SPG 4 Denovo

Here’s what is currently known about the prevalence of HSP overall, SPG4 subtype, and the de novo p.Arg499His (R499H) mutation in SPAST:

1. Hereditary Spastic Paraplegia (HSP) – All Types

Global prevalence is estimated between 2 to 6 cases per 100,000 people, though some studies report up to ~9.6/100,000 depending on region and methodology  .

A pooled meta‐analysis estimated global prevalence at 3.6/100,000 (95% CI: ~2.0–5.3)  .

In the United States, HSP is classified as a rare disease (fewer than 200,000 affected individuals), which corresponds to a prevalence around less than 0.06% (~6/100,000)  .

2. SPG4 (HSP Type 4, caused by SPAST mutations)

Globally, SPG4 is the most common subtype. The same BMC model estimates its prevalence at ~0.90 per 100,000 population  .

SPG4 accounts for approximately 40–50% of dominant HSP cases, and roughly 25% of all HSP cases overall  .

The U.S.–specific model estimate: ~3,365 symptomatic SPG4 patients in the U.S.

Other sources cite worldwide SPG4 prevalence between 2–6 per 100,000, but that likely reflects overall HSP spectrum; subtype‐specific prevalence from modeling is ~0.9/100,000  .

3. De novo p.Arg499His (R499H) variant in SPAST

This is an ultra‑rare, early‑onset de novo form of SPG4, associated with rapid progression in childhood.

As of current knowledge, only ~22 individuals worldwide have been identified with this variant, based on patient registries  .

That corresponds to an extremely low prevalence (~22 cases globally; incidence unknown due to spontaneous mutation pattern).

No reliable U.S. or global prevalence/incidence data exist beyond these case counts—in numerical terms, prevalence <0.000005% (~1 in 20 million).

📋 Summary Table

Condition	Global Prevalence	U.S. Estimate
All HSP (all types)	2–6 per 100,000 (∼3.6/100,000)	< 200,000 people (≤6/100,000)
SPG4 subtype	~0.90 per 100,000	~3,365 SPG4 symptomatic individuals
De novo p.Arg499His (R499H) SPAST	~22 cases total worldwide (<1/100M)	Extremely rare; essentially anecdotal

✅ Final Take‑aways

HSP (all subtypes) affects roughly 3–4 people per 100,000 globally; in the U.S., likely under 200,000 total.

SPG4 (most common HSP subtype) prevalence: ~0.9/100,000 globally, translating to a few thousand U.S. cases.

De novo R499H SPAST variant: exceedingly rare (< 25 known cases worldwide), representing a tiny fraction of SPG4.