Amino acid metabolism and disorders

Amino acid metabolism and disorders US Medical PG Question 1: An 8-day-old boy is brought to the physician by his mother because of vomiting and poor feeding. The pregnancy was uncomplicated, and he was born at full term. He appears pale and lethargic. Physical examination shows diffusely increased muscle tone. His urine is noted to have a sweet odor. This patient's symptoms are most likely caused by the accumulation of which of the following?

• A. Phenylalanine
• B. Homogentisic acid
• C. Isoleucine (Correct Answer)
• D. Homocysteine
• E. Phytanic acid

Amino acid metabolism and disorders Explanation: ***Isoleucine*** - The combination of **vomiting**, poor feeding, lethargy, **increased muscle tone**, and a **sweet-smelling urine** (often described as maple syrup odor) in a neonate strongly points to **Maple Syrup Urine Disease (MSUD)**. - MSUD is caused by a defect in the **branched-chain alpha-keto acid dehydrogenase complex**, leading to the accumulation of branched-chain amino acids (leucine, isoleucine, and valine) and their corresponding alpha-keto acids. *Phenylalanine* - Accumulation of **phenylalanine** is characteristic of **Phenylketonuria (PKU)**, which typically presents with intellectual disability, seizures, and an eczematous rash if untreated, but not a maple syrup odor in urine or acute neonatal crisis. - The urine odor in PKU is often described as **mousy** or musty, distinctly different from a sweet or maple syrup odor. *Homogentisic acid* - Accumulation of **homogentisic acid** is seen in **Alkaptonuria**, an inborn error of metabolism that primarily causes dark urine upon standing (due to oxidation of homogentisic acid), ochronosis (blue-black pigmentation of cartilage and connective tissue later in life), and arthritis. - It does not present with acute neonatal symptoms such as vomiting, lethargy, or a sweet urine odor. *Homocysteine* - Elevated levels of **homocysteine** are found in **Homocystinuria**, which can lead to intellectual disability, developmental delay, dislocation of the ocular lens (ectopia lentis), Marfanoid habitus, and thromboembolic events. - It does not typically present in the neonatal period with a sweet urine odor or acute neurological symptoms like increased muscle tone. *Phytanic acid* - Accumulation of **phytanic acid** is characteristic of **Refsum disease**, a rare peroxisomal disorder that causes progressive neurological symptoms such as retinitis pigmentosa, peripheral neuropathy, ataxia, and deafness in childhood or adulthood. - It does not present in the neonatal period with the described acute symptoms or unique urine odor.

Amino acid metabolism and disorders US Medical PG Question 2: An investigator is studying severely ill patients who experience hypoglycemia and ketonuria during times of fasting. The investigator determines that during these episodes, amino acids liberated from muscle proteins are metabolized to serve as substrates for gluconeogenesis. Nitrogen from this process is transported to the liver primarily in the form of which of the following molecules?

• A. Glutamate
• B. α-ketoglutarate
• C. Alanine (Correct Answer)
• D. Arginine
• E. Pyruvate

Amino acid metabolism and disorders Explanation: ***Alanine*** - During prolonged fasting, **muscle proteins are catabolized** to provide amino acids for gluconeogenesis in the liver. - **Alanine** is the primary amino acid released from muscle into the bloodstream to transport nitrogen to the liver through the **glucose-alanine cycle (Cahill cycle)**. - In this cycle, pyruvate in muscle accepts an amino group from glutamate to form alanine, which is then transported to the liver, where it is deaminated back to pyruvate (for gluconeogenesis) and ammonia (for the urea cycle). - **Glutamine** also serves as an important nitrogen transporter, particularly to the kidneys and intestines. *Glutamate* - **Glutamate** is an important amino acid in nitrogen metabolism within tissues, but it is not the primary form in which nitrogen is transported from muscle to the liver in significant quantities. - While glutamate participates in transamination reactions within muscle, its efflux from muscle into the blood is less prominent than alanine for inter-organ nitrogen transport. *α-ketoglutarate* - **α-ketoglutarate** is a key intermediate in the **Krebs cycle** and accepts an amino group to form glutamate. - It is an alpha-keto acid, not an amino acid, and therefore does not directly transport nitrogen in the form of an amino group to the liver via the bloodstream. *Arginine* - **Arginine** is primarily involved in the **urea cycle** within the liver, where it helps in the detoxification of ammonia, but it is not a major transporter of nitrogen from peripheral tissues to the liver for gluconeogenesis. - Its role is mainly within the liver for urea synthesis, not for inter-organ nitrogen transport in this context. *Pyruvate* - **Pyruvate** is a keto acid that can be converted to alanine via transamination. - While pyruvate is a precursor to alanine and a substrate for gluconeogenesis, it transports carbon skeletons and not nitrogen itself; **alanine is the actual nitrogen carrier** in this cycle.

Amino acid metabolism and disorders US Medical PG Question 3: A 6-month-old boy is brought to a pediatrician by his parents for his first visit after they adopt him from a European country. His parents are concerned about the boy’s short episodes of shaking of his arms and legs; they believe it might be epilepsy. They also note that the child is less responsive than other children of his age. The family is unable to provide any vaccination, birth, or family history. His pulse is 130/min, respiratory rate is 28/min, and blood pressure is 90/50 mm Hg. The boy has a light skin tone and emits a noticeable musty body odor. Which of the following should be supplemented in this patient’s diet?

• A. Isoleucine
• B. Leucine
• C. Tyrosine (Correct Answer)
• D. Phenylalanine
• E. Histidine

Amino acid metabolism and disorders Explanation: ***Tyrosine*** - The patient's presentation with **seizures**, **developmental delay** (less responsive), **light skin tone**, and a **musty body odor** is highly suggestive of **phenylketonuria (PKU)**. - In PKU, there is a deficiency in the enzyme **phenylalanine hydroxylase**, which converts **phenylalanine** to **tyrosine**. Therefore, **tyrosine** becomes an **essential amino acid** and must be supplemented in the diet. *Isoleucine* - **Isoleucine** is a **branched-chain amino acid** that is typically restricted, along with leucine and valine, in conditions like **maple syrup urine disease (MSUD)**, not PKU. - Supplementation of isoleucine would be detrimental in MSUD and is not indicated for PKU. *Leucine* - Similar to isoleucine, **leucine** is a **branched-chain amino acid** whose metabolism is impaired in **MSUD**, not PKU. - Supplementing leucine is not beneficial for PKU and would be harmful in MSUD. *Phenylalanine* - **Phenylalanine** is the amino acid that accumulates to toxic levels in **PKU** due to the enzyme deficiency. - Therefore, phenylalanine must be **strictly restricted** in the patient's diet, not supplemented. *Histidine* - **Histidine** is an essential amino acid but is not directly involved in the metabolic pathway affected by PKU. - There is no indication for histidine supplementation in the management of PKU.

Amino acid metabolism and disorders US Medical PG Question 4: A 30-year-old African American G1P0 mother gives birth to a male infant at 33 weeks' gestation. The mother had no prenatal care and took no prenatal vitamins. The child’s postnatal period was complicated by neonatal sepsis due to group B Streptococcus. He required a two week stay in the neonatal intensive care unit to receive antibiotics, cardiopulmonary support, and intravenous nutrition. He eventually recovered and was discharged. At a normal follow-up visit to the pediatrician’s office one month later, the mother asks about the child’s skin color and hair color. On examination, the child has white hair and diffusely pale skin. The child’s irises appear translucent. Further questioning of the mother reveals that there is a distant family history of blindness. This child most likely has a defect in an enzyme involved in the metabolism of which of the following molecules?

• A. Leucine
• B. Homocysteine
• C. Phenylalanine
• D. Homogentisic acid
• E. DOPA (Correct Answer)

Amino acid metabolism and disorders Explanation: ***DOPA*** - The symptoms of **white hair**, **pale skin**, and **translucent irises**, along with a family history of **blindness**, are classic signs of **oculocutaneous albinism**. - **Oculocutaneous albinism** results from a defect in **tyrosinase**, an enzyme responsible for converting **DOPA** (3,4-dihydroxyphenylalanine) into **melanin**. *Leucine* - Defects in **leucine** metabolism are associated with **Maple Syrup Urine Disease**, characterized by sweet-smelling urine and neurological complications, not albinism. - This condition involves impaired **branched-chain alpha-keto acid dehydrogenase** complex activity, leading to an accumulation of branched-chain amino acids. *Homocysteine* - Problems with **homocysteine** metabolism are seen in conditions like **homocystinuria**, which can cause developmental delay, skeletal abnormalities, and vascular issues, but not hypopigmentation. - This is often due to deficiencies in **cystathionine beta-synthase** or other enzymes involved in folate and vitamin B12 metabolism. *Phenylalanine* - A defect in **phenylalanine** metabolism, specifically **phenylalanine hydroxylase**, leads to **phenylketonuria (PKU)**, which causes intellectual disability, seizures, and a musty odor, but not the specific ocular and cutaneous features described for albinism. - While PKU can cause milder hypopigmentation due to reduced tyrosine availability, the described translucent irises and severe white hair are more indicative of albinism. *Homogentisic acid* - A defect in **homogentisic acid** metabolism causes **alkaptonuria**, characterized by dark urine upon standing, blue-black discoloration of cartilage (ochronosis), and early-onset arthritis, which are not present in this case. - This condition results from a deficiency of **homogentisate 1,2-dioxygenase**.

Amino acid metabolism and disorders US Medical PG Question 5: A 4-day-old male newborn delivered at 39 weeks' gestation is evaluated because of poor feeding, recurrent vomiting, and lethargy. Physical examination shows tachypnea with subcostal retractions. An enzyme assay performed on a liver biopsy specimen shows decreased activity of carbamoyl phosphate synthetase I. This enzyme plays an important role in the breakdown and excretion of amino groups that result from protein digestion. Which of the following is an immediate substrate for the synthesis of the molecule needed for the excretion of amino groups?

• A. N-acetylglutamate
• B. Homocysteine
• C. Phenylalanine
• D. Valine
• E. Aspartate (Correct Answer)

Amino acid metabolism and disorders Explanation: ***Aspartate*** - The question describes a case of **carbamoyl phosphate synthetase I (CPS I)** deficiency, which leads to **hyperammonemia** due to impaired urea cycle function. - The urea cycle is responsible for excreting **amino groups** as urea; one of the key molecules directly incorporated into the urea molecule is **aspartate**, which donates an amino group to form **argininosuccinate**. *N-acetylglutamate* - **N-acetylglutamate** is an essential activator of **carbamoyl phosphate synthetase I (CPS I)**, the enzyme deficient in this patient. - While crucial for the urea cycle's regulation, it is an **allosteric activator** rather than a direct substrate for the synthesis of molecules needed for amino group excretion. *Homocysteine* - **Homocysteine** is an intermediate in **methionine metabolism** and is primarily associated with cardiovascular disease and neurological issues when elevated. - It plays no direct role as a substrate in the urea cycle for the excretion of amino groups. *Phenylalanine* - **Phenylalanine** is an **essential amino acid** that is a precursor to tyrosine and neurotransmitters. - Its metabolism is separate from the urea cycle, and it is not a direct substrate for ammonia excretion in this pathway. *Valine* - **Valine** is a **branched-chain amino acid (BCAA)** primarily catabolized in muscles and used for energy. - It is not a direct substrate in the urea cycle, which processes nitrogen from various amino acids into urea for excretion.

Amino acid metabolism and disorders US Medical PG Question 6: A 29-year-old female presents to the family physician concerned over the blue-black discoloration of her sclera and skin. She notes that at the end of her day, there are black stains in her underwear. The incomplete breakdown of which of the following amino acids is responsible for this presentation?

• A. Leucine
• B. Valine
• C. Tyrosine (Correct Answer)
• D. Methionine
• E. Isoleucine

Amino acid metabolism and disorders Explanation: ***Tyrosine*** - The symptoms described (blue-black **scleral and skin discoloration**, and dark urine staining underwear) are classic for **alkaptonuria**. - Alkaptonuria results from a deficiency of **homogentisate oxidase**, an enzyme in the catabolic pathway of **tyrosine**, which leads to the accumulation of **homogentisic acid**. *Leucine* - Leucine is a **branched-chain amino acid**; disorders in its metabolism are typically associated with conditions like **Maple Syrup Urine Disease**. - **Maple Syrup Urine Disease** presents with neurological symptoms, poor feeding, and a characteristic odor, not blue-black discoloration. *Valine* - Valine is another **branched-chain amino acid**, and its metabolic defects are also associated with conditions like **Maple Syrup Urine Disease**. - Its accumulation does not lead to the specific pigmentary changes seen in alkaptonuria. *Methionine* - Methionine metabolism disorders include conditions such as **homocystinuria**. - **Homocystinuria** is characterized by skeletal abnormalities, ocular problems, and intellectual disability, not blue-black discoloration. *Isoleucine* - Isoleucine is the third **branched-chain amino acid** and is also implicated in **Maple Syrup Urine Disease** when its metabolism is impaired. - Clinical features of isoleucine metabolism defects do not include the blue-black pigmentation described.

Amino acid metabolism and disorders US Medical PG Question 7: You are counseling a mother whose newborn has just screened positive for a deficit of phenylalanine hydroxylase enzyme. You inform her that her child will require dietary supplementation of which of the following?

• A. Aspartame
• B. Niacin
• C. Homogentisic Acid
• D. Tyrosine (Correct Answer)
• E. Leucine

Amino acid metabolism and disorders Explanation: ***Tyrosine*** - A deficit of **phenylalanine hydroxylase** prevents the conversion of phenylalanine to tyrosine, making **tyrosine** an essential amino acid that must be supplemented. - Dietary restriction of **phenylalanine** is also crucial to prevent the accumulation of toxic byproducts that can cause severe neurological damage. *Aspartame* - **Aspartame** is an artificial sweetener that contains **phenylalanine**, which would be harmful for a child with phenylalanine hydroxylase deficiency. - Consumption of aspartame would increase the body's phenylalanine load, exacerbating the metabolic disorder. *Niacin* - **Niacin** (vitamin B3) is a vitamin and its supplementation is not related to the phenylalanine hydroxylase pathway or its deficiency. - Deficiency of niacin is associated with **pellagra**, characterized by dermatitis, diarrhea, and dementia. *Homogentisic Acid* - **Homogentisic acid** is an intermediate in the metabolism of tyrosine, and its accumulation is characteristic of **alkaptonuria**, a different metabolic disorder. - It is not a therapeutic supplement for phenylalanine hydroxylase deficiency. *Leucine* - **Leucine** is a branched-chain amino acid, and its metabolism is unrelated to phenylalanine hydroxylase deficiency. - Supplemental leucine is not required in this condition and would not address the metabolic defect.

Amino acid metabolism and disorders US Medical PG Question 8: A 9-month-old infant presents to your office for a check-up. Exam reveals developmental delay, microcephaly, and a mousy odor to his breath. You should be concerned that the infant may have which of the following?

• A. Excess tetrahydrobiopterin cofactor
• B. Deficit of porphobilinogen deaminase activity
• C. Deficit of tyrosine hydroxylase activity
• D. Excess phenylalanine hydroxylase activity
• E. Deficit of phenylalanine hydroxylase activity (Correct Answer)

Amino acid metabolism and disorders Explanation: ***Deficit of phenylalanine hydroxylase activity*** - The combination of **developmental delay**, **microcephaly**, and a **mousy odor** is characteristic of **phenylketonuria (PKU)**. - PKU is caused by a deficient **phenylalanine hydroxylase** enzyme, leading to a buildup of phenylalanine and its metabolites, which are toxic to the developing brain. *Excess tetrahydrobiopterin cofactor* - This condition (**BH4 excess**) is rare and does not typically present with the classic signs of PKU; rather, it often involves neurological symptoms due to other metabolic imbalances. - An excess of the BH4 cofactor would theoretically enhance rather than inhibit phenylalanine hydroxylase activity, if the enzyme itself were functional. *Deficit of porphobilinogen deaminase activity* - A deficit in **porphobilinogen deaminase** is associated with **Acute Intermittent Porphyria (AIP)**, which presents with acute neurovisceral attacks. - Symptoms of AIP include severe abdominal pain, psychiatric disturbances, and neurological deficits, but not developmental delay or a mousy odor. *Deficit of tyrosine hydroxylase activity* - A deficiency in **tyrosine hydroxylase** affects the synthesis of **dopamine** and other catecholamines, leading to neurological disorders, including **dystonia** and **Parkinsonian symptoms**. - While it can cause developmental delay, it does not typically present with a mousy odor or microcephaly, and its primary symptoms relate to motor control. *Excess phenylalanine hydroxylase activity* - An **excess** of phenylalanine hydroxylase activity would lead to increased breakdown of phenylalanine, preventing its buildup. - This would not cause the symptoms described; instead, it would likely result in lower-than-normal phenylalanine levels, which is generally not problematic.

Amino acid metabolism and disorders US Medical PG Question 9: A 6-day-old female newborn is brought to the physician because of yellowish discoloration of her eyes and body, vomiting, and poor feeding for 3 days. She has had diarrhea for the past 2 days. She was born at 38 weeks' gestation and the antenatal period was uncomplicated. She appears lethargic. Vital signs are within normal limits. Examination shows jaundice of the skin and conjunctivae. Bilateral cataracts are present. The abdomen is soft and nontender. The liver is palpated 4-cm below the right costal margin; there is no splenomegaly. Muscle tone is decreased in all extremities. Serum glucose concentration is 37 mg/dL. Which of the following is the most appropriate recommendation to prevent long-term complications of this illness?

• A. Phototherapy
• B. Thiamine therapy
• C. Levothyroxine therapy
• D. Frequent glucose feeds
• E. Stop milk feeds (Correct Answer)

Amino acid metabolism and disorders Explanation: ***Stop milk feeds*** - The constellation of **jaundice**, **vomiting**, **diarrhea**, **lethargy**, **hepatomegaly**, **hypoglycemia**, **decreased muscle tone**, and **bilateral cataracts** in a newborn is highly suggestive of **galactosemia**. - **Stopping milk feeds** (specifically those containing lactose and galactose) is the primary and most crucial intervention to prevent long-term complications such as intellectual disability, liver damage, and kidney failure. *Phototherapy* - While phototherapy is used to treat **neonatal jaundice**, it addresses only the symptom of hyperbilirubinemia, not the underlying cause in galactosemia. - It would not prevent the systemic devastating effects on other organs caused by galactose and its metabolites. *Thiamine therapy* - **Thiamine therapy** is indicated for conditions like **Wernicke-Korsakoff syndrome** or **thiamine-dependent metabolic disorders**, which do not align with the presented symptoms. - There is no evidence to support its use in galactosemia. *Levothyroxine therapy* - **Levothyroxine therapy** is used for **hypothyroidism**, a condition characterized by feeding problems, jaundice, and lethargy but typically lacks the specific findings of cataracts, vomiting/diarrhea in this acute presentation, and hepatomegaly, as seen in this clinical picture. - The combination of symptoms described points more specifically to a metabolic disorder affecting galactose metabolism. *Frequent glucose feeds* - While the newborn has **hypoglycemia**, simply providing frequent glucose feeds addresses **only a symptom** and does not resolve the underlying metabolic defect in galactosemia. - Continuing milk feeds would worsen the primary disease, despite potentially correcting blood glucose temporarily.

Amino acid metabolism and disorders US Medical PG Question 10: A medical student is studying digestive enzymes at the brush border of the duodenum. He isolates and inactivates an enzyme in the brush border that has a high affinity for the pancreatic proenzyme trypsinogen. When the enzyme is inactivated, trypsinogen is no longer converted to its active form. Which of the following is the most likely underlying mechanism of this enzyme?

• A. Attachment of a carbohydrate to a side chain
• B. Phosphorylation of an amino acid side chain
• C. Carboxylation of a glutamate residue
• D. Cleavage of a propeptide from an N-terminus (Correct Answer)
• E. Conjugation of ubiquitin to lysine residue

Amino acid metabolism and disorders Explanation: ***Cleavage of a propeptide from an N-terminus*** - The enzyme described is **enteropeptidase (also known as enterokinase)**, which is located in the **duodenal brush border**. - Enteropeptidase's primary function is to activate **trypsinogen** by cleaving a small **N-terminal hexapeptide**, converting it into its active form, **trypsin**. *Attachment of a carbohydrate to a side chain* - This process is known as **glycosylation** and can affect protein folding, stability, and recognition, but it's not the primary mechanism by which brush border enzymes like enteropeptidase activate zymogens. - While some enzymes are glycosylated, inactivation of this mechanism would not halt trypsinogen activation in this specific enzymatic pathway. *Phosphorylation of an amino acid side chain* - **Phosphorylation** is a common post-translational modification that regulates enzyme activity by adding a phosphate group, often to serine, threonine, or tyrosine residues. - While important for many cellular signaling pathways and enzyme regulation, it is not the mechanism by which enteropeptidase activates trypsinogen. *Carboxylation of a glutamate residue* - **Carboxylation** typically involves the addition of a carboxyl group, notably important for blood clotting factors (e.g., vitamin K-dependent carboxylation). - This modification is not involved in the activation of pancreatic proenzymes by brush border enzymes in the duodenum. *Conjugation of ubiquitin to lysine residue* - **Ubiquitination** is a process that tags proteins for degradation by the proteasome or can regulate protein function and localization. - This is a mechanism for protein turnover and regulation, not for the activation of a proenzyme like trypsinogen.

Amino acid metabolism and disorders Flashcard 1 of 10

Question: S-adenosylmethionine (SAM) donates a CH3 group to anabolic pathways, forming _____

Answer: S-adenosylhomocysteine

Amino acid metabolism and disorders Flashcard 2 of 10

Question: Pyruvate dehydrogenase deficiency is characterized by _____ serum alanine starting at infancy

Answer: increased

Amino acid metabolism and disorders Flashcard 3 of 10

Question: Most disorders of the urea cycle require _____ as an essential amino acid, particularly during episodes of hyperammonemia

Answer: arginine

Amino acid metabolism and disorders Flashcard 4 of 10

Question: What vitamin acts as a cofactor for aminotransferase enzymes? _____

Answer: B6 (Pyridoxal phosphate)

Amino acid metabolism and disorders Flashcard 5 of 10

Question: Are the essential amino acids methionine, valine, and histidine ketogenic or glucogenic? _____

Answer: Glucogenic

Amino acid metabolism and disorders Flashcard 6 of 10

Question: _____ disease presents with vomiting, poor feeding, and urine that smells like maple syrup/burnt sugar

Answer: Maple syrup urine

Amino acid metabolism and disorders Flashcard 7 of 10

Question: Are the essential amino acids phenylalanine, isoleucine, threonine, tryptophan, and tyrosine ketogenic or glucogenic? _____

Answer: Both

Amino acid metabolism and disorders Flashcard 8 of 10

Question: What stainable protein is abundant in astrocytes?

Answer: GFAP

Amino acid metabolism and disorders Flashcard 9 of 10

Question: What enzyme converts pyruvate to alanine?

Answer: alanine aminotransferase (ALT)

Amino acid metabolism and disorders Flashcard 10 of 10

Question: myeloperoxidase

Answer: respiratory burst

Extra Information: H2O2HOClPMNs