabry’s disease:-
Rare, Autosomal recessive disorder.
Caused due to the deficiency of an enzyme called alpha galactosidase -A.
Affect many parts of the body that is skin , eyes , gastrointestinal system , kidneys , heart
, brain and nervous system.
Symptoms include episodes of pain and burning sensation.
TREATMENT :-There is no cure for Fabry disease.
Recombinant alpha-galactosidase A (alpha-Gal A), the enzyme that is
deficient in patients with Fabry disease, and migalastat hydrochloride, an oral
pharmacologic chaperone that facilitates trafficking of alpha-Gal A to
lysosomes, are therapeutic options for eligible individuals.
24. MITOCHONDRIAL DISORDERS.
1) Kearns – Sayre Syndrome:-
Caused due to the mitochondrial DNA deletion.
Mitochondrial DNA deletion result in the loss of gene important for mitochondrial protein formation
and oxidative phosphorylation.
This result into weakness or paralysis of the eye muscles that impairs eye movement and cause drooping
eyelids (progressive external ophthalmoplegia) , pigmentary retinopathy which results from the
breakdown of light – sensing tissue.
TREATMENT :-There is typically no treatment for limitation in eye movement.
Endocrinology abnormalities can be treated with drugs.
There is currently no effective way to treat mitochondria abnormalities in KSS.
Treatment is generally symptomatic and supportive.
26. DISORDERS OF STEROIDS
METABOLISM.
1) Congenital adrenal hyperplasia :-
Autosomal recessive disorder
It is caused by the deficiency of 21- hydroxylase.
21-hydroxylase is an enzyme required to synthesize hormones ( Cortisol , Mineralocorticoids and androgens).
This led to the impairment of cortisol synthesis which leads to excessive stimulation of the adrenal glands by
adrenocorticotrophic hormone , adrenal hyperplasia and excessive androgen synthesis.
Symptoms include irregular or absent menstrual cycle , characteristics such as facial hair , excessive body hair ,
deepening of voice, severe acne.
TREATMENT :- Classic CAH is treated with steroids that replace the low hormones.
Infants and children usually take a form of cortisol called hydrocortisone.
Adults take hydrocortisone, prednisone, or dexamethasone, which also replace cortisol.
28. DISORDERS OF PIGMENT
METABOLISM.
1) Albinism:-
Autosomal recessive disorder.
Caused by the deficiency of tyrosinase enzyme.
Characterized by little or no production of the pigment melanin.
This enzyme help to change amino acid tyrosine into melanin pigment.
White hair and very light skin colour.
◦ TREATMENT :- There’s no cure for albinism.
◦ Treatment can relieve symptoms and prevent sun damage , Treatment may include :
• sunglasses to protect the eyes from the sun’s ultraviolet (UV) rays.
• protective clothing and sunscreen to protect the skin from UV rays.
• prescription eyeglasses to correct vision problems.
• surgery on the muscles of the eyes to correct abnormal eye movements.
30. GALACTOSEMIA.
It is the inability of a body to utilize Galactose.
Galactose accumulates in blood.
It is caused due to deficiency of enzyme galactose-1-phosphate uridyl transferase.
GALT breaks galactose to glucose
Main source of galactose is milk products so galactose rich foods should be removed from the patient’s
diet.
If not treated , infants develop cataract , liver disease , kidney problems , brain damage , and in some
cases lead to death.
TREATMENT:- The only treatment for galactosemia is avoiding foods that
contain lactose and galactose.
32. HEREDITARY FRUCTOSE
INTOLERANCE.
Caused due to the deficiency of Fructose-1-phosphate aldolase or
aldolase B.
This result into Fructose-1-phosphate accumulation in the blood.
Symptoms :- vomiting , hypoglycemia , failure to thrive cachexia ,
hepatomegaly , jaundice , coma.
TREATMENT :- eliminating fructose and sucrose from the diet.
In the severe form, eliminating these sugars from the diet may
not prevent progressive liver disease.