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Zorluk: Çok zorPediatric Genetic and Metabolic Disorders

A 9-month-old boy is brought to the pediatric clinic by his parents due to progressive lethargy, poor feeding, and loss of motor milestones over the past two months. Previously, he was able to sit without support, but he now has pronounced head lag and generalized weakness. Physical examination reveals a pale, apathetic infant with generalized hypotonia and a smooth, erythematous tongue. There is no hepatosplenomegaly, and no dysmorphic facial features are noted.

Laboratory studies are obtained and reveal the following:

Laboratory TestResultReference Range
Hemoglobin8.2 g/dL10.5–13.5 g/dL
Mean corpuscular volume108 fL70–86 fL
Reticulocyte count0.5%0.5–1.5%
Vitamin B12 (cobalamin)450 pg/mL160–950 pg/mL
Folate12 ng/mL2.5–20.0 ng/mL
Homocysteine85 µmol/L5–15 µmol/L
Methylmalonic acid14.2 µmol/L0.0–0.4 µmol/L

Which of the following is the most likely primary underlying defect in this patient?

  1. Impaired intracellular reduction and processing of cobalaminCevap
  2. B
    Absent activity of methylmalonyl-CoA mutase
  3. C
    Decreased activity of cystathionine beta-synthase
  4. D
    Defective production of gastric intrinsic factor
  5. E
    Decreased activity of methylenetetrahydrofolate reductase

Cevap

The most likely underlying cause is an impaired intracellular reduction and processing of cobalamin, which prevents the formation of both active vitamin B12 coenzymes despite adequate serum B12 levels.
The correct answer describes a defect in the intracellular processing of vitamin B12 (cobalamin). Once vitamin B12 enters the target cells, it must be chemically reduced and processed to form two active coenzymes: methylcobalamin (required by methionine synthase to convert homocysteine to methionine) and adenosylcobalamin (required by methylmalonyl-CoA mutase to convert methylmalonyl-CoA to succinyl-CoA). An intracellular processing defect (such as cblC disease) prevents the synthesis of both coenzymes. This results in the accumulation of both homocysteine and methylmalonic acid, causing severe developmental regression, hypotonia, and megaloblastic anemia, even though the serum concentration of vitamin B12 is completely normal.

Adım Adım Çözüm

1
Analyze the complete blood count (CBC) and reticulocyte count.
The patient has a macrocytic anemia (high MCV, low hemoglobin) with an inappropriately low reticulocyte count, suggesting a megaloblastic process (typically folate or B12 dysfunction).
Identifying the mechanism of anemia narrows the differential to DNA synthesis defects, primarily involving the folate/B12 pathways.
2
Evaluate the serum vitamin levels.
Both serum vitamin B12 and folate levels are well within the normal reference ranges.
Normal serum levels rule out simple dietary deficiency, malabsorption (e.g., intrinsic factor deficiency), or transport defects in the gastrointestinal tract.
3
Interpret the specialized metabolic markers (homocysteine and methylmalonic acid).
Both plasma homocysteine and serum methylmalonic acid (MMA) are significantly elevated.
Elevated homocysteine indicates impaired methionine synthase activity (which requires methylcobalamin). Elevated MMA indicates impaired methylmalonyl-CoA mutase activity (which requires adenosylcobalamin).
4
Synthesize the biochemical data to identify the exact enzymatic block.
A defect upstream of both the methylcobalamin and adenosylcobalamin synthesis pathways is present inside the cell, despite adequate cobalamin in the blood.
This isolates the pathology to an intracellular cobalamin processing defect (most commonly the MMACHC gene mutation causing cblC disease), which presents in infancy with regression, hypotonia, and combined MMA/homocystinemia.

Anahtar Kavram

Intracellular cobalamin metabolism defects (e.g., cblC disease)
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Konular

Pediatric Genetic and Metabolic Disorders

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