AP-4-Associated Hereditary Spastic Paraplegia

Excerpt

Clinical characteristics: AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders 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 children become nonambulatory and usually wheelchair bound. Over time spasticity progresses 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 affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.

Diagnosis/testing: The diagnosis of AP-4-associated HSP is established in a proband by identification of biallelic pathogenic variants in one of four genes: AP4B1, AP4E1, AP4M1, or AP4S1.

Management: Treatment of manifestations: Management by an interdisciplinary team (including a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and a speech and language pathologist) to address spasticity/weakness, secondary musculoskeletal findings, developmental delay and intellectual disability, seizures, and swallowing and feeding difficulties.

Surveillance: Evaluation every six to 12 months by an interdisciplinary team to assess disease progression and to maximize ambulation and communication skills while reducing the effect of other manifestations (e.g., musculoskeletal complications, dysphagia / feeding difficulties, and seizures).

Genetic counseling: AP-4-associated HSP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AP-4-associated HSP-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.