An integrated modelling methodology for estimating global incidence and prevalence of hereditary spastic paraplegia subtypes SPG4, SPG7, SPG11, and SPG15

Abstract

Background: Hereditary spastic paraplegias (HSPs) are progressively debilitating neurodegenerative disorders that follow heterogenous patterns of Mendelian inheritance. Available epidemiological evidence provides limited incidence and prevalence data, especially at the genetic subtype level, preventing a realistic estimation of the true social burden of the disease. The objectives of this study were to (1) review the literature on epidemiology of HSPs; and (2) develop an epidemiological model of the prevalence of HSP, focusing on four common HSP genetic subtypes at the country and region-level.

Methods: A model was constructed estimating the incidence at birth, survival, and prevalence of four genetic subtypes of HSP based on the most appropriate published literature. The key model parameters were assessed by HSP clinical experts, who provided feedback on the validity of assumptions. A model was then finalized and validated through comparison of outputs against available evidence. The global, regional, and national prevalence and patient pool were calculated per geographic region and per genetic subtype.

Results: The HSP global prevalence was estimated to be 3.6 per 100,000 for all HSP forms, whilst the estimated global prevalence per genetic subtype was 0.90 (SPG4), 0.22 (SPG7), 0.34 (SPG11), and 0.13 (SPG15), respectively. This equates to an estimated 3365 (SPG4) and 872 (SPG11) symptomatic patients, respectively, in the USA.

Conclusions: This is the first epidemiological model of HSP prevalence at the genetic subtype-level reported at multiple geographic levels. This study offers additional data to better capture the burden of illness due to mutations in common genes causing HSP, that can inform public health policy and healthcare service planning, especially in regions with higher estimated prevalence of HSP.

Keywords: Epidemiological model; Epidemiology; Hereditary spastic paraplegia; Incidence; Prevalence.

Fig. 1

Model Logic Flow. Schematic overview of the methodology to estimate key measures. Step 1: collect information on incidence ratio and average years lived. Step 2: determine prevalence per country/region and disease type. Step 3: using additional population data, determine the patient pool per country/region and disease type. Step 4: estimate the patient pool per genetic subtype and age group for each country/region. Step 5: sample data visualizations of results from key countries and regions

Fig. 2

Reported population-based prevalence. a Prevalence of Sporadic, AD, AR, and all HSP cases per 100,000 in Ortega Suero et al. 2021, and in key studies assessed in Ruano et al. 2014. Total population assessed, and number of HSP cases are represented on the right. b Reported SPG4 and SPG11 prevalence per 100,000 in Estonia, Norway and Portugal based on detailed genetic analysis. Total population assessed and number of HSP cases, divided by SPG4 and SPG11, are reported on the right. c Reported proportion of SPG4 and SPG11 in all HSP in selected studies

Fig. 3

Reported age-related prevalence of HSP. a Reported age-related prevalence of all HSP cases per 100.000, based on three studies from Italy, Estonia and Norway. Total population and number of HSP cases identified are reported on the right. b Reported average ages at onset in years of SPG4 and in SPG11, based on studies from Hungary, Germany, Portugal Greece, Italy, Canada, and in a worldwide review

Fig. 4

Modelled survival curves across countries. Survival curves for high- (a), upper middle-(b), lower middle-(c), and low-income (d) countries, based on UN income level. Red: general population, SPG4 and SPG7; blue: SPG11 and SPG15

Fig. 5

Worldwide distribution of symptomatic patients per genetic subtype. Worldwide estimated distribution of SPG4 (a), SPG11 (b), SPG7 (c), and SPG15 (d) symptomatic patients, divided by UN regions: Sub-Saharan Africa, Northern Africa and Western Asia, Central and Southern Asia, Eastern and South-Eastern Asia, Latin America and The Caribbean, Australia/New Zealand, Oceania (no Australia and New Zealand), Europe, and Northern America

Fig. 6

Modelled symptomatic and pre-symptomatic patient pool per country of interest, and per HSP genetic subtype. SPG4 (a), SPG11 (b), SPG7 (c), and SPG15 (d). Pre-symptomatic (black) and symptomatic (green) populations are highlighted