Biallelic mutations in DDHD2 can disrupt its membrane-binding domain and abolish phospholipase and triglyceride hydrolase activities, causing hereditary spastic paraplegia 54 (HSP54), a childhood-onset autosomal recessive disorder marked by progressive neuromuscular and cognitive impairments6–15. Here, DDHD2 is linked to hereditary spastic paraplegia 54.