Term
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Definition
| Metabolism is all chemical reactions that occur within the cells of the body. The goal of metabolism is to provide a constant energy source for the body, even between meals. |
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Term
| Inborn error of metabolism |
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Definition
A class of disease -- a genetic disease involving a problem with an individual’s metabolism.
This is usually due to a change in an enzyme and is usually caused by a single-gene error.
This causes problems either because:
1. A substance needed cannot be made
2. A substance builds up and becomes toxic |
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Term
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Definition
| A change in consciousness due to liver failure. A common feature of inborn errors of metabolism. |
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Term
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Definition
| An enlarged liver. A common feature of inborn errors of metabolism. |
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Term
| Dilated or hypertrophic cardiomyopathy |
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Definition
A portion of the myocardium (heart muscle) is dilated (enlarged) or hypertrophic (the muscle is thicker than it should be). This makes it hard to pump blood and can lead to arrhythmia (abnormal heart rhythms) and shortness of breath.
This is a common feature of inborn errors of metabolism. |
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Term
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Definition
| Partial paralysis of the lower limbs |
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Term
| Molecular/pharmacological chaperone therapy |
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Definition
The goal of this therapy is to restore enzyme activity.
You supplement small molecules that specifically bind to and stabilize the misfolded enzyme proteins in the endoplasmic reticulum of the cell. This chaperone molecule helps the enzyme stay in the correct shape |
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Term
| Substrate reduction therapy |
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Definition
This is when an individual affected by an inborn error of metabolism intakes less substrate, as their enzyme level is not high enough to turn it all to product.
This can be achieved through diet. |
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Term
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Definition
If the inborn error of metabolism affects the central nervous system, enzyme might have be be delivered directly to the intrathecal space. This is the fluid-filled area surrounding the brain and spinal cord.
This is because enzymes delivered to the body would not pass the blood-brain barrier. |
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Term
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Definition
This is the feeding/fed state of the body.
This is when larger molecules are made from smaller subunits. Anabolism results in:
1. The manufacturing of products
2. The storage of excess nutrients |
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Term
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Definition
This is the fasting state of the body.
This is when larger molecules are broken down.
Catabolism results in:
1. The breakdown of products
2. The breakdown of stored energy resources |
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Term
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Definition
How the body creates energy when it’s fasting. It happens in three stages:
1. Glycogenolysis
2. Gluconeogenesis
3. Ketogenesis |
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Term
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Definition
The first stage in the fasting fuel system. Happens about 1-4 hours after eating.
Glycogen breakdown. Glycogen is broken down to glucose. |
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Term
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Definition
The second stage in the fasting fuel system. Happens about 3-12 hours after eating.
Glucose is created from amino acids. |
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Term
| Ketogenesis (Fatty acid oxidation) |
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Definition
The third stage in the fasting fuel system. Happens about 10+ hours after eating.
This is when fatty acids are turned into ketones, which are used for energy. |
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Term
| Lysosomal Storage Disorders |
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Definition
Lysosomes are an organelle that digest unwanted material in the cell. Lysosomal storage disorders are metabolic disorders where an enzyme in the lysosome does not work properly. The lysosome swells and bursts.
Disorders include:
1. Deficient activity of an enzyme in the lysosome
2. Failure of enzymes to localize to the lysosome
3. Defects in transporting stuff out of the lysosome |
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Term
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Definition
Disorders of the peroxisomes, an organelle in the cell that works as a waste treatment center. The product of this is hydrogen peroxide, which is destructive. Also contain enzymes for breaking down long chain fatty acids.
Peroxisomal disorders can include:
1. Problems forming the peroxisomal membrane, letting out the hydrogen peroxide
2. Problems forming the enzymes contained in the peroxisome |
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Term
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Definition
| Something regarding the blood |
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Term
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Definition
| Something regarding the urine |
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Term
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Definition
| Amino acids that cannot be made by the body and therefore must be acquired through one's diet |
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Term
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Definition
| Materials needed by the body that must be eaten. For most people, they are all acquired through a regular diet, but additional vitamins may be needed for someone with a metabolic disease. |
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Term
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Definition
| Materials needed by the body that the body can produce. However, a person with a metabolic disease might need to injest them. |
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Term
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Definition
Too little glucose in the blood. Glucose is the main source of energy (ATP) in the body, so this is an issue.
Some alternate energy sources that can be used are:
1. Fatty acid oxidation
2. Ketone production
3. Metabolism of lactate
However, hypoglycemia is common (ie because of liver failure and toxic exposure) and inborn errors of metabolism are not. Therefore, hypoglycemia does not necessarily mean a metabolic disorder, it is just a clue in that direction. |
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Term
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Definition
Too much ammonia in the blood. Ammonia is constantly being produced by the liver, intestines, and kidney. Normally it is removed through the urea cycle.
Major hyperammonemia is seen in a limited number of metabolic errors when there are urea cycle defects.
Limited hyperammonemia can be seen in mitochondrial disorders and protein metabolism problems. It can also be caused by liver failure.
Neurologic symptoms often result from hyperammonemia. |
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Term
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Definition
Metabolic acidosis is all types of acidosis (low pH of the blood) caused by reasons other than respiratory ones.
Can be caused by diarrhea, diabetes, exercise, renal failure, infection, intoxication, etc.
If you find metabolic acidosis, #1 check the anion gap.
If there is an anion gap, you can have several subtypes of metabolic acidosis based on what's causing it. Subtypes include:
1. Lactic acidosis
2. Ketoacidosis |
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Term
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Definition
Calculate this if you find metabolic acidosis.
A value calculated from multiple individual lab tests.
It is the difference between the cations (the positively charged ions) and the anions (the negatively charged ions) in the body.
Metabolic acidosis and an increased anion gap indicate an inborn error of metabolism. If the gap is increased, you must figure out what is present in extra quantities. Possibilities include lactate, ketones, or organic acids. You can measure these in the blood or urine. |
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Term
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Definition
A subtype of metabolic acidosis. It is caused by too much lactic acid in the blood.
Elevated lactate (and its precursor, pyruvate) indicate disrupted mitochondria metabolism.
Lactate is easier to measure. Lactic acidosis can be primary or secondary, ie, it can be caused by the error of metabolism itself or it can be a side effect of the error of metabolism |
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Term
| Primary Hyperlacticacidemia |
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Definition
Primary lactic acidosis. Caused by the inborn error of metabolism. These can include:
1. Mitochondrial disease
2. Carbohydrate metabolism (disorders of the glycogen metabolism) |
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Term
| Secondary Hyperlacticacidemia |
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Definition
| Secondary lactic acidosis. An inborn error of metabolism ends up secondarily causing lactic acidosis. Protein or fat metabolism errors can do this. |
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Term
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Definition
A subtype of metabolic acidosis. It is metabolic acidosis caused by too many ketones.
This is rarely primary -- ie, it is rarely the symptom of an error of metabolism. It is usually secondary, or the side effect of an error of metabolism that mostly does something else. |
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Term
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Definition
Measuring creatine kinase (CK) can tell you about muscle breakdown or injury. CK varies per person based on gender, race, and activity. CK might be elevated because of muscular dystrophy or muscle trauma.
Very helpful for seeing if there is heart muscle trauma. |
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Term
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Definition
A sudden increase in CK levels. This can be observed in inborn errors of metabolism that cause muscle disease (mitochondrial, carbohydrate, fat).
If this get’s too bad muscle tissue pigment can make the urine tea-colored. |
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Term
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Definition
Carnitine serves as a shuttle bus to bring energy substrates (carbon chain backbones from fats and proteins) across the mitochondrial membrane where they are broken down.
L-carnitine is the unbound, free form. |
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Term
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Definition
Carnitine serves as a shuttle bus to bring energy substrates (carbon chain backbones from fats and proteins) across the mitochondrial membrane where they are broken down.
AcylCarnitine is the bound form. They are varying lengths. Long/very long, medium, and short. |
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Term
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Definition
Due to a deficiency in GALT (galactose-1-phosphate Uridyltransferase) which means the individual can’t break down galactose.
Autosomal recessive and diagnosed via newborn screening.
Treatment is to avoid lactose and supply calcium. Can be classic galactosemia, where there is near complete enzyme deficiency, or partial transferase deficiency where there is less enzyme activity but the individual is generally asymptomatic.
Other complications include early risk for ovarian failure, cataracts, growth problems, and speech apraxia |
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Term
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Definition
Causes hyperphenylalaninemia, or high phenylalanine in the blood. It is an inborn error of metabolism of protein. It is considered an aminoacidopathy because it is a problem in the pathways that break down amino acids.
Also causes microcephaly, epilepsy, severe mental delays if untreated.
Urine will have mousy smell.
Phenylalanine restrictions will be lifelong.
Poor control during pregnancy can affect fetus.
Caused by being unable to break down phenylalanine, either because of a problem with:
1. Phenylalanine hydroxylase
2. Biopterin (a cofactor) recycling defects |
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Term
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Definition
| High phenylalanine in the blood. Can be caused by PKU. |
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Term
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Definition
| Rids the body of waste nitrogen derived mainly from amino acid metabolism. Liver conjugates waste nitrogen as urea. This is excreted by the kidneys. Inherited defects of this cycle manifest in high blood ammonia levels, which is toxic to the brain. |
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Term
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Definition
| A problem with the metabolism of amino acids. An example is maple syrup urine disorder. Classically the individual is well at birth and for a few days aftewards, but then will have vomiting, poor feeding, hypotonia, lethargy, coma, seizures, metabolic acidosis, and secondary hyperammonemia. There are also cerebral organic acidurias. Cerebral symptoms only, without lactic acidosis or hypoglycemia. |
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Term
| Fat metabolism error characteristics |
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Definition
| Often the cause of infant or childhood deaths following minor illness when fasting. Affects multiple siblings in a family. Associated symptoms are hypoglycemia, coma, seizures, heart failure, and muscle breakdown. |
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Term
| MCAD (Medium Chain Acyl-CoA Dehydrogenase Deficiency) |
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Definition
Fat metabolism error that is due to a carnitine disorder (there is a problem with the "shuttle bus" molecule that helps bring carbon chain backbones into the mitochondria).
Risk of death when ill or fasting. 1/40 carrier frequency among Northern Europeans. Low plasma carnitine. Typical infant feeding, but supplement carnitine as needed. Avoid prolonged fasts, and understand chronic health needs. |
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Term
| What are the symptoms of an inborn error of metabolism in infancy? |
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Definition
Features you can see:
- Dysmorphic or course features
- Abnormalities of the hair (kinky) and skin
- Skeletal abnormalities
- Failure to thrive
- Hypertonia or hypotonia
Stomach symptoms:
- Poor feeding
- Cyclic vomiting
Liver symptoms:
- Jaundice
- Hepatoencephalopathy (altered consciousness due to liver failure)
- Hepatomegaly (enlarged liver)
- Liver disfunction
Mental symptoms:
- Ataxia (lack of coordination)
- Hepatoencephalopathy
- Seizures
- Lethargy
- Coma
- Developmental delays
Heart symptoms:
- Dilated or hypertrophic cardiomyopathy |
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Term
| What does an inborn error of metabolism look like in an older child/teenager/adult? |
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Definition
Observable symptoms:
- Exercise intolerance
- Muscle weakness
- Paralysis of lower limbs
Mental symptoms:
- Intellectual disability
- Autism
- Behavioral disturbances
- Hallucinations
- Anxiety and panic attacks
- Seizures
- Dizziness
There's a pattern!
Usually brought on by:
- Diet
- Medication
- Stress
Patient history might include:
- Unusual diet preferences
- Very bad health after infections
- Sudden infant death in siblings |
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Term
| What should make you suspect an inborn error of metabolism? |
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Definition
1. Timing of sickness in relation to meals
2. Sickness in relation to food or drugs
3. Sickness in relation to stress |
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Term
| How can we treat an inborn error of metabolism? |
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Definition
1. Substrate reduction therapy
2. Cofactor supplementation
3. Provide the enzyme
4. Increase alternate pathway use
5. Supplement products
6. Molecular/pharmacological chaperone therapy
7. Intrathecal therapy |
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Term
| What are the three primary food groups? |
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Definition
1. Carbohydrates
2. Proteins
3. Fats |
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Term
| Where is glycogen stored? |
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Definition
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Term
| What are the three stages of the Fasting Fuel System? |
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Definition
1. Glucogenolysis
2. Gluconeogenesis
3. Ketogenesis |
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Term
| Where are the three places glucose can come from in the body? |
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Definition
1. Exogenous glucose
2. Glycogenolysis
3. Gluconeogenesis |
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Term
| What is the normal pH of the body? What is it called with the pH is too high? What is it called when the pH is too low? |
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Definition
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Term
| What can an abnormal blood pH indicate? |
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Definition
1. A respiratory problem. Hyper or hypoventilation can cause a change in CO2 levels which changes the pH.
2. Metabolic alkalosis is often due to vomiting or alkaline drugs
3. Metabolic acidosis can be due to normal metabolic reasons (diarrhea, renal failure, infection, exercise) but can also be due to an inborn error of metabolism. If you find metabolic acidosis, check the anion gap. |
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Term
| Lactic acidosis is usually associated with what inborn error of metabolism? |
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Definition
Mitochondrial disease
However, it can also be secondary to other inborn errors of metabolism |
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Term
| What is the PKU paradigm? |
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Definition
The "PKU paradigm" is the basis for putting diseases on the NBS. It says that if:
1. A disorder has severe consequences if not treated right after birth
2. A simple and inexpensive test is available for mass screening
3. Treatment is available and effective
Then the disease should be put on the NBS. |
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Term
| Glycogen storage disorders |
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Definition
These disorders are caused by an error in carbohydrate metabolism. There are hepatic forms (where the issue is storing glycogen in the liver) and muscular forms (where the issue is storing gylcogen in the muscles).
They can be treated by eating cornstarch, as it releases glucose very slowly.
An example of a muscular gycogen storage disorder is Pompe's disease (also called Glycogen Storage Disorder II). This disorder causes muscle weakness and respiratory problems in adults and cardiac failure in infants (it happens along a scale). |
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Term
| Hereditary Fructose Intolerance |
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Definition
| A disorder caused by an error in carbohydrate metabolism. Individuals can't break down fructose (found in honey, fruit, and some veggies) and must avoid it. Often eat the skin of fruits. |
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Term
| Maple Syrup Urine Disease |
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Definition
A disorder caused by an error in protein metabolism. It is considered an organic adicuria because it is caused by an issue metabolizing particular amino acids.
Because these individuals are unable to process certain amino acids they have:
- Vomiting
- Poor feeding
- Hypotonia
- Lethargy
- Coma
- Seizures
- Metabolic acidosis
- Hyperammonemia
This is all within the first few days of life. Their urine will also smell of maple syrup. |
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Term
| Ornithine Transcarbamylase Deficiency (OTC) |
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Definition
An inborn error of metabolism of the urea cycle (protein). It is one of the only X-linked metabolic deficiencies.
Causes hyperammonemia and coma.
Treatments include dietary restrictions, liver transplants, oral medication, product supplementation, or increasing alternate pathway use. |
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