Disorders of amino acid metabolism: Pathology review

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Case studies0:00–1:22

A 6 month old infant girl named Joanna is brought to the emergency department by her mother. She’s concerned because, over the past couple of weeks, Joanna has been having repetitive episodes of sudden and rapid jerking movements associated with loss of consciousness.
Upon physical examination, you notice that her sweat and urine has a musty odor, and that her head circumfernce is smaller compared with other babies of the same age and sex.
Joanna’s mother mentions that she lives in a remote area and gave birth at home. Next to her, 17 year old Andreas comes in with left calf pain and swelling, which has been gradually increasing over the past few weeks.
On further questioning, Andreas also mentions he has recently started to experience blurry vision, and has scheduled an appointment with his ophthalmologist.
He has no history of immobilization, trauma or malignancy, and does not smoke or use recreational drugs. On physical examination, Andreas is unusually tall and thin, with long arms and legs, and long fingers.
When you look into his eyes, you also notice that both his lenses have a partial dislocation down and inward.Okay, based on the initial presentation, both Joanna and Andreas seem to have some form of amino acid metabolism disorder.
But first a bit of physiology real quick. Amino acids are the building blocks of proteins, and we have 20 of them.

Physiology1:22–2:18

Now, all of them are made of a nitrogen group, a carbon skeleton, and a side chain that is unique to each amino acid. When amino acids are metabolized, the nitrogen is formed into a toxic compound called ammonia, which is sent to the liver.
In liver cells, ammonia goes through a series of enzymatic reactions, known as the urea cycle, to be converted into the less toxic urea.
Once urea is formed, it can go into the bloodstream and get excreted by the kidneys. Now, another way for liver cells to get rid of ammonia is to recycle it back to amino acids.
For your exams, the most important recycling pathway involves pairing ammonia with alpha-ketoglutarate to form glutamate, which in turn combines with another ammonia molecule to make the amino acid glutamine.
Now in cases of hyperammonemia, or elevated blood levels of ammonia, some of the excess ammonia may combine with alpha-ketoglutarate to form glutamate, which is the main excitatory neurotransmitter in the brain.

Hyperammonemia2:18–6:05

Glutamate can then combine with another ammonia molecule to form glutamine, or with the help of vitamin B6, it can then get converted to GABA, which is the main inhibitory neurotransmitter in the brain.
But since with hyperammonemia, there’s plenty of ammonia around, more glutamate will get converted to glutamine than to GABA.
So, for your tests, note that this results in a buildup of glutamine, which is taken up by astrocytes, causing them to swell, as well as a decrease in GABA, which impairs neurotransmission.
Over time though, the body’s pools of alpha-ketoglutarate will get depleted. The problem is that alpha-ketoglutarate is also a key intermediate of the Krebs cycle, also known as tricarboxylic acid cycle or TCA cycle for short.
Now, remember that the Krebs cycle is one of the main cellular pathways to produce energy in the form of ATP, which is used for various cellular processes.
One of them is ion transport by sodium- potassium pumps, which serve to pump sodium out of the cell, and potassium in. So as alpha-ketoglutarate levels fall, the Krebs cycle slows down, in turn reducing the production of ATP.
As a consequence, the sodium- potassium pumps can’t do their job. This causes a build up of sodium ions in the cell, which allows water to flow into the cells via osmosis, leading to cellular swelling.
For your exams, keep in mind that this primarily affects cells with high energy requirements like neurons, and the result is cerebral edema.
The telltale sign of hyperammonemia is asterixis, which is a flapping tremor of the hand that appears when the wrist is extended, like a bird that’s flapping its wings.
Additional signs and symptoms can include insomnia or hypersomnia, nausea, vomiting, mood changes, blurred vision, along with confusion, and even coma in some cases.
Now, diagnosis of hyperammonemia mainly involves blood tests revealing increased ammonia levels, and the main treatment consists of a strict diet that limits protein consumption.
For your exams, note that ammonia levels can be lowered with lactulose, which is a non-absorbable sugar, meaning it can’t be absorbed by the gastrointestinal tract.
So once in the small intestine, lactulose gets broken down into lactic acid. This decreases the pH in the lumen, promoting the conversion of ammonia into ammonium ions.
And ammonium anions can’t be reabsorbed, so they get excreted in the stool. Other treatment options include rifaximin or neomycin, which are antibiotics that kill ammonia- producing bacteria in the intestines.
Other choices include benzoate, phenylbutyrate, or phenylacetate, which provide an alternative to the urea cycle, by combining with amino acids, like glycine or glutamine, and turning them into products that can be excreted in the urine.Now, hyperammonemia can occur either due to acquired or hereditary causes.
A high yield acquired cause is chronic liver disease, where the liver isn’t able to remove ammonia from the blood, while hereditary causes include urea cycle defects, where a defect in an enzyme results in the overproduction of ammonia.
Okay, then! The most common urea cycle disorder is ornithine transcarbamylase deficiency, or OTC deficiency for short.

Ornith transcarb def6:05–9:07

This is caused by mutations in the OTC gene on the X chromosome. So, ornithine transcarbamylase deficiency is an X-linked recessive disorder, which means that all carrier males develop the disease, because they only have one X chromosome and thus one OTC gene available.
On the other hand, females have two X chromosomes, so having a single mutation makes them a carrier, and two mutations are needed to have the disease.
Now, the OTC gene codes for an enzyme called ornithine transcarbamylase. Normally, ornithine transcarbamylase works in the urea cycle by combining ornithine with carbamoyl phosphate to form citrulline.
So, deficiency of ornithine transcarbamylase results in an increase of carbamoyl phosphate in blood, which is then converted to orotic acid.
Ultimately, this excess orotic acid gets excreted through urine, giving it a characteristic cloudy appearance. And the problem is that the orotic acid in urine can form crystals, which can obstruct the urinary tract.
In addition, affected children can present with physical and mental developmental delay, along with failure to thrive. If a test question mentions elevated orotic acid in urine, make sure you rule out orotic aciduria; this is an autosomal recessive disease that’s caused by a deficiency in the enzyme uridine monophosphate synthase, or UMPS for short.
Orotic aciduria results in a defect in the pyrimidine synthesis pathway, leading to a decreased pyrimidine synthesis and an increase in orotic acid in the urine.
One way to tell the two apart is that in orotic aciduria there is no hyperammonemia, and unlike OTC, it’s associated with megaloblastic anemia, which is a form of macrocytic anemia, with a mean corpuscular volume or MCV larger than 100 fL, and it's also characterized by the presence of megaloblasts.
Megaloblastic anemia is caused by impaired DNA synthesis during red blood cell production in the bone marrow, which leads to continuing cell growth without division.Diagnosis of ornithine transcarbamylase deficiency is done by genetic testing, looking for mutations in the OTC gene.
Additional tests that can solidify the diagnosis include urinalysis revealing the presence of orotic acid in urine, as well as blood tests showing high orotic acid levels, hyperammonemia, high carbamoyl phosphate, and low citrulline.
Treatment includes ammonia-lowering medications, such as lactulose, rifaximin, neomycin, and benzoate, phenylbutyrate, or phenylacetate.Next is phenylketonuria or PKU, which is an autosomal recessive disease, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition.

Phenylketonuria9:07–13:18

Individuals affected by phenylketonuria have an impaired ability to use the amino acid phenylalanine. Normally, phenylalanine is processed into tyrosine by the enzyme phenylalanine hydroxylase with the help of a cofactor called tetrahydrobiopterin or BH4.
Tyrosine is then made into several products including melanin, which is responsible for the pigmentation of skin, hair, and the iris of the eye.
Now, phenylketonuria can be divided into classic phenylketonuria, which occurs when there’s a deficiency in phenylalanine hydroxylase, and malignant phenylketonuria, which is caused by a deficiency in tetrahydrobiopterin.
There’s also maternal phenylketonuria, which affects newborns whose mothers had untreated phenylketonuria during pregnancy.
Mind that in maternal PKU, it is the mother and not the baby who actually has PKU. In all cases, phenylalanine can’t be broken down into tyrosine, causing melanin levels to decrease.
At the same time, excess phenylalanine is broken down by other enzymes into several potentially harmful metabolites called phenylketones, including phenylacetate, phenyllactate, and phenylpyruvate.
These end up being excreted in the urine and sweat. And that’s where the name phenylketonuria comes from!
Another thing to note is that tetrahydrobiopterin also plays a role in the synthesis of neurotransmitters in the brain. Specifically, it’s a cofactor for tyrosine to be converted to L-dopa, which can then be converted to dopamine, as well as for tryptophan to be converted to 5-hydroxy-L-tryptophan, which can then be turned into serotonin.
So, in malignant phenylketonuria, reduced levels of tetrahydrobiopterin will result in impaired neurotransmission in the brain.Okay, so, symptoms of phenylketonuria usually present within the first few months of life and include a light skin tone and hair color, as well as blue eyes and a characteristic scent of urine and sweat.
In a test question, that’s classically described as a “musty” or “mousy” odor. For unknown reasons, individuals with phenylketonuria also often present eczema, which is characterized by skin dryness, itchiness, and blistering.
Neurological symptoms can also be present, including intellectual disability, abnormal gait, behavioral issues, and seizures.
For your exams, keep in mind that these are going to be more severe in the case of malignant phenylketonuria. Finally, newborns with maternal phenylketonuria classically have microcephaly, or an undersized head, associated with intellectual disability, low birth weight, growth retardation, and congenital heart defects.Okay, now, diagnosis of classic and malignant phenylketonuria, in many countries, is based on newborn screening to measure the blood levels of phenylalanine.
For your exams, it’s important to remember that the blood sample is usually taken 2 to 3 days after birth. That’s because phenylalanine levels are typically normal right after birth due to circulating maternal phenylalanine hydroxylase.
Treatment should begin as early as possible and be maintained for life. It consists of a low phenylalanine and high tyrosine diet.
What’s important to remember here is that the artificial sweetener aspartame contains phenylalanine and should be avoided.
Sticking to this diet regimen is particularly important for individuals with phenylketonuria during pregnancy to prevent maternal phenylketonuria.
And that’s a high yield fact! For those with malignant phenylketonuria, tetrahydrobiopterin supplements as well as L-dopa and 5-hydroxytryptophan administration will be also needed.Moving on to maple syrup urine disease, this is an autosomal recessive disorder, in which the body cannot break down branched chain amino acids, so valine, leucine, and isoleucine.

Maple syrup urine dse13:18–16:53

Normally, branched chain amino acids require special steps for their metabolism. First, the enzyme branched-chain amino transferase, or BCAT, converts them into branched- chain keto acids.
Valine into alpha-ketoisovalerate, leucine into alpha-ketoisocaproate, and isoleucine into alpha-keto-beta-methylvalerate.
And second, branched-chain alpha-keto acid dehydrogenase complex, or BCKD, turns these keto acids into isobutyryl-CoA, isovaleryl-CoA, and alpha-methylbutyryl-CoA respectively.
For your test, keep in mind that BCKD needs a cofactor to work, which is thiamine or vitamin B1. And that's a very high yield fact!
Now, in maple syrup urine disease, there is a mutation in one of the genes that codes for the BCKD complex. Decreased BCKD complex activity means that all the branched chain amino acids and their branched- chain keto acids will build up in the blood.
And some of these branched- chain keto acids use up other amino acids like aspartate, glutamine, and alanine, which are important for brain function and development, in order to get converted back into leucine, isoleucine, and valine.
High levels of the branched- chain keto acid alpha- ketoisocaproate can also inhibit the Krebs cycle, slowing down the production of ATP.
This impairs the function of sodium- potassium pumps, ultimately leading to cellular swelling and cerebral edema. At the same time, isoleucine is spontaneously converted into alloisoleucine, which can be then converted to sotolone, which has a very strong sweet smell.
This molecule is excreted in the urine with the other metabolic products, giving the urine a distinct, sweet odor, and that’s why it’s called maple syrup urine disease!Symptoms of maple syrup urine disease typically appear within 48 hours after birth, but they can also show up later in life.
In a test question, look for sweet smelling urine, along with irritability, vomiting, poor feeding, and lethargy or sleepiness.
In addition, some individuals may have intellectual disability. Another classic manifestation is opisthotonos, which is a severe simultaneous spasm of all muscles in the body, resulting in backward arching of the head, neck, and back.
In some cases, these symptoms could be triggered by metabolic stressors like heavy exercise, infections, or fasting, where the body starts to break down its own proteins.
For your exams, remember that if untreated, in seven to ten days, individuals can develop cerebral edema, seizures, coma, and respiratory failure can occur.Diagnosis for maple syrup urine disease is based on blood tests that show elevated valine, leucine, isoleucine, and alloisoleucine in the blood, and urinalysis revealing increased alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, and alpha-ketoisovalerate.The main treatment consists of a diet that limits consumption of valine, leucine, and isoleucine.
Thiamine supplementation may also be beneficial.Next is alkaptonuria. This is an autosomal recessive disorder caused by a mutation in the HGD gene coding for homogentisate oxidase.
This enzyme normally catalyzes conversion of homogentisate to maleylacetoacetate, which is a step in the catabolism of tyrosine into acetoacetate and fumarate.
So without homogentisate oxidase, homogentisic acid builds up in multiple organs and tissues, including the skin, connective tissue, ear cartilage, sclera, and articular cartilage.
Signs and symptoms vary depending on the tissue affected. If that’s the skin, connective tissue, tympanic membranes, sclera, there can be bluish or black discoloration of these tissues, also known as ochronosis.

Alkaptonuria16:53–18:20

For your exams, another extremely high yield finding is arthralgias or joint pain, which sometimes can interfere with activities of daily life.
At the same time, remember that all that homogentisic acid will get excreted in the urine, so the telltale sign is black colored urine.Diagnosis of alkaptonuria starts with urine tests showing elevated homogentisic acid levels, and is confirmed via genetic testing of the HGD gene.
Unfortunately, no cure for the disease is currently available, but a low protein diet might be helpful.Homocystinuria is an autosomal recessive disorder where there’s a defect in the metabolism of methionine.
Normally, methionine is converted into homocysteine. Then, the enzyme cystathionine beta-synthase, which requires vitamin B6 as a substrate, combines homocysteine and serine to create cystathionine.
Finally, another enzyme, called cystathionase, converts cystathionine into cysteine. Any homocysteine that does not undergo this process can be converted back into methionine by methionine synthase, which requires vitamin B12, or cobalamin, and vitamin B9 or folate as substrates.
Now, homocystinuria is most often caused by cystathionine beta-synthase deficiency, but it can also be caused by decreased affinity of cystathionine beta- synthase for vitamin B6.
As a result, less cysteine is produced, and homocysteine builds up in the body. Homocystinuria can be also caused by methionine synthase deficiency or deficiencies in vitamin B12 or in folate, which remember are required by methionine synthase.

Homocystinuria18:20–24:07

What’s high yield here is that folate deficiency can be caused by deficiency of methylenetetrahydrofolate reductase or MTHFR, which is an enzyme involved in the synthesis of folate.
So, if methionine synthase is defective or there isn’t enough vitamin B12 or folate around, homocysteine can be converted into cysteine, but it can’t be converted back into methionine, which also leads to homocysteine accumulation.
Whatever the cause, some of the excess homocysteine will be excreted in the urine, leading to homocystinuria. Homocysteine also builds up in the blood, where it binds to platelets, causing them to stick to one another and make blood clots, as well as stick to endothelial cells lining the blood vessels.
This leads to atherosclerosis or plaque build-up, which narrows the arteries and could lead to ischemia of their supplied tissues.
And that’s a high yield fact! In the bones, homocysteine binds to structural proteins called fibrillin-1, blocking them from binding to one another, and causing bones to become weaker or deformed.
In the eye, homocysteine can build up in the zonular fibers, which help hold the lens in place, causing them to degenerate.
For your exam, remember that this leads to ectopia lentis or dislocation of the lens down and inward. Finally, when homocysteine accumulates in the brain, it causes neurons to undergo apoptosis or programmed cell death, leading to neurodegeneration.
Symptoms of homocystinuria can manifest during infancy or later in life. In a test question, look for an individual with a marfanoid habitus, meaning that they are unusually tall and thin, with long arms and legs, and arachnodactyly or long thin fingers and toes.
Other high yield features include limited joint mobility, pectus excavatum or caved in sternum, pectus carinatum or protruding sternum, genu valgum, where the knees angle towards each other, and kyphosis or an abnormally convexed spine.
Next, the combination of atherosclerosis and thrombosis can increase the risk of strokes, myocardial infarctions and thromboembolism.
For your exams, the classic scenario is a young individual presenting with stroke, my ocardial infarction or thromboembolism, without any risk factors.
Finally, ectopia lentis can cause nearsightedness, blurred vision, and neurodegeneration can lead to intellectual disability, and seizures.
If a test question describes an individual with a marfanoid habitus, pectus excavatum, or pectus carinatum, it’s extremely important to differentiate homocystinuria from Marfan syndrome.
This is an autosomal dominant disorder caused by mutations in the genes coding for fibrillin-1. Now, unlike homocystinuria, Marfan syndrome causes lax or hyperflexible joints, while intelligence remains normal.
In the cardiovascular system, keep in mind that Marfan syndrome isn’t associated with atherosclerosis or thrombosis. Instead, it can result in an abnormal dilation of the aorta, which makes it susceptible to aneurysms, dissection, and rupture.
But what’s even more important is that in Marfan syndrome, the lens is dislocated up and outward, rather than down and inward.Okay, so diagnosis of homocystinuria is based on elevated levels of homocysteine in the urine and blood.
If a test question mentions blood levels of methionine, keep in mind that they will be elevated in cystathionine beta-synthase deficiency, and decreased cystathionine beta-synthase affinity for B6, but they will be decreased in methionine synthase or methylenetetrahydrofolate reductase deficiency.Treatment of homocystinuria varies depending on its cause.
So, in cystathionine beta-synthase deficiency, it’s recommended to modify the diet to decrease methionine intake and increase cysteine, B6, B12, and folate.
Remember the goal is to drive homocysteine back into methionine. If the problem is decreased affinity of cystathionine synthase for vitamin B6, we should increase the dietary intake of vitamin B6 and cysteine.
In methionine synthase deficiency, treatment involves increasing methionine, and finally, methylenetetrahydrofolate reductase deficiency requires an increase in folate consumption.Cystinuria is an autosomal-recessive condition that affects the amino acid transporter in the proximal convoluted tubule and intestines.
This causes a decrease in the reabsorption of ornithine, lysine, arginine, and most importantly, cystine. As cystine builds up, it leaks into the urine to crystallize and form a yellow or light pink colored cystine stone that’s hexagonal.
For your tests, you can remember this using the following memory trick! SIXtine-stones have SIX sides.
And cystine stones crystalize even more if the urine pH is acidic. Just like any type of kidney stones, symptoms include unilateral flank tenderness and pain, meaning between the ribs and the hip, that’s typically colicky and can radiate to the groin.
There can also be hematuria that can either be macroscopic or gross, meaning it’s clearly visible, or can be microscopic, which is detected using urinalysis.
Diagnosis is based on the sodium cyanide nitroprusside test that can detect cystine in the urine. On an X-ray, cystine stones are faintly radiolucent and on a CT scan, they’re moderately radiopaque.

Cystinuria24:07–25:34

Treatment of cystinuria involves alkalinization of the urine with potassium citrate or acetazolamide. If this doesn’t work, chelating agents like penicillamine are administered.
Okay, the last thing we’re gonna talk about is organic acidemia. This is a term used to describe a group of disorders characterized by increased excretion of organic acids in urine.
The disorders you need to know for your exams are propionic acidemia and methylmalonic acidemia. So, propionic acidemia is an autosomal recessive disorder, caused by a mutation in the gene coding for propionyl-CoA carboxylase.
Normally, this enzyme converts propionyl-CoA, which is a breakdown product of isoleucine, valine, methionine, and threonine as well as odd chain fatty acids and cholesterol, to methylmalonic acid.
So, when propionyl-CoA carboxylase is deficient, methylmalonic acid decreases, and propionyl-CoA turns to propionic acid, which builds up in the blood.
On the other hand, methylmalonic acidemia results from a decreased activity of methylmalonyl-CoA mutase. Normally, methylmalonyl-CoA mutase converts methylmalonyl-CoA to succinyl-CoA, using vitamin B12 as a cofactor.
So, decreased activity of this enzyme can occur either due to an autosomal recessive mutation in the gene coding for methylmalonyl-CoA mutase or due to a deficiency of vitamin B12.
The end result is the accumulation of methylmalonic acid, as well as its precursor propionyl-CoA, which turns into propionic acid.

Organic acidemias25:34–29:22

So, bear in mind that in propionic acidemia, there’s an increase of propionic acid and decrease of methylmalonic acid, while in methylmalonic acidemia, both methylmalonic acid and propionic acid are increased, and that's an extremely high yield fact!
Now, buildup of these organic acids inhibits gluconeogenesis, decreasing fasting blood glucose. This forces cells to use fats as primary energy fuel instead of glucose.
Fats are then converted to keto acids, such as acetoacetic acid and β-hydroxybutyric acid. So, the accumulation of both organic acids and keto acids can result in a high anion gap metabolic acidosis, where acidosis means that the blood pH is lower than 7.35, metabolic, that HCO3 levels are less than 20mEq/L, and high anion gap that the the anion gap, which equals sodium minus chloride plus bicarbonate is above 12 mEq/L.
Meanwhile, the accumulation of organic acids inhibits the urea cycle, leading to hyperammonemia. Symptoms of organic acidemia typically present during the first year of life, and most importantly include nausea, vomiting, poor feeding, and failure to thrive, as well as hypotonia, or low muscle tone, seizures, and hepatomegaly, or an enlarged liver.Diagnosis involves blood tests and urinalysis, revealing elevated levels of propionic acid in both propionic acidemia and methylmalonic acidemia, and elevated methylmalonic acid only in methylmalonic acidemia alone.
Blood tests may also show low levels of glucose, a high anion gap acidosis, and increased ammonia.Treatment involves a low protein diet.
For your exams, it’s important to remember that individuals with organic acidemias should avoid substances that metabolize into propionyl-CoA, including isoleucine, valine, methionine, threonine, odd chain fatty acids and cholesterol.All right, as a quick recap… Hyperammonemia can occur due to hereditary urea cycle defects.
The most common one is ornithine transcarbamylase deficiency, which leads to a buildup of carbamoyl phosphate that gets converted to orotic acid.
Symptoms include urinary tract obstruction, physical and mental developmental delay, and failure to thrive. Ornithine transcarbamylase deficiency must be differentiated from orotic aciduria, which has no hyperammonemia and causes megaloblastic anemia.
Phenylketonuria can be caused by a deficiency of the enzyme phenylalanine hydroxylase or its cofactor tetrahydrobiopterin, which impairs the breakdown of phenylalanine into tyrosine, resulting in light skin, hair, and eyes, a musty scent of urine and sweat, intellectual disability, microcephaly, and eczema.
Maple syrup urine disease is caused by a deficiency in branched-chain alpha-ketoacid dehydrogenase. This results in the buildup of branched chain amino acids, so valine, leucine, and isoleucine, and their branched- chain keto acids, which can disrupt brain development, neurotransmitter synthesis, cause cerebral edema, and give the urine a sweet odor.
Alkaptonuria occurs due to deficiency of homogentisate oxidase, leading to the accumulation of homogentisic acid and presenting with bluish skin, connective tissue, ear cartilage ,and sclera, as well as arthralgias, and black colored urine.
Homocystinuria can be caused by cystathionine beta-synthase deficiency, decreased affinity of cystathionine beta- synthase for vitamin B6, methionine synthase deficiency or deficiencies in vitamin B12, or folate, which may result from methylenetetrahydrofolate reductase deficiency.

Review29:22–32:31

Symptoms include connective tissue abnormalities like marfanoid habitus, as well as ectopia lentis, intellectual disability, seizures, atherosclerosis, and thrombosis.
Cystinuria is caused by decrease in the reabsorption of cystine in the kidney and intestines, which results in cystine kidney stones.
Finally, organic acidemias include propionic acidemia, which is caused by the deficiency of propionyl-CoA carboxylase and leads to accumulation of propionic acid and decreased methylmalonic acid, and methylmalonic acidemia which is caused by deficiency of methylmalonyl-CoA mutase or vitamin B12 and leads to the accumulation of methylmalonic acid and propionic acid.
Both can cause hypoglycemia, high anion gap metabolic acidosis and hyperammonemia, and present with poor feeding in infancy, vomiting, hypotonia, hepatomegaly, and seizures.
Regarding inheritance, remember that all these are autosomal recessive, except for ornithine transcarbamylase deficiency syndrome, which is X-linked recessive.
Okay, back to our cases. Joanna is the 6 month old girl who presented recurring episodes of sudden and rapid jerking movements with loss of consciousness, which are classic findings in seizures.
Also, her sweat and urine have a characteristic musty odor. This combined with the microcephaly found on physical examination, all point to phenylketonuria.
And the fact that she was born at home suggests that perhaps she didn’t get newborn screening tests. Blood tests confirmed the elevated serum phenylalanine levels and Joanna was started on a low phenylalanine and high tyrosine diet.
On the other hand, Andreas, the 17 year old boy, came in with left calf pain and swelling, which are clues for deep vein thrombosis.
However, he has no risk factors, like immobilization, trauma, malignancy, smoking or use of recreational drugs. He also has the typical tall and thin marfanoid habitus, with unusually long arms, legs, and fingers.
On top of that, he has blurry vision and a down and inward dislocation of the lens, which are telltale signs of ectopia lentis.
So this is a pretty straight forward case of homocystinuria, so diagnosis was confirmed with blood tests and urinalysis showing elevated levels of homocysteine.
hyperammonemia a with poor feeding in infancy, vomiting hypotonia hepatomegaly, and seizures regarding inheritance. Remember that all these are autosomal recessive except for ornithine transcarbamylase deficiency syndrome, which is x-linked recessive.
Okay, back to our cases. Joanna is a 6 month old girl who presented recurrent episodes of sudden and rabbit jerky movements with loss of consciousness, which are classic findings and seizures.

Summary32:31–33:48

Also her sweat in your and have a characteristic musty odor. This combined with microcephaly found on physical examination, Allpoint to phenylketonuria, and the fact that she was born at home suggest that perhaps she didn't get newborn screening test.
Blood test, confirmed the elevated serum phenylalanine levels and Joanna was started on a low phenylalanine and tyrosine diet.
On the other hand, Andreas. The 17-year old boy came in with left calf pain and swelling which are clues for deep vein thrombosis.
However, he has no risk factors, like immobilization trauma, malignancy smoking or use of recreational drugs. He also has the typical tall and thin marfanoid.
Habitus with unusually long arms legs and fingers. On top of that.
He has blurry vision and it down and Edward dislocation of the lens which are telltale signs of ectopic Atlantis. So this is a pretty straightforward case of homocystinuria to diagnosis was confirmed with blood test and your analysis showing elevated levels of homocysteine.
Disorders of amino acid metabolism: Video | Osmosis