AP4E1-associated hereditary spastic paraplegia (also known as SPG51) is a rare childhood-onset and complex form of hereditary spastic paraplegia. AP4E1-associated hereditary spastic paraplegia is part of a group four syndromes caused by bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4: AP4E1, AP4B1 (or SPG47), AP4M1 (or SPG50) and AP4S1 (or SPG52). All four diseases share a common phenotype known as AP-4-associated hereditary spastic paraplegia or AP-4 deficiency syndrome. To data, less than 500 individuals with AP-4 associated hereditary spastic paraplegia have been described in the literature.
AP4E1-associated hereditary spastic paraplegia is characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of patients become non-ambulatory and usually wheelchair bound. Over time spasticity may progress to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of patients have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All patients have significant and early motor and speech delay. Many patients remain nonverbal. Intellectual disability in older children is usually moderate to severe.
AP4E1