Analysis of spastic paraplegia phenotype caused by SYNE1 gene mutation

Objective The SYNE1 gene is the pathogenic gene for autosomal recessive cerebellar ataxia type 1 (ARCA1), which mainly presents as cerebellar ataxia. This study aims to collect clinical data of a proband and his family with a SYNE1 gene mutation, who presents with spastic paraplegia, to analyze the clinical and genetic characteristics and to explore the possible pathogenic mechanisms of this mutation. Methods The study subject was a 35-year-old male patient who had been experiencing "stiffness in both lower limbs and unstable gait for 15 years" and were admitted to the Affiliated Hospital of Xuzhou Medical University. The clinical data of the patient (proband) and his parents were collected, and relevant examinations were conducted, including brain MRI, diffusion tensor imaging (DTI), electromyography (EMG), and neuropsychological scale assessments. Whole exome sequencing was performed, and Sanger sequencing was used for validation. Results The proband exhibited only spastic paraplegia, a phenotype of upper motor neuron involvement. Clinical symptoms, signs, and brain MRI did not suggest cerebellar involvement. Genetic testing revealed that the patient carried compound heterozygous mutations in the SYNE1 gene: c.11798A>G (p.Gln3933Arg) and c.19789G>T (p.Ala6597Ser), inherited from his mother (p.Gln3933Arg) and father (p.Ala6597Ser), respectively. Various bioinformatic tools predicted that these mutations may have harmful effects on the protein structure and be associated with pathogenicity. Conclusions The c.11798A>G and c.19789G>T mutations in the SYNE1 gene may manifest solely as spastic paraplegia without cerebellar involvement. This study enriches the mutation spectrum of the SYNE1 gene and provides new insights for further investigation into the pathogenic mechanisms of spastic paraplegia.