De novovariants cause complex symptoms in HSP-ATL1(SPG3A) and uncover genotype–phenotype correlations

Abstract

Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly ‘pure’ HSP phenotype. Although a relatively large number of patients have been reported, no genotype–phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster. Establishing genotype–phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.

Clinical and Genetic Spectrum in a Large Cohort of Hereditary Spastic Paraplegia

“…The difference in the frequency of exon 1 involvement may explain the discrepancy between our and other studies. Interestingly, we observed that rearrangement‐related SPG3A patients had onset after puberty (33.60 ± 11.28 years), seemingly inconsistent with the common sense that SPG3A is almost exclusively early onset 37‐39 . A reanalysis of 51 reported studies showed that 84.79% SPG3A patients exhibited early AAO (<10 years), whereas 15.21% SPG3A patients had a later AAO (>10 years), and no significant difference was found among different mutation types (missense and small insertion/deletion) 40 .…”

“…Interestingly, we observed that rearrangement-related SPG3A patients had onset after puberty (33.60 AE 11.28 years), seemingly inconsistent with the common sense that SPG3A is almost exclusively early onset. [37][38][39] A reanalysis of 51 reported studies showed that 84.79% SPG3A patients exhibited early AAO (<10 years), whereas 15.21% SPG3A patients had a later AAO (>10 years), and no significant difference was found among different mutation types (missense and small insertion/deletion). 40 Whether rearrangement mutations correlate with late onset and the underlying mechanisms necessitates further studies.…”

Reply to: Early‐Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST

“…The case presented by Damásio et al highlights the important notion that atypical symptoms, including ataxia and other cerebellar signs, can precede pyramidal signs in children with complex HSP. This has been noted in multiple cases and cohorts of autosomal dominant 2,3 and recessive forms, 4,5 and it underscores the phenotypic pleiotropy seen in HSP. These findings demonstrate the importance of careful phenotyping through longitudinal natural history studies.…”

Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4‐Related Hereditary Spastic Paraplegia

“…Our findings highlight the important role of comprehensive phenotyping when evaluating potential biomarkers and the need to include matched controls, particularly in the pediatric age group. The former is particularly relevant for neurological disorders with profound phenotypic pleiotropy, such as HSP 25‐28 . Our study provides a data set that adds to the few available data for pNfL in neurologically healthy children 29‐33 .…”

“…The former is particularly relevant for neurological disorders with profound phenotypic pleiotropy, such as HSP. [25][26][27][28] Our study provides a data set that adds to the few available data for pNfL in neurologically healthy children. [29][30][31][32][33] In summary, by establishing a baseline of elevated pNfL levels in patients with AP-4-HSP, this first crosssectional study provides the basis for future longitudinal measurement of pNfL, which will help determine whether pNfL is a prognostic biomarker sensitive to disease progression and disease modifying intervention.…”