Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST

Abstract

Background: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype.

Objective: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST.

Methods: This study used a systematic cross-sectional analysis of clinical and molecular features.

Results: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation).

Conclusions: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.

Keywords: SPAST; cerebral palsy; childhood-onset movement disorders; hereditary spastic paraplegia; neurogenetics.

Figure 1.. Molecular and clinical spectrum of 40 patient with de novo SPAST variants.

(A) This cohort includes 40 patients with HSP-SPAST (SPG4) caused by pathogenic de novo variants in SPAST. The male to female ratio was 24:16. (B) The median (+95% confidence interval) and range for the age at onset of symptoms, age at genetic diagnosis and age at last follow up are shown. The median diagnostic delay (time between onset of symptoms and a molecular diagnosis) was 3.1 years (IQR:4.3). Most of the patients in this cohort are children (33/40). (C) Schematic of the spastin protein structure. Information on functional domains was adapted from Solowska et al. Coding impacts are depicted by colored points. Allele frequencies in this cohort are represented by the size of each point. All variants, except one, were missense variants, and 40% of the cohort (16/40) carries the c.1496G>A (p.Arg499His) variant. The lower panel shows CADD PHRED scores computed for all possible missense variants in SPAST (NM_014946.4) aligned to the linear protein structure. A generalized additive model was used to predict the tolerance for genetic variation across the protein (blue line). The recommended cut off value for deleteriousness (CADD PHRED = 20) is marked by a red line. (D) Developmental delay is a universal feature of patients with de novo SPAST variants and motor milestones are often prominently delayed. Bar graphs indicate the proportions of patients who achieved a given motor milestone. The median age at which each milestone was achieved is shown above the graph. (E) Level of ambulation at last follow up, measured on the 4-Stage Mobility Scale (1 = mild symptoms walking without an aid; 2 = walking without aid but unable to run; 3 = walking with aid; and 4 = wheelchair dependent). Most patients depend on walking aids or are wheelchair-dependent. The median age at which walking aids and/or wheelchair-dependency was reached is shown above the graph. (F) SPRS scores correlate with age as an indicator of disease duration. The SPRS ranges from 0 to 52 measuring speed of gait, stair climbing, quality of gait, arising from a chair, degree of leg spasticity, weakness, contractures, and bladder dysfunction, with higher scores indicating more severe disability. The black line indicates a linear regression model (R_adj² = 0.27, p= 0.0019). Spearman’s rank correlation analysis shows a positive correlation between age and motor function (r = 0.66, p< 0.0001). Patients with the p.Arg499His variant are highlighted in purple. (G) Longitudinal assessment of SPATAX disability stages (0 = no disability; 1 = no functional handicap but signs at examination; 2 = mild, able to run, 3 = moderate, unable to run, limited walking without aid; 4 = severe, walking with one stick; 5 = walking with two sticks or walker, 6 = unable to walk, requiring wheelchair; 7 = confined to bed (not shown)). A general trend towards higher scores, indicating greater motor disability, with increasing age becomes apparent using a mixed-effects linear regression model (R_m² = 0.64, R_c² = 0.64, p<0.0001). (H) Lower CPCHILD scores, indicating lower health-related quality of life, correlate with age as a surrogate for disease duration (R_adj²=0.35, p=0.009, r=−0.63, p=0.01). (F) Lower CPCHILD scores, indicating lower health-related quality of life, correlate with SPRS scores as an indicator for disease severity (R_adj²=0.26, p=0.04, r=−0.70, p<0.01). (G) Rating of importance for each item on the CPCHILD questionnaire. No items were rated below the threshold level of importance (2.0 = slightly important). Items relating to positioning, transferring, and mobility, communication and social interaction, and comfort and emotions, are, on average, considered the most important contributors to quality of life. Abbreviations: CPCHILD (Caregiver Priorities & Child Health Index of Life with Disabilities); IQR (interquartile range); SD (standard deviation); SPRS (Spastic Paraplegia Rating Scale); yr (years)