Spastic paraplegia type 3A (SPG3A) is the second most common form of hereditary spastic paraplegia (HSP). This autosomal-dominant-inherited motor disorder is caused by heterozygous variants in the ATL1 gene which usually presents as a pure childhood-onset spastic paraplegia. Affected individuals present muscle weakness and spasticity in the lower limbs, with symptom onset in the first decade of life. Individuals with SPG3A typically present a slow progression and remain ambulatory throughout their life. Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability). For 2 of the 3 patients, these phenotypes led to the initial diagnosis of cerebral palsy (CP). These individuals carried novel ATL1 pathogenic variants (a de novo ATL1 missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a homozygous missense variant (p.Tyr367His)). The parents carrying the heterozygous frameshift and missense variants were asymptomatic. Through these observations, we increase the knowledge on genotype-phenotype correlations in SPG3A and offer additional proof for possible autosomal recessive forms of SPG3A, while raising awareness on these exceptional phenotypes. Their ability to mimic CP also implies that genetic testing should be considered for patients with atypical forms of CP, given the implications for genetic counseling.

Spastic paraplegia 3A (SPG3A) has long been considered as an autosomal dominant disorder till the report in 2014 and 2016 of two consanguineous Arabic families, showing that ATL1 mutations may cause autosomal recessive paraplegia. Here, a third report of a consanguineous Arabic family with recessive SPG3A is described. Exome sequencing reveals homozygosity for a novel likely pathogenic ATL1 splice donor variant (c.522+1G>T) in an affected 5-year-old infant whereas the parents, heterozygous carriers, are asymptomatic. The infant's phenotype is consistent with an early onset complicated SPG3A with severe progressive spasticity of the lower limbs and intellectual disability.

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.

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by progressive dysfunction of corticospinal motor neurons. Mutations in Atlastin1/Spg3, a small GTPase required for membrane fusion in the endoplasmic reticulum, are responsible for 10% of HSPs. Patients with the same Atlastin1/Spg3 mutation present high variability in age at onset and severity, suggesting a fundamental role of the environment and genetic background. Here, we used a Drosophila model of HSPs to identify genetic modifiers of decreased locomotion associated with atlastin knockdown in motor neurons. First, we screened for genomic regions that modify the climbing performance or viability of flies expressing atl RNAi in motor neurons. We tested 364 deficiencies spanning chromosomes two and three and found 35 enhancer and four suppressor regions of the climbing phenotype. We found that candidate genomic regions can also rescue atlastin effects at synapse morphology, suggesting a role in developing or maintaining the neuromuscular junction. Motor neuron-specific knockdown of 84 genes spanning candidate regions of the second chromosome identified 48 genes required for climbing behavior in motor neurons and 7 for viability, mapping to 11 modifier regions. We found that atl interacts genetically with Su(z)2, a component of the Polycomb repressive complex 1, suggesting that epigenetic regulation plays a role in the variability of HSP-like phenotypes caused by atl alleles. Our results identify new candidate genes and epigenetic regulation as a mechanism modifying neuronal atl pathogenic phenotypes, providing new targets for clinical studies.

An increasing number of cases of comorbid hereditary spastic paraplegia (HSP) and multiple sclerosis (MS) have been described. We report a patient with the SPG3A form of HSP and features of relapsing-remitting MS (RRMS). We took this opportunity to review the current literature of co-occurring MS and HSP. The patient underwent clinical, laboratory and neuroimaging evaluations. We performed a literature search for cases of HSP and MS. The 2017 McDonalds Criteria for MS were retrospectively applied to the selected cases. A 34-year-old woman, presenting a molecular diagnosis of SPG3A, complained subacute sensory-motor symptoms. Spinal MRI disclosed T2-hyperintense lesions at C2, T6 and T4 level, the latter presenting contrast-enhancement. CSF analysis showed oligoclonal bands. She was treated with intravenous high-dose steroids, with symptom resolution. The literature review yielded 13 papers reporting 20 possible cases of MS and HSP. Nine patients (5 M, median age 34) met the 2017 McDonald criteria. Five (25%) received a diagnosis of RRMS and four (20%) of primary progressive MS. Brain MRI showed multiple WM lesions, mostly periventricular. Six of seven cases (85.7%) had spinal cord involvement. Oligoclonal bands were found in 6/8 (75%) patients. Seven patients (77.7%) improved/stabilized on immunotherapy. This is the first description on the association between SPG3A type of HSP and MS. This report adds to the other reported cases of co-occurring HSPs and MS. Although it remains unclear if this association is casual or causal, clinicians should be aware that an HSP diagnosis does not always exclude a concomitant MS.