Spastic paraplegia-54 mainly affects the fibers of the corticospinal tract, and it belongs to a genetically heterogeneous group of neurodegenerative disorders; spastic paraplegias. Patients suffer delayed psychomotor development, mental retardation, and early-onset (by age 2 years) spasticity of the lower limbs. Further neurological manifestations can be identified through brain MRI, such as thinning of corpus callosum and periventricular white matter lesions. Additionally, magnetic resonance spectroscopy of the brain shows an abnormal lipid peak indicating accumulation of lipids. The symptoms of SPG54 are not limited to the central nervous system; head and neck, gastrointestinal and skeletal features are also observed. Examples include; strabismus, dysphagia and foot contractures. These signs and symptoms make the basis for diagnosing SPG54, especially using cerebral magnetic resonance spectroscopy to detect the abnormal lipid peak.   

SPG54 is caused by homozygous or compound heterozygous mutations in the DDHD domain-containing protein 2 gene (DDHD2), which is located on chromosome 8. The latter gene is thought to play an essential role in the human CNS, and specifically in synaptic functioning. All identified mutations affect the enzyme’s DDHD domain, which is essential for its phospholipase activity, thus supporting the gene’s role in lipid metabolism.