Clinical Guidance

No genotype-phenotype correlations have been reported for any of the four genes known to cause AP-4-HSP (AP4B1, AP4E1, AP4M1, and AP4S1).

Source: GeneReviews — "AP-4-Associated Hereditary Spastic Paraplegia"

Diagnostic Criteria

No consensus clinical diagnostic criteria for AP-4-associated hereditary spastic paraplegia (AP-4-HSP) have been published.

Suggestive Findings

AP-4-HSP should be suspected in individuals with the following clinical findings, characteristic brain imaging findings, and family history [; ; ; ; Ebrahimi-Fakhari et al 2020; Ebrahimi-Fakhari et al 2021b; D Ebrahimi-Fakhari, unpublished data].

Clinical findings

• Core clinical features

Source: GeneReviews — "AP-4-Associated Hereditary Spastic Paraplegia"

Differential Diagnosis

Many of the initial manifestations of AP-4-associated hereditary spastic paraplegia (AP-4-HSP) are nonspecific and may resemble other disorders characterized by spasticity, developmental delay/ intellectual disability, and a thin corpus callosum. Children with AP-4-HSP are often diagnosed with cerebral palsy before genetic testing is obtained. summarizes the features that distinguish the disorders most likely considered in the differential diagnosis from AP-4-HSP.

Table 3.

Genetic Disorders in the Differential Diagnosis of AP-4-Associated Hereditary Spastic Paraplegia

Gene(s) | Disorder1 | MOI | Features of Disorder Distinguishing from AP-4-HSP

AMPD2

| SPG63 | AR | • Central visual impairment

• Cerebellar hypoplasia/atrophy

MTRFR

| SPG55 | AR | • Optic atrophy

• Motor sensory neuropathy

CYP2U1

| SPG56 | ...

Source: GeneReviews — "AP-4-Associated Hereditary Spastic Paraplegia"

Management Guidelines

No clinical practice guidelines for AP-4-associated hereditary spastic paraplegia (AP-4-HSP) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with AP-4-HSP, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

AP-4-Associated Hereditary Spastic Paraplegia: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval | With attention to:

• Muscle tone (hypotonia, spasticity, pyramidal signs)

• Possible seizures

Development

| Developmental assessment | • To incl motor, adaptive, cognitive

• Eval for early intervention/ special education

Speech/Language

| By speech-language pathologist | Consider need for augmentative alternative communication [AAC])

Therapies Under Investigation

Several disease-modifying therapies for AP-4-HSP are currently under development, including AAV9-based gene replacement therapies and small molecule screens. For AP4M1-related HSP, an AAV9-based gene therapy vector delivering the human gene AP4M1 via a single lumbar intrathecal infusion has successfully completed preclinical development and has entered a Phase I/II clinical trial [NCT05518188]. Additionally, individuals in Canada and Spain have received the same vector under expanded access protocols . A similar strategy for AP4B1-related HSP has undergone successful preclinical development ; however, it has not yet progressed to clinical trials.

Source: GeneReviews — "AP-4-Associated Hereditary Spastic Paraplegia"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Affected individuals should be evaluated periodically (i.e., every 6-12 months) by their multidisciplinary care team that includes a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and speech-language pathologist to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations.

Table 6.

AP-4-Associated Hereditary Spastic Paraplegia: Recommended Surveillance

System/Concern | Evaluation | Frequency

Eyes | Ophthalmologic eval for visual acuity need for support services for visually impaired | As needed

Gastrointestinal/

Feeding

| • Evaluate for aspiration risk nutritional status.

• Monitor for constipation bowel dysfunction.

Pulmonary

| Monitor for aspiration pulmonary complications.

Genitourinary

| Urodynamic testing

Musculoskeletal

| • PT/OT eval; assess for contractures, scoliosis, foot deformities.

• Hip/spine radiographs

| Annually; more frequently if needed

Neurologic

| • Monitor treat spasticity.

• Monitor those w/seizures as clinically indicated.

Development

| Monitor developmental educational progress.

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions ari...

Source: GeneReviews — "AP-4-Associated Hereditary Spastic Paraplegia"