Novel missense ALDH18A1 variant in a family with autosomal dominant spastic paraplegia

We aim to characterize a novel heterozygous missense variant c.1703A > G/p. (Gln568Arg) in the ALDH18A1 gene, identified in a family with autosomal dominant hereditary spastic paraplegia (HSP). We evaluated clinical, neurophysiological, genetic, fluid biomarkers, and neuroimaging expression in different family members with and without the mutation.

A comprehensive multimodal evaluation was performed, including neurological examination, motor and sensory conduction studies, transcranial magnetic stimulation, targeted genetic sequencing, biomarker analysis (amino acid profiling and plasma neurofilament light chain levels (pNfL)), and brain and spinal cord MRI. Mutation pathogenicity was assessed using in silico prediction tools and confirmed by segregation analysis in family members.

The index case, a 53-year-old male, presented with progressive bladder and gait disturbances, with spasticity, weakness, brisk reflexes and reduced deep sensation in the lower limbs. Neurophysiological findings confirmed corticospinal tract involvement. MRI showed selective cerebellar atrophy. Genetic analysis identified the c.1703A > G/p. (Gln568Arg) mutation in the index case and in his father, presenting with similar clinical expression. pNfL was numerically higher in mutation carriers than the healthy brother and daughter of the index case, indicating neuro-axonal damage. Amino acid profiling showed normal levels of ornithine, citrulline, arginine, and proline.

This study expands the spectrum of ALDH18A1-associated HSP, highlighting a novel mutation with a relatively late-onset and mild clinical phenotype. Further functional studies and longitudinal assessments are needed to confirm the pathogenicity of this variant and its potential implications for disease progression and therapeutic strategies.