Homocystinuria and methionine metabolism disorders US Medical PG Practice Questions and MCQs
Practice US Medical PG questions for Homocystinuria and methionine metabolism disorders. These multiple choice questions (MCQs) cover important concepts and help you prepare for your exams.
Homocystinuria and methionine metabolism 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
Homocystinuria and methionine metabolism 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.
Homocystinuria and methionine metabolism disorders US Medical PG Question 2: A 35-year-old woman comes to the physician because of a 1-day history of swelling and pain in the left leg. Two days ago, she returned from a business trip on a long-distance flight. She has alcohol use disorder. Physical examination shows a tender, swollen, and warm left calf. Serum studies show an increased homocysteine concentration and a methylmalonic acid concentration within the reference range. Further evaluation of this patient is most likely to show which of the following serum findings?
- A. Decreased cobalamin concentration
- B. Decreased protein C concentration
- C. Increased fibrinogen concentration
- D. Decreased folate concentration (Correct Answer)
- E. Increased pyridoxine concentration
Homocystinuria and methionine metabolism disorders Explanation: ***Decreased folate concentration***
- The patient's presentation with **pain and swelling in the left leg following a long flight** suggests a **deep vein thrombosis (DVT)**. Increased homocysteine levels are a risk factor for DVT.
- Alcohol use disorder often leads to **malabsorption and poor nutritional intake**, profoundly affecting **folate metabolism** and leading to **folate deficiency**. This deficiency is a common cause of **hyperhomocysteinemia**, especially when methylmalonic acid levels are normal (ruling out B12 deficiency as the primary cause of hyperhomocysteinemia).
*Decreased cobalamin concentration*
- While alcohol use disorder can decrease **cobalamin (vitamin B12) concentration**, the **normal methylmalonic acid (MMA) concentration** in this patient makes a significant B12 deficiency unlikely to be the cause of the elevated homocysteine.
- Elevated MMA is a more specific indicator of **cobalamin deficiency**, as B12 is a cofactor for the enzyme that converts methylmalonyl-CoA to succinyl-CoA.
*Decreased protein C concentration*
- Decreased protein C concentration is a **thrombophilic condition** that increases the risk of DVT, but there is no direct evidence in the patient's history or lab results pointing specifically to this deficiency.
- While hereditary thrombophilias can contribute, a **primary nutritional deficiency** explains the constellation of findings better in this context.
*Increased fibrinogen concentration*
- **Fibrinogen** is an **acute-phase reactant** and would likely be elevated in the context of inflammation or thrombosis, but it is not directly linked to the patient's hyperhomocysteinemia due to alcohol use disorder.
- Elevated fibrinogen is a **consequence** of the thrombotic process, not typically a direct cause of the hyperhomocysteinemia in this scenario.
*Increased pyridoxine concentration*
- **Pyridoxine (vitamin B6) levels** are generally not increased in individuals with alcohol use disorder; in fact, chronic alcohol abuse can lead to **pyridoxine deficiency**.
- Pyridoxine is a cofactor in homocysteine metabolism, and deficiency can lead to elevated homocysteine, but an *increase* is not expected.
Homocystinuria and methionine metabolism disorders US Medical PG Question 3: A 48-year-old woman is brought to the emergency department by police because of confusion and agitation. Her medical record indicates that she has peptic ulcer disease that is treated with omeprazole. The patient's brother arrives shortly after. He reports that she drinks around 17 oz. of vodka daily. Neurological examination shows horizontal nystagmus. Her gait is wide-based with small steps. Her hemoglobin concentration is 9.1 g/dL. A peripheral blood smear shows hypersegmented neutrophils. Homocysteine levels are elevated. Methylmalonic acid levels are within normal limits. Which of the following is the most likely direct cause of this patient's anemia?
- A. Vitamin E deficiency
- B. Vitamin B1 deficiency
- C. Folate deficiency (Correct Answer)
- D. Vitamin B12 deficiency
- E. Alcohol toxicity
Homocystinuria and methionine metabolism disorders Explanation: ***Folate deficiency***
- The combination of **anemia**, **hypersegmented neutrophils**, elevated **homocysteine**, and *normal methylmalonic acid* levels strongly points to folate deficiency.
- **Alcoholism** is a significant risk factor for folate deficiency due to poor nutritional intake and impaired folate absorption and metabolism.
*Vitamin E deficiency*
- This deficiency typically causes **neurological dysfunction** and **hemolytic anemia**, but it does not lead to hypersegmented neutrophils or elevated homocysteine.
- It is often seen in conditions causing **fat malabsorption**, which is not explicitly indicated as the primary driver here.
*Vitamin B1 deficiency*
- **Thiamine (B1) deficiency** is associated with **Wernicke-Korsakoff syndrome**, characterized by confusion, nystagmus, and ataxia, which are present in this patient.
- Although alcohol abuse causes thiamine deficiency, it does not explain the **megaloblastic anemia** with hypersegmented neutrophils evident in the peripheral blood smear.
*Vitamin B12 deficiency*
- Vitamin B12 deficiency also causes **megaloblastic anemia** and elevated **homocysteine** levels, but it would also present with **elevated methylmalonic acid (MMA)** levels, which are explicitly stated as normal here.
- The patient's use of omeprazole (a proton pump inhibitor) can contribute to B12 deficiency over time by reducing gastric acid necessary for B12 release from food proteins, but the MMA levels rule it out as the *direct cause* of anemia in this specific instance.
*Alcohol toxicity*
- While chronic alcohol abuse can lead to **anemia** through various mechanisms, including **bone marrow suppression** or **gastrointestinal bleeding**, it does not directly explain the specific findings of **hypersegmented neutrophils** and the particular pattern of homocysteine and methylmalonic acid levels.
- Alcohol toxicity is an underlying cause for other deficiencies, but not the direct cause of this specific type of anemia.
Homocystinuria and methionine metabolism disorders US Medical PG Question 4: A 43-year-old woman visits her primary care provider complaining of fatigue. Although she has had it for several months, her fatigue has been worsening over the past few weeks. She has no other symptoms. Past medical history is significant for hypertension. She takes chlorthalidone, an oral contraceptive pill, and a multivitamin every day. Family history is noncontributory. She drinks about 1 bottle of wine every day and started taking a shot or two of whisky or vodka every morning before work to “clear out the cobwebs”. She was recently fired from her job. Today, her heart rate is 90/min, respiratory rate is 17/min, blood pressure is 110/65 mm Hg, and temperature is 36.7°C (98.1°F). On physical exam, she appears malnourished and anxious. Her conjunctiva are pale, and glossitis is noted on oral exam. Her heart has a regular rate and rhythm and her lungs are clear to auscultation bilaterally. She has no gait or balance abnormalities. Lab results show a hemoglobin of 10 g/dL, with a mean corpuscular volume (MCV) of 108 fl. Elevated level of which of the following will most likely to be found in this patient?
- A. Methionine
- B. Phenylalanine
- C. Cysteine
- D. Homocysteine
- E. Methylmalonic acid (Correct Answer)
Homocystinuria and methionine metabolism disorders Explanation: ***Methylmalonic acid***
- The patient's presentation with **macrocytic anemia** (MCV 108 fl, Hb 10 g/dL), **glossitis**, and **fatigue** suggests a **vitamin B12 deficiency**.
- **Elevated methylmalonic acid (MMA)** is a sensitive and specific marker for **vitamin B12 deficiency**, as **B12** acts as a cofactor for the enzyme **methylmalonyl-CoA mutase**, which converts MMA to succinyl-CoA.
*Methionine*
- **Methionine** is an essential amino acid, and its levels are not directly elevated in **vitamin B12 deficiency**; rather, **B12** is involved in the conversion of **homocysteine to methionine**.
- In **B12 deficiency**, the conversion of **homocysteine to methionine** is impaired, leading to **elevated homocysteine**, not necessarily methionine.
*Phenylalanine*
- **Phenylalanine** is an essential amino acid whose metabolism is primarily linked to **phenylketonuria (PKU)** if its levels are elevated due to deficient **phenylalanine hydroxylase**, which is unrelated to **vitamin B12 deficiency**.
- Elevated phenylalanine would not be an expected finding in this patient's clinical scenario.
*Cysteine*
- **Cysteine** is a non-essential amino acid, and its levels are not typically elevated as a direct consequence or marker of **vitamin B12 deficiency**.
- While involved in various metabolic pathways, it doesn't serve as a diagnostic indicator for B12 status.
*Homocysteine*
- While **homocysteine levels are elevated in vitamin B12 deficiency**, as B12 is a cofactor for **methionine synthase**, which converts homocysteine to methionine, **methylmalonic acid** is a more specific marker for **B12 deficiency**.
- **Elevated homocysteine** can also be caused by **folate deficiency** or **vitamin B6 deficiency**, making it less specific than **MMA** for isolating B12 deficiency.
Homocystinuria and methionine metabolism disorders US Medical PG Question 5: A 6-year-old boy is brought to the office by his mother. She reports that her son is well but has some concerns about his overall health: he is shorter and, physically, seems less developed compared to his siblings when they were the same age. He recently started school and the mother reports that the boy’s teachers are concerned with his learning capability. His height and weight are in the 10th and 15th percentiles, respectively. Lab results reveal:
Hemoglobin 10 gm/dL
Mean corpuscular volume 110 fL
Multi-segmented neutrophils are seen on peripheral blood smear. Urinary orotic acid levels are found to be high. What is the most likely cause of this patient’s condition?
- A. Deficiency of cobalamin
- B. Inhibition of carbamoyl phosphate synthetase II
- C. Deficiency of uridine monophosphate synthase (Correct Answer)
- D. Activation of inosine monophosphate dehydrogenase
- E. Overactivity of uridine monophosphate synthase
Homocystinuria and methionine metabolism disorders Explanation: ***Deficiency of uridine monophosphate synthase***
- The patient presents with **macrocytic anemia** (low hemoglobin, high MCV) and features of **orotic aciduria** (developmental delay, growth retardation, high urinary orotic acid).
- **Uridine monophosphate synthase** is a bifunctional enzyme containing both **orotate phosphoribosyltransferase** and **OMP decarboxylase** activities, whose deficiency leads to the buildup of orotic acid and impaired **pyrimidine synthesis**.
*Deficiency of cobalamin*
- **Cobalamin deficiency** causes **macrocytic anemia** and elevated **mean corpuscular volume** (MCV), but it does not lead to elevated urinary orotic acid levels.
- This deficiency is also associated with **neurological symptoms** (paresthesias, subacute combined degeneration) which are not the primary concern here.
*Inhibition of carbamoyl phosphate synthetase II*
- **Carbamoyl phosphate synthetase II** catalyzes the first committed step of **pyrimidine synthesis**, forming carbamoyl phosphate from glutamine and CO2.
- Deficiency of CPS II would block pyrimidine synthesis at an early step, preventing orotic acid formation rather than causing its accumulation, and would not present with **elevated urinary orotic acid**.
- This is distinct from **ornithine transcarbamylase deficiency** (a urea cycle disorder) which does cause orotic aciduria through a different mechanism.
*Activation of inosine monophosphate dehydrogenase*
- **Inosine monophosphate dehydrogenase** is involved in **purine synthesis**, not pyrimidine synthesis, and its activation would not lead to **elevated orotic acid** or the described symptoms of orotic aciduria.
- The use of **mycophenolate mofetil**, an IMPDH inhibitor, is known to cause myelosuppression, but this is an exogenous effect, not a primary metabolic disorder.
*Overactivity of uridine monophosphate synthase*
- **Overactivity of uridine monophosphate synthase** would enhance **pyrimidine synthesis**, leading to *lower* rather than *higher* levels of **orotic acid**.
- This would not cause the symptoms of **orotic aciduria** or **macrocytic anemia** seen in the patient.
Homocystinuria and methionine metabolism disorders US Medical PG Question 6: A 4-year-old boy presents to the ophthalmologist for a down- and inward dislocation of the lens in his left eye. On physical exam, the boy has a marfanoid habitus and intellectual disability. Biochemical tests were performed to locate the exact defect in this boy. It was found that there was a significant deficiency in cystathionine beta-synthase activity with elevated homocysteine levels. Which of the following is the diagnosis?
- A. Marfan syndrome
- B. Homocystinuria (Correct Answer)
- C. Alkaptonuria
- D. Phenylketonuria
- E. Maple syrup urine disease
Homocystinuria and methionine metabolism disorders Explanation: ***Homocystinuria***
- The combination of **ectopia lentis** (lens dislocation), **marfanoid habitus**, and **intellectual disability** is characteristic of homocystinuria.
- The **deficiency in cystathionine beta-synthase** leading to **elevated homocysteine levels** is the biochemical hallmark of this disorder.
*Marfan syndrome*
- While it presents with **marfanoid habitus** and **ectopia lentis**, the lens dislocation is typically **upward and outward**, unlike the down- and inward dislocation seen here.
- Marfan syndrome is caused by a defect in **fibrillin-1**, and biochemical tests would not show elevated homocysteine.
*Alkaptonuria*
- This disorder is characterized by **dark urine** upon standing, **ochronosis** (darkening of cartilage and connective tissue), and **arthropathy**.
- It results from a deficiency in **homogentisate oxidase** and does not present with lens dislocation or intellectual disability.
*Phenylketonuria*
- PKU is caused by a deficiency in **phenylalanine hydroxylase**, leading to an accumulation of phenylalanine.
- It primarily causes **severe intellectual disability**, seizures, and a musty odor, but not ectopia lentis or marfanoid habitus.
*Maple syrup urine disease*
- This is a metabolic disorder affecting the metabolism of **branched-chain amino acids** (leucine, isoleucine, valine).
- It presents with a characteristic **maple syrup odor** in urine, poor feeding, lethargy, and developmental delay, but not the specific features seen in this case.
Homocystinuria and methionine metabolism disorders US Medical PG Question 7: A 38-year-old, working, first-time mother brings her 9-month-old male infant to the pediatrician for "wounds that simply won't heal" and bleeding gums. She exclaims, "I have been extra careful with him making sure to not let him get dirty, I boil his baby formula for 15 minutes each morning before I leave for work to give to the caregiver, and he has gotten all of his vaccinations." This infant is deficient in a molecule that is also an essential co-factor for which of the following reactions?
- A. Conversion of homocysteine to methionine
- B. Conversion of alpha ketoglutarate to succinyl-CoA
- C. Conversion of dopamine to norepinephrine (Correct Answer)
- D. Conversion of pyruvate to acetyl-CoA
- E. Conversion of pyruvate to oxaloacetate
Homocystinuria and methionine metabolism disorders Explanation: ***Conversion of dopamine to norepinephrine***
- The infant's symptoms of "wounds that simply won't heal" and **bleeding gums** are classic signs of **scurvy**, caused by a deficiency in **vitamin C (ascorbic acid)**.
- **Vitamin C** is an essential cofactor for **dopamine beta-hydroxylase**, the enzyme responsible for converting **dopamine to norepinephrine**.
*Conversion of homocysteine to methionine*
- This reaction is catalyzed by **methionine synthase**, which requires **vitamin B12** (cobalamin) and **folate (vitamin B9)** as cofactors.
- Deficiency in these vitamins would lead to **megaloblastic anemia** and neurological symptoms, not delayed wound healing and bleeding gums.
*Conversion of alpha ketoglutarate to succinyl-CoA*
- This step in the **Krebs cycle** is catalyzed by **alpha-ketoglutarate dehydrogenase**, which requires **thiamine (vitamin B1)**, **lipoic acid**, **Mg2+**, **NAD+**, and **FAD** as cofactors.
- Thiamine deficiency can cause **beriberi** or **Wernicke-Korsakoff syndrome**, not scurvy symptoms.
*Conversion of pyruvate to acetyl-CoA*
- This reaction is catalyzed by the **pyruvate dehydrogenase complex**, which requires **thiamine (vitamin B1)**, **lipoic acid**, **coenzyme A**, **FAD**, and **NAD+** as cofactors.
- A deficiency in any of these, particularly thiamine, leads to impaired carbohydrate metabolism and lactic acidosis.
*Conversion of pyruvate to oxaloacetate*
- This reaction is catalyzed by **pyruvate carboxylase**, which requires **biotin (vitamin B7)** as a cofactor and is essential for **gluconeogenesis**.
- Biotin deficiency is rare and can present with dermatitis, hair loss, and neurological symptoms, not the classic signs of scurvy.
Homocystinuria and methionine metabolism disorders US Medical PG Question 8: A 4-year-old boy is brought to the physician for a well-child examination. He started walking at 20 months of age. He can use a cup to drink but cannot use silverware. He speaks in 2-word sentences and can build a tower of 4 blocks. He can scribble but cannot draw a circle. He is above the 99th percentile for height and at the 15th percentile for weight. Vital signs are within normal limits. Examination shows bilateral inferior lens dislocation. His fingers are long and slender. He has a high-arched palate. The thumb and 5th finger overlap when he grips a wrist with the opposite hand. The skin over the neck can be extended and stretched easily. Which of the following is the most likely cause of these findings?
- A. Hypoxanthine-guanine-phosphoribosyl transferase deficiency
- B. Galactokinase deficiency
- C. Fibrillin 1 deficiency
- D. Cystathionine synthase deficiency (Correct Answer)
- E. Type V collagen deficiency
Homocystinuria and methionine metabolism disorders Explanation: ***Cystathionine synthase deficiency***
- The combination of **inferior lens dislocation**, **marfanoid habitus** (tall stature, long slender fingers, high-arched palate), **developmental delay** (late walking, speech delay), and **hyperelastic skin** is highly suggestive of **homocystinuria** due to cystathionine synthase deficiency.
- **Homocystinuria** is an autosomal recessive disorder causing accumulation of **homocysteine**, leading to multisystem involvement.
*Hypoxanthine-guanine-phosphoribosyl transferase deficiency*
- This deficiency causes **Lesch-Nyhan syndrome**, characterized by **gout, intellectual disability, choreoathetosis, and self-mutilation**.
- It does not present with lens dislocation or marfanoid features.
*Galactokinase deficiency*
- This is a rare form of **galactosemia** primarily causing **cataracts**.
- It does not explain the developmental delay, marfanoid features, or lens dislocation.
*Fibrillin 1 deficiency*
- This causes **Marfan syndrome**, which shares features like **tall stature, long slender fingers, high-arched palate, and lens dislocation**.
- However, in Marfan syndrome, lens dislocation is typically **superior**, while in this case, it is **inferior**, pointing towards homocystinuria.
*Type V collagen deficiency*
- This can be associated with **Ehlers-Danlos syndrome**, which features **hyperelastic skin** and joint hypermobility.
- However, it does not typically cause lens dislocation or the specific marfanoid habitus described, and developmental delay is not a primary feature.
Homocystinuria and methionine metabolism disorders US Medical PG Question 9: A 9-year-old girl is brought to the emergency department for sudden-onset slurring of speech and weakness of her right arm and leg. She has a mild intellectual disability. She is at the 10th percentile for weight and at the 85th percentile for height. Physical examination shows bilateral inferonasal subluxation of the lens and a high-arched palate. Her fingers are long and slender. Neurological examination shows an extensor plantar response on the left. This patient is most likely to respond to treatment with which of the following?
- A. Supplementation of vitamin B6 (Correct Answer)
- B. Restriction of phenylalanine
- C. Restriction of cysteine
- D. Alkalinization of urine
- E. Supplementation of methionine
Homocystinuria and methionine metabolism disorders Explanation: ***Supplementation of vitamin B6***
- The patient's presentation with **sudden-onset neurological symptoms** (slurred speech, right-sided weakness), **marfanoid habitus** (tall stature, long slender fingers, high-arched palate), **mild intellectual disability**, and **bilateral inferonasal lens subluxation** is highly suggestive of **homocystinuria**.
- Many cases of homocystinuria, specifically those caused by cystathionine beta-synthase deficiency, are **pyridoxine (vitamin B6) responsive**, meaning clinical symptoms and homocysteine levels can improve with B6 supplementation.
*Restriction of phenylalanine*
- This is the primary treatment for **phenylketonuria (PKU)**, a genetic disorder characterized by intellectual disability, seizures, and a distinctive musty odor, none of which fully align with this patient's presentation.
- While PKU can cause intellectual disability, the marfanoid features and lens subluxation are not typical findings.
*Restriction of cysteine*
- Cysteine is an essential amino acid in individuals with homocystinuria because the metabolic pathway to synthesize it from methionine is impaired; therefore, **cysteine restriction is inappropriate** and would exacerbate the deficiency.
- In homocystinuria, dietary management usually involves **methionine restriction** and **cysteine supplementation** (along with B6).
*Alkalinization of urine*
- **Urine alkalinization** is primarily used to prevent the formation of certain types of kidney stones (e.g., uric acid, cystine) or to enhance the excretion of certain drugs.
- It has no direct role in the treatment of homocystinuria or its neurological and skeletal manifestations.
*Supplementation of methionine*
- Methionine is a precursor to homocysteine; therefore, **methionine supplementation would worsen homocystinuria** by increasing homocysteine levels.
- Treatment for homocystinuria often includes **restriction of dietary methionine** to reduce the production of homocysteine.
Homocystinuria and methionine metabolism disorders US Medical PG Question 10: A 7-year-old boy is brought to the physician for evaluation of developmental delay and intellectual disability. He has been admitted to the hospital twice in the past 6 months because of a cerebral venous thrombosis and a pulmonary embolism, respectively. He is at 10th percentile for weight and 95th percentile for height. Physical examination shows bilateral downward and inward subluxation of the lenses. He has a high-arched palate and kyphosis. Laboratory studies show increased serum concentration of 5-methyltetrahydrofolate. Which of the following additional findings is most likely in this patient's serum?
- A. Decreased methionine concentration (Correct Answer)
- B. Increased propionyl-CoA concentration
- C. Increased S-adenosylhomocysteine concentration
- D. Decreased cystathionine concentration
- E. Decreased cysteine concentration
Homocystinuria and methionine metabolism disorders Explanation: ***Decreased methionine concentration***
- The patient presents with **homocystinuria**, evidenced by developmental delay, intellectual disability, marfanoid habitus (tall stature, high-arched palate, kyphosis), **downward/inward lens subluxation**, and recurrent **thromboembolic events**.
- The key diagnostic finding is **increased serum 5-methyltetrahydrofolate (5-MTHF)**, which indicates a defect in **methionine synthase** or **cobalamin (vitamin B12) metabolism**, NOT MTHFR deficiency.
- **Methionine synthase** uses 5-MTHF as a methyl donor to convert homocysteine to methionine. When this enzyme is deficient (or cobalamin cofactor is unavailable), 5-MTHF accumulates (**methyl-trap hypothesis**), homocysteine increases, and **methionine decreases**.
- This biochemical pattern (↑ homocysteine, ↓ methionine, ↑ 5-MTHF) distinguishes methionine synthase deficiency from the more common **CBS deficiency**, which would show ↑ homocysteine, normal/↑ methionine, and normal/↓ 5-MTHF.
*Increased propionyl-CoA concentration*
- Elevated **propionyl-CoA** is characteristic of **propionic acidemia** (propionyl-CoA carboxylase deficiency) or **methylmalonic acidemia**.
- These organic acidemias present with metabolic acidosis, ketosis, hyperammonemia, and developmental delay, but do NOT cause recurrent thromboembolism, lens subluxation, or elevated 5-MTHF.
*Increased S-adenosylhomocysteine concentration*
- **S-adenosylhomocysteine (SAH)** accumulates when homocysteine clearance is impaired, as SAH is hydrolyzed to homocysteine and adenosine.
- While SAH may be elevated in this patient, it is a **secondary consequence** of elevated homocysteine rather than a primary diagnostic finding. The question asks for the "most likely" additional finding that helps establish the specific enzymatic defect.
*Decreased cystathionine concentration*
- **Cystathionine** is an intermediate in the **transsulfuration pathway** (homocysteine → cystathionine → cysteine) catalyzed by **cystathionine β-synthase (CBS)**.
- In **CBS deficiency** (the most common cause of homocystinuria), cystathionine would be decreased because the enzyme forming it is deficient.
- However, in **methionine synthase deficiency** (indicated by ↑ 5-MTHF), the transsulfuration pathway remains intact, so cystathionine levels would be normal or even increased as homocysteine is shunted through this alternative pathway.
*Decreased cysteine concentration*
- **Cysteine** is the end product of the transsulfuration pathway.
- Decreased cysteine is characteristic of **CBS deficiency**, where cysteine becomes a conditionally essential amino acid.
- In **methionine synthase deficiency**, the transsulfuration pathway (CBS and cystathionine γ-lyase) remains functional, so cysteine production continues normally or may even be increased due to excess homocysteine being directed through this pathway. Therefore, cysteine would NOT be decreased in this patient.
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