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Review

AP-4-Associated Hereditary Spastic Paraplegia

Julian Alecu  1 , Luca Schierbaum  1 , Darius Ebrahimi-Fakhari  1
Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Anne Amemiya
, editors.
In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].
Affiliations
Free Books & Documents
Review

AP-4-Associated Hereditary Spastic Paraplegia

Julian Alecu et al.
Free Books & Documents

Excerpt

Clinical characteristics: AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged febrile seizures. As the disease progresses, older children have intellectual disability that is usually moderate to severe; most affected individuals communicate nonverbally. Neurobehavioral/psychiatric manifestations (e.g., impulsivity, hyperactivity, and inattention) are common. Hypotonia transitions to progressive lower-extremity weakness and spasticity, accompanied by pyramidal signs such as plantar extension, ankle clonus, and hyperreflexia. Although some children achieve independent ambulation, most eventually lose this ability and rely on mobility aids or wheelchairs. In adolescence or early adulthood, spasticity may affect the upper extremities in some individuals but is generally less severe and not significantly disabling. Complications in some individuals include contractures, foot deformities, and bladder and bowel dysfunction. Dysphagia may emerge in advanced stages of the disease.

Diagnosis/testing: The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing.

Management: Treatment of manifestations: Supportive multidisciplinary care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (including neurology, orthopedics/physiatry, physical therapy, occupational therapy, developmental pediatrics, and speech-language pathology) and clinical genetics.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, affected individuals should be evaluated periodically (i.e., every 6-12 months) by their multidisciplinary care specialists.

Genetic counseling: AP-4-HSP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variant, each sib of an affected individual has at conception 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 AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

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