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Zorluk: OrtaGenetic and Molecular Mechanisms

Parents bring their 5-year-old son to the physician for evaluation of delayed motor milestones and a waddling gait. When rising from the floor, he places his hands on his thighs and pushes upwards to stand. Physical examination demonstrates prominent proximal muscle weakness and bilaterally enlarged, firm calf muscles. The physician strongly suspects an underlying X-linked recessive neuromuscular disorder. Arrange the following diagnostic interventions in the most appropriate sequential order to definitively establish the diagnosis according to current guidelines.

  1. 1Measurement of serum creatine kinase (CK) level
  2. 2Multiplex ligation-dependent probe amplification (MLPA) of the DMD gene
  3. 3Next-generation sequencing of the entire DMD gene
  4. 4Muscle biopsy for dystrophin protein immunohistochemistry

Cevap

The correct diagnostic sequence begins with initial biochemical screening (serum CK), followed by targeted structural genetic testing for the most common defects (MLPA for large deletions/duplications). If negative, high-resolution genetic testing (gene sequencing) is performed. Finally, if all genetic testing is inconclusive, invasive tissue evaluation (muscle biopsy) is used.
The algorithm for diagnosing Duchenne muscular dystrophy requires a progression from the least invasive and most sensitive screening (CK level) to the most common genetic etiology (deletions/duplications via MLPA). If structural defects are absent, sequencing is performed to find point mutations. Muscle biopsy is the final, invasive alternative if genetics are unrevealing.

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1
Assess for biochemical evidence of generalized muscle breakdown.
Obtain a serum creatine kinase (CK) level.
It is a highly sensitive, rapid, and non-invasive initial screening test that will show massive elevations in Duchenne muscular dystrophy.
2
Perform first-line molecular diagnostic testing.
Order MLPA (or chromosomal microarray) to detect large structural variations.
Large deletions and duplications in the DMD gene account for the vast majority (roughly 70%) of cases and are easily identifiable with this technique.
3
Perform second-line molecular diagnostic testing if initial genetics are negative.
Order next-generation sequencing of the DMD gene.
Sequencing detects point mutations and small insertions/deletions that MLPA cannot identify, completing the genetic evaluation.
4
Proceed to invasive tissue sampling only if molecular tests fail.
Perform a muscle biopsy with immunohistochemistry.
Biopsy is definitive for absent dystrophin protein but is invasive; it is now reserved strictly for cases where genetic sequencing is non-diagnostic despite high clinical suspicion.

Anahtar Kavram

The stepwise diagnostic algorithm for Duchenne muscular dystrophy prioritizes non-invasive screening and targeted molecular genetic testing before invasive tissue biopsy.
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Genetic and Molecular Mechanisms

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