A 38-year-old man presents with a 5-year history of progressive stiffness and weakness in both lower limbs. On examination, he has a scissor gait, brisk reflexes, bilateral ankle clonus, and extensor plantar responses. MRI brain and spine are normal. Genetic testing reveals a mutation in the SPAST gene. The inheritance pattern marked **B** in the diagram (Autosomal dominant SPAST/SPG4) accounts for what proportion of autosomal dominant hereditary spastic paraplegia cases?

Question

Accepted Answer

C. 40-45%. ## Why 40-45% is right

SPG4 (SPAST gene mutations) is the most common autosomal dominant form of hereditary spastic paraplegia, accounting for 40-45% of all AD-HSP cases. The SPAST gene encodes spastin, a microtubule-severing ATPase critical for axonal microtubule dynamics and maintenance of corticospinal tract integrity. This patient's clinical presentation (progressive lower limb spasticity, hyperreflexia, ankle clonus, bilateral Babinski signs, normal MRI, and SPAST mutation) is pathognomonic for SPG4/AD-HSP. Understanding the relative frequency of SPG4 among AD-HSP subtypes is essential for genetic counseling and anticipating disease course in Indian populations where HSP prevalence is 1-9 per 100,000.

## Why each distractor is wrong

- **25-30%**: This underestimates the true frequency of SPG4. While other AD forms (SPG3A, SPG31) exist, SPG4 remains the dominant subtype and accounts for nearly half of AD-HSP, not one-quarter.
- **60-70%**: This overestimates SPG4 frequency. Although AD-HSP comprises 70-80% of all HSP cases, SPG4 accounts for 40-45% of AD-HSP specifically, not 60-70%.
- **15-20%**: This significantly underestimates SPG4 prevalence. Such a low figure would place SPG4 among rare AD-HSP subtypes, contradicting its status as the most common form.

**High-Yield:** SPG4 (SPAST mutations) = 40-45% of AD-HSP; AD-HSP = 70-80% of all HSP; therefore SPG4 ≈ 30-35% of total HSP burden.

[cite: GeneReviews HSP 2024; Brain 2023]

Answer

A. 15-20%

Answer

B. 60-70%

Answer

D. 25-30%

Explanation

Why 40-45% is right

Why each distractor is wrong

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