Expanding the Phenotypic Spectrum of SPG4: Autism Spectrum Disorder in Early-Onset and Complex SPAST-HSP and Case Study.

Researchers found a 4-year-old boy with autism and developmental delays who also had a rare genetic condition affecting movement (hereditary spastic paraplegia). He had changes in a gene called SPAST that usually causes leg weakness and stiffness, but in this case also appeared linked to his autism. This suggests that problems with this gene might cause autism in some children, especially those who also have early movement difficulties.

This case report describes a 4-year-old male with two novel de novo variants in the SPAST gene, presenting with early-onset hereditary spastic paraplegia (HSP) alongside severe autism spectrum disorder and global developmental delay. The SPAST gene encodes spastin, a protein crucial for neuronal connectivity and synaptic formation. While HSP typically manifests as progressive lower limb spasticity and weakness, this case demonstrates an expanded phenotype including ASD. The findings suggest that SPAST variants may contribute to neurodevelopmental disorders through disrupted neuronal connectivity mechanisms.

The authors recommend considering SPAST gene analysis in children presenting with ASD and early motor delays, even with subtle pyramidal signs, and advocate for comprehensive neuropsychiatric assessment in early-onset complex HSP cases.

Clinicians should consider SPAST gene analysis in children presenting with ASD accompanied by early motor delays, even with subtle motor signs. Comprehensive neuropsychiatric assessment may be warranted in early-onset complex HSP cases to identify concurrent neurodevelopmental features.

Single case report limits generalizability of findings. No functional studies confirm the pathogenic effects of the identified variants. Unclear whether the association between SPAST variants and ASD represents a consistent pattern or isolated occurrence.

Hereditary spastic paraplegias (HSPs) comprise a heterogenous spectrum of rare neurogenetic disorders predominantly characterized by progressive spasticity and weakness of the lower extremities. Among autosomal-dominant forms of HSP, molecular defects in thegene-particularly those associated with the SPG4 subtype-represent the most frequent genetic cause. SPAST encodes spastin, a microtubule-severing ATPase, crucial for cytoskeletal remodeling, neuronal connectivity, and intracellular trafficking. Disruption of spastin function can impair neurite outgrowth and synaptic formation, processes increasingly implicated in neurodevelopmental disorders (NDDs).

We conducted a comprehensive clinical, neurological, and dysmorphological evaluation of a 4-year-old male. Standardized neuropsychological assessments were administered. Whole-exome sequencing (WES) was performed to identify underlying genetic causes. EEG and 3T-brain MRI were also acquired.

The proband harbored two novel de novo heterozygous missense variants in cis of the SPAST gene, displaying the typical features of early-onset and complex HSP, in addition to global developmental delay and severe autism spectrum disorder (ASD), an underexplored manifestation in this rare genetic disorder. These findings broaden the clinical and mutational spectrum of SPG4, underscoring the importance of considering SPAST gene analysis in patients with ASD in the early years of life and early motor delay, even in the presence of only subtle pyramidal signs. We advocate for comprehensive neuropsychiatric assessment in the diagnostic pathway of early-onset complex HSP presentations and support further investigation into the role of spastin in neuronal connectivity.