Cure SPG52
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SPG52 in one page

AP4S1-related hereditary spastic paraplegia, OMIM 614067. One of four AP-4 deficiency disorders with a shared phenotype. What to look for, what to order, and where to send the family.

Last reviewed 2026-10-21

Essentials

Gene
AP4S1 (sigma-4 subunit of adaptor protein complex 4), autosomal recessive. OMIM 614067.
Group
AP-4-HSP: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1), SPG52 (AP4S1). Severity and major phenotypes are equally distributed among the four [1]; no genotype-phenotype correlation reported [2].
Mechanism
Loss of any subunit abolishes complex assembly [3]. AP-4 exports ATG9A from the trans-Golgi network; without it ATG9A accumulates in the Golgi and distal axonal autophagy fails.
Reference
GeneReviews: AP-4-Associated HSP, updated February 6, 2025 [2].
Known cases
43 molecularly confirmed in the literature (2025) [11]; about 50 to 55 known children worldwide per the Barcelona gene therapy team.

Phenotype in brief

Neonatal or infantile hypotonia (92%), global developmental delay (99%), postnatally acquired microcephaly (83% postnatal versus 8% congenital; 72% in AP4S1), evolution to spastic diplegia then tetraplegia (leg spasticity 60% under age 4, 96% at 4 and older; tetraplegia mean onset 16.1 years), hyperreflexia (92%) and Babinski sign (88%) preceding overt spasticity, speech significantly impaired or absent (97%), intellectual disability (severe 58%), stereotypic laughter (46 to 62%), shy character, short stature [1,2]. Mean wheelchair dependence at 9.0 years (SD 5.3) [1].

Seizures in 61 to 67%, typically fever-triggered in the first two years, with status epilepticus in about a third, often at the first seizure; most respond to standard antiseizure medication and seizures become less frequent with age [1,2]. The only cohort that is mostly AP4S1 found a combined focal and generalised EEG pattern, reflex features in two thirds, and no drug resistance [17]. Polymicrogyria on MRI marks the harder seizure course [20]. Epilepsy correlates with worse motor scores [1].

The four core MRI features

  1. Thin corpus callosum, worst posteriorly: splenium below the 3rd percentile in 94%; never completely absent [1,20].
  2. Absent (82%) or thin (14%) anterior commissure, not seen in SPG15 and SPG49 comparators, so relatively specific [20].
  3. Forceps minor signal change: the "ears of the grizzly bear" sign in 48%, the older "ears of the lynx" in 11% [20].
  4. Periventricular white matter changes (55%) with dysmyelination (80%) [20].

At least two of the four features were present in 99% of patients, all four in 45% [20]. Also common: colpocephaly (65%), reduced white matter volume (53%), polymicrogyria (26% on systematic review, mostly bilateral perisylvian, easily missed on a routine read), iron deposition in the globus pallidus rarely [1,20]. Delayed myelination was stable or caught up in 16 of 17 children with repeat scans; white matter volume loss, not demyelination, is what progresses [20,23]. A normal MRI does not exclude the diagnosis [11,15]. Fetal and neonatal ventriculomegaly and callosal hypoplasia are described [23].

The misdiagnosis trap

Variants of uncertain significance: the ATG9A assay

The ATG9A ratio (Golgi-retained versus peripheral ATG9A in cultured patient fibroblasts) is a functional assay that can confirm or reclassify uncertain AP4 variants in about four to six weeks. It is positioned explicitly as relevant to gene-therapy trial eligibility, which requires molecular confirmation. It is a research assay, not yet a CLIA-certified clinical test [8]. Contact the Boston registry team (below) to arrange it. Plasma neurofilament light chain is elevated in AP-4-HSP and higher in a "severe early" cluster, but has no validated role in individual prognosis [27].

Surveillance, from GeneReviews

Every 6 to 12 months: neurology, developmental paediatrics, orthopaedics or physiatry, PT, OT and speech-language pathology; hip and spine radiographs at least annually from diagnosis; swallowing and aspiration-risk evaluation at diagnosis and ongoing; urology with urodynamics; ophthalmology; nutrition; and a pediatric pain referral when contractures hurt. Early AAC is recommended. No current treatment prevents, halts or reverses neurologic progression [2].

Where to send the family

Registry
Registry and Natural History Study for Early Onset HSP, Boston Children's Hospital, NCT04712812. PI Darius Ebrahimi-Fakhari. Remote enrolment, no cost, interpreters available [60]. [email protected], +1 617-355-6388.
Trial observation arm
SPG50 MELPIDA Phase 3, NCT06692712, enrols SPG47, SPG50 and SPG52 children aged 4 to 72 months as untreated concurrent controls at UT Southwestern and Sant Joan de Déu [31]. [email protected].
Families
This site's first 90 days page, and the caregivers' group via the families page.
Centre of expertise
Boston Children's Hospital leads the NIH-funded Spastic Paraplegia Centers of Excellence Research Network [9].

Sources

Numbers in brackets refer to this list. Last reviewed: 2026-10-21. Sources checked on 2026-10-20.

  1. [1] Ebrahimi-Fakhari D, Teinert J, Behne R, et al. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020;143(10):2929-2944. PMID 32979048
  2. [2] Ebrahimi-Fakhari D, Behne R, Davies AK, Hirst J. AP-4-Associated Hereditary Spastic Paraplegia. GeneReviews, University of Washington. Last update February 6, 2025. www.ncbi.nlm.nih.gov/books/NBK535153
  3. [3] Hardies K, May P, Djémié T, et al. Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum Mol Genet. 2015;24(8):2218-2227. www.ncbi.nlm.nih.gov/pmc/articles/PMC4380070
  4. [8] Agianda HAP, Kim HM, Battaglia N, et al. Diagnostic utility of the ATG9A ratio in AP-4-associated hereditary spastic paraplegia. Ann Clin Transl Neurol. 2026;13(4):834-839. PMID 41491634
  5. [9] Fliesler N. The journey to a treatment for hereditary spastic paraplegia. Boston Children's Answers, October 14, 2025. answers.childrenshospital.org/hereditary-spastic-paraplegia-treatment
  6. [10] Tessa A, Battini R, Rubegni A, et al. Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families. Eur J Neurol. 2016;23(10):1580-1587. PMID 27444738
  7. [11] Günay Ç, Gazeteci Tekin H. Hereditary spastic paraplegy associated with the AP4S1 gene: a case series highlighting diagnostic pitfalls and phenotypic variability. Mol Syndromol. 2025;16(5):489-497. PMID 41059447
  8. [12] D'Amore A, Tessa A, Naef V, et al. Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52. Ann Clin Transl Neurol. 2020;7(4):584-589. PMID 32216065
  9. [15] Niyoyita S, Uwibambe E, Ndinkabandi J, et al. A rare homozygous AP4S1 variant in Rwandan siblings with autosomal recessive hereditary spastic paraplegia type 52 (SPG52). Genes (Basel). 2025;16(5):542. PMID 40428364
  10. [17] Bartolini E, Ferrari AR, Santorelli FM, et al. Combined generalized and focal epilepsy with reflex features in adaptor protein complex 4-associated hereditary spastic paraplegias: a cohort observational study. Seizure. 2024;121:186-193. PMID 39208719
  11. [20] Ebrahimi-Fakhari D, Alecu JE, Ziegler M, et al. Systematic analysis of brain MRI findings in adaptor protein complex 4-associated hereditary spastic paraplegia. Neurology. 2021;97(19):e1942-e1954. PMID 34544818
  12. [23] Brooks AK, Quiroz V, Schierbaum L, et al. Fetal and perinatal brain MRI findings in adaptor protein complex 4-associated hereditary spastic paraplegia. Ann Child Neurol Soc. 2025;3(3):226-231. PMID 41815511
  13. [27] Alecu JE, Saffari A, Ziegler M, et al. Plasma neurofilament light chain is elevated in adaptor protein complex 4-related hereditary spastic paraplegia. Mov Disord. 2023;38(9):1742-1750. www.ncbi.nlm.nih.gov/pmc/articles/PMC10529494
  14. [31] ClinicalTrials.gov NCT06692712. Phase 3 open-label study of intrathecal MELPIDA (AAV9/AP4M1) for SPG50 with a matched prospective concurrent control arm. Sponsor Elpida Therapeutics; collaborators UT Southwestern and Hospital Sant Joan de Déu. Start April 1, 2026; last update posted April 20, 2026. clinicaltrials.gov/study/NCT06692712
  15. [60] ClinicalTrials.gov NCT04712812. Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP). Sponsor Boston Children's Hospital; PI Darius Ebrahimi-Fakhari. Last update posted March 18, 2026. clinicaltrials.gov/study/NCT04712812