OTC Deficiency vs Orotic Aciduria Flashcards
A 3-day-old male presents with lethargy, vomiting, and poor feeding. On examination, the infant appears irritable with no dysmorphic features. Laboratory findings show hyperammonemia (>150 μmol/L), elevated orotic acid in urine, decreased BUN, and normal blood glucose and ketone levels. Genetic testing confirms an X-linked inheritance pattern. Which of the following is the most likely cause of these findings?
A) Deficiency of carbamoyl phosphate synthetase I
B) Deficiency of ornithine transcarbamylase
C) Deficiency of argininosuccinate synthetase
D) Deficiency of arginase
E) Deficiency of uridine monophosphate synthase
Answer: Deficiency of ornithine transcarbamylase
Explanation: Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder and is inherited in an X-linked recessive pattern. It results in the inability to convert carbamoyl phosphate and ornithine into citrulline, leading to hyperammonemia and increased orotic acid (due to carbamoyl phosphate shunting into pyrimidine synthesis). This condition presents with lethargy, vomiting, and poor feeding, typically within the first few days of life. The absence of megaloblastic anemia differentiates OTC deficiency from orotic aciduria.
Incorrect Answers:
A) Carbamoyl phosphate synthetase I deficiency also causes hyperammonemia but does not lead to orotic aciduria.
C) Argininosuccinate synthetase deficiency (citrullinemia) presents with elevated citrulline, not orotic acid.
D) Arginase deficiency leads to elevated arginine and spasticity, not orotic aciduria or neonatal hyperammonemia.
E) Uridine monophosphate synthase deficiency (orotic aciduria) causes megaloblastic anemia and does not lead to hyperammonemia.
A 4-year-old girl is brought to the pediatrician due to fatigue and poor growth. Her parents report a history of developmental delay and frequent illnesses. Physical examination reveals pallor and no hepatosplenomegaly. Laboratory studies show a hemoglobin level of 7.8 g/dL, mean corpuscular volume (MCV) of 110 fL, and low reticulocyte count. Serum ammonia levels are normal. Urinalysis reveals the presence of orotic acid crystals. Which of the following is the most likely underlying defect in this patient?
A) Deficiency of ornithine transcarbamylase
B) Deficiency of uridine monophosphate (UMP) synthase
C) Deficiency of argininosuccinate synthetase
D) Deficiency of glucose-6-phosphatase
E) Deficiency of folate
Answer: Deficiency of uridine monophosphate (UMP) synthase
Explanation: Orotic aciduria is an autosomal recessive disorder caused by a defect in UMP synthase, an enzyme involved in pyrimidine synthesis. This condition presents with megaloblastic anemia that does not improve with folate or vitamin B12 supplementation, failure to thrive, developmental delay, and excretion of orotic acid crystals in the urine. The absence of hyperammonemia differentiates it from Ornithine Transcarbamylase (OTC) deficiency. Treatment includes uridine monophosphate supplementation to bypass the metabolic block.
Incorrect Answers:
A) OTC deficiency causes hyperammonemia and orotic aciduria but does not result in megaloblastic anemia.
C) Argininosuccinate synthetase deficiency presents with hyperammonemia and elevated citrulline, not megaloblastic anemia.
D) Glucose-6-phosphatase deficiency (Von Gierke disease) leads to fasting hypoglycemia and hepatomegaly, not megaloblastic anemia.
E) Folate deficiency causes megaloblastic anemia but would not result in orotic aciduria or the presence of orotic acid crystals.
What is the inheritance pattern of Ornithine Transcarbamylase (OTC) Deficiency?
X-linked recessive (in contrast to other urea cycle disorders, which are autosomal recessive)
What is the primary defect in OTC Deficiency?
Most common urea cycle disorder.
Defect in the enzyme ornithine transcarbamylase, leading to impaired conversion of carbamoyl phosphate and ornithine to citrulline.
Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway; vs. carbamoyl phosphate synthetase I deficiency).
What is the main consequence of the enzyme defect in OTC Deficiency?
Accumulation of ammonia (hyperammonemia) and conversion of excess carbamoyl phosphate to orotic acid
What clinical features are commonly seen in OTC Deficiency?
Nausea, vomiting, irritability, poor feeding, delayed growth, cognitive impairment, recurrent infections, metabolic encephalopathy with coma in severe cases, facial dysmorphia, congenital ureteric or heart defects, crystals in the urine causing your urethral obstruction.
What is the characteristic laboratory finding in OTC Deficiency?
- Hyperammonemia (>100 μmol/L)
- Elevated orotic acid in urine and blood
- Low BUN
- Increased carbamoyl phosphate
- Decreased citrulline in serum.
- Hematology: NO megaloblastic anemia.
How does OTC Deficiency differ from orotic aciduria?
OTC Deficiency does not cause megaloblastic anemia, unlike orotic aciduria
What diagnostic tests are used to confirm OTC Deficiency?
- Hyperammonemia
- Elevated orotic acid
- Enzyme analysis of OTC activity
What are the key components of treatment for OTC Deficiency?
Low-protein diet, nitrogen scavengers (e.g., sodium benzoate), arginine supplementation, fluid management, and dialysis in severe cases
What enzyme deficiency causes Orotic Aciduria?
Deficiency of uridine monophosphate (UMP) synthase.
Inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) because of defect in UMP synthase.
What is the mode of inheritance for Orotic Aciduria?
Autosomal recessive
What are the key clinical features of Orotic Aciduria?
- Failure to thrive
- Faltering growth
- Developmental delay
- Megaloblastic anemia
- Excretion of orotic acid crystals in urine
How does Orotic Aciduria differ from Ornithine Transcarbamylase (OTC) Deficiency?
Orotic Aciduria causes megaloblastic anemia, which is not seen in OTC deficiency. This form of megaloblastic anemia not respond to folate and vitamin B12 supplementation.
Hyperammonemia is absent in Orotic Aciduria.
What is the main diagnostic finding in Orotic Aciduria?
- Elevated orotic acid in the urine
- Normal ammonia and BUN levels
- Megaloblastic anemia
