Disorders of amino acid metabolism: Pathology review

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. 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. 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.