Clinical scenario: Premature ageing | Normal intelligence | Pathogenesis
A 2-year-old boy is referred because of progressive growth failure despite adequate nutrition. He was born at term with normal birth weight and length. Over the past year, he has developed alopecia, loss of subcutaneous fat, a pinched nose, micrognathia, and tight skin over the extremities. His developmental milestones and cognition are normal. There is no family history of a similar disorder.
Genetic testing confirms Hutchinson-Gilford Progeria Syndrome (HGPS).
Which of the following molecular abnormalities is most directly responsible for the pathogenesis of this disorder?
A. Defective collagen type III synthesis
B. Expansion of CGG trinucleotide repeats
C. Failure of DNA mismatch repair
D. Persistent farnesylation of an abnormal lamin A protein
E. Telomerase deficiency causing premature telomere shortening
Correct answer & Explanation:
Correct Answer
D. Persistent farnesylation of an abnormal lamin A protein
Explanation
Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a de novo autosomal dominant mutation in the LMNA gene, most commonly c.1824C>T (p.G608G). Although this is a silent mutation, it activates a cryptic splice site, resulting in production of an abnormal lamin A protein known as progerin.
Unlike normal lamin A, progerin retains its farnesyl group because the cleavage site required for post-translational processing is absent. Persistent farnesylation causes abnormal attachment of progerin to the nuclear membrane, leading to:
- Distorted nuclear architecture
- Genomic instability
- Impaired DNA repair
- Premature cellular senescence
- Progressive vascular smooth muscle cell loss
These cellular abnormalities explain the characteristic phenotype of growth failure, lipodystrophy, alopecia, skeletal abnormalities, and accelerated atherosclerosis.
Why the other options are incorrect
A. Defective collagen type III synthesis
- Causes vascular Ehlers-Danlos syndrome, characterized by fragile blood vessels and hyperextensible tissues.
B. Expansion of CGG trinucleotide repeats
- Causes Fragile X syndrome.
C. Failure of DNA mismatch repair
- Seen in Lynch syndrome, not progeria.
E. Telomerase deficiency causing premature telomere shortening
- Associated with disorders such as dyskeratosis congenita, but not the primary mechanism of HGPS.
High-Yield MRCPCH Pearls
- Normal intelligence is preserved in HGPS.
- Children usually appear normal at birth; clinical features become evident during the first 1–2 years.
- The LMNA c.1824C>T mutation is the classic genetic defect tested in examinations.
- Progerin is an abnormal farnesylated lamin A protein.
- The leading cause of death is premature myocardial infarction or stroke due to accelerated atherosclerosis.
- Lonafarnib, a farnesyltransferase inhibitor, is the only approved disease-modifying therapy and improves survival.
