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Beta-Thalassemia
- Patho/Etiology: Point mutations in the β-globin gene often create abnormal splice sites. This leads to aberrant splicing of pre-mRNA, causing reduced (β+) or absent (β0) synthesis of β-globin chains. The resulting excess of α-globin chains precipitates, causing ineffective erythropoiesis and hemolysis.
- Dx: Microcytic anemia, target cells. ↑ HbA2 (>3.5%) and ↑ HbF on hemoglobin electrophoresis are key findings.
- Mgmt (Major): Lifelong blood transfusions + iron chelation (e.g., Deferoxamine).
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Myotonic Dystrophy Type 1 (DM1)
- Patho/Etiology: Autosomal dominant disease from a CTG trinucleotide repeat expansion in the DMPK gene. The toxic RNA transcripts sequester the Muscleblind-like 1 (MBNL1) protein, a key splicing regulator. This leads to widespread mis-splicing of many pre-mRNAs, causing multisystemic symptoms.
- Clinical Presentation: Myotonia (inability to relax muscles, e.g., after handshake), progressive distal muscle weakness, cataracts, cardiac conduction defects, and “hatchet facies.”
- Buzzwords: Anticipation (disease worsens in subsequent generations).
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Spinal Muscular Atrophy (SMA)
- Patho/Etiology: Autosomal recessive disorder from deletion/mutation of the SMN1 gene. The body relies on the backup SMN2 gene, but its pre-mRNA is poorly spliced, leading to the skipping of exon 7. This produces a truncated, unstable SMN protein, causing degeneration of anterior horn cells in the spinal cord.
- Clinical Presentation: Symmetric proximal muscle weakness, hypotonia (“floppy baby”), and absent deep tendon reflexes.
- Mgmt: Nusinersen, an antisense oligonucleotide (ASO), corrects SMN2 splicing to increase functional SMN protein levels.
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Cystic Fibrosis (CF)
- Patho/Etiology: While many mutations affect protein folding (e.g., ΔF508), a subset (~10%) are splicing mutations in the CFTR gene. These mutations disrupt the correct reading of the gene’s instructions, leading to a reduced amount or total absence of functional CFTR protein.
- Clinical Presentation: Recurrent sinopulmonary infections (esp. Pseudomonas), pancreatic insufficiency, and infertility in males.
- Dx: Elevated sweat chloride test is the gold standard. Genetic testing confirms the mutation type.