Ap-4-Associated Hereditary Spastic Paraplegia

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 non-ambulatory 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.

Suggestive Findings

AP-4-associated HSP should be suspected in individuals with the following clinical findings and characteristic brain imaging findings [Verkerk et al 2009, Abou Jamra et al 2011, Moreno-De-Luca et al 2011, Ebrahimi-Fakhari et al 2018].

Establishing the Diagnosis

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 (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (typically exome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

Developmental delay / intellectual disability, spasticity, epilepsy, or microcephaly multigene panels that include AP4B1, AP4E1, AP4M1, AP4S1, and other genes of interest (see Differential Diagnosis) are most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of AP-4-associated HSP, some panels for developmental delay / intellectual disability and/or spasticity and/or epilepsy and/or microcephaly may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option when the clinician cannot determine which multigene panel best fits the affected individual's clinical findings. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

AP-4-associated hereditary spastic paraplegia (HSP) is characterized by complex spastic paraplegia in all affected individuals reported to date. Onset is usually before age one year. Infants manifest hypotonia, microcephaly, and delayed developmental milestones; some also have seizures. The early-childhood hypotonia evolves into progressive lower-extremity weakness and spasticity with pyramidal signs (plantar extension and hyperreflexia). Over time children often become non-ambulatory and ultimately require mobility aids / wheelchairs. Spasticity progresses to involve the upper extremities, resulting in spastic tetraplegia.

Associated complications include dysphagia, contractures secondary to progressive spasticity, foot deformities, and dysregulation of bladder and bowel function.

Microcephaly becomes evident in infancy in the majority and is often in the -2 SD to -3 SD range.

Developmental delay is universal. Delayed motor milestones are often the presenting manifestation:

• Rolling (mean age: 6.5 months)
• Sitting (mean age: 10.2 months)
• Crawling (mean age: 22.8 months)

Only a subset of children achieve independent walking (mean age: 33.5 months), a skill that is often lost as the disease progresses [Data from the International Registry and Natural History Study of AP-4-Related HSP; updated 5-20-18].

Speech and language development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.

Seizures often occur in the first two years of life; about 50% of individuals with AP-4-associated HSP have a diagnosis of epilepsy. Seizure types include focal-onset seizures (often with secondary generalization) as well as primary generalized seizures. Status epilepticus has been reported in a significant subset of patients. About 50% of affected individuals, including individuals with and without epilepsy, have seizures in the setting of fever. In general, seizures become less frequent with age and are often well controlled with standard antiepileptic drugs.

Episodes of stereotypic laughter, perhaps indicating a pseudobulbar affect, are a characteristic finding in a subset of individuals [Ebrahimi-Fakhari et al 2018].

Less frequent clinical manifestations include short stature, nonspecific dysmorphic facial features, optic nerve atrophy, dystonia, and ataxia.

To date, uncomplicated hereditary spastic paraplegia, a pure spastic paraplegia without other neurological manifestations, has not been reported in individuals with AP-4 deficiency.

Prognosis. Natural history data are not currently available. The oldest reported individuals are young adults.

Phenotype Correlations by Gene

AP-4-associated HSP is caused by biallelic loss-of-function variants in one of the four genes that encode subunits of the AP-4 complex (β4, ε, μ4, σ4). Because loss of any one subunit renders the entire complex nonfunctional, biallelic loss-of-function variants in any one of the four genes cause the same molecular defect – loss of AP-4 complex function – and the same phenotype.

Brain iron accumulation has been reported in one family with AP4M1-related AP-4 deficiency syndrome [Roubertie et al 2018] and one individual with AP4S1-related AP-4 deficiency syndrome [Vill et al 2017]. Given the rarity of this finding and a potential age bias, it is unknown if brain iron accumulation is a feature of AP-4-associated HSP regardless of cause.

Genotype-Phenotype Correlations

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

Nomenclature

Recommendations for the nomenclature of genetic movement disorders, including AP-4-associated HSP, have been published [Marras et al 2016].

Prevalence

AP-4-associated HSP is rare. To date about 80 individuals are known; all have been included in the International Registry and Natural History Study of AP-4-Related Hereditary Spastic Paraplegia (updated 5-20-18).

Families with AP-4-associated HSP have been reported from North America, Europe, the Middle East, and the Indian subcontinent. *

About two thirds of individuals with AP-4-associated HSP have consanguineous parents; * however, this could be the result of ascertainment bias, as initial reports have mainly focused on families from countries with high rates of consanguinity [Verkerk et al 2009, Abou Jamra et al 2011, Moreno-De-Luca et al 2011]. More recently, AP-4-associated HSP has been reported in populations with low rates of consanguinity [Ebrahimi-Fakhari et al 2018].

* International Registry and Natural History Study of AP-4-Related HSP

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

At present, no treatment prevents, halts, or reverses neuronal degeneration in AP-4-associated HSP. Treatment is directed at reducing symptoms and preventing secondary complications.