What is AP-4 HSP?

AP-4 Hereditary Spastic Paraplegia, also know as AP-4 Deficiency Syndrome, includes four sub-types of Hereditary Spastic Paraplegia: SPG47, SPG50, SPG51 and SPG52. Each of these HSP sub-types is associated with a defective autosomal recessive gene which causes a failure in the AP-4 Adaptor Complex. The phenotype and prognosis for each of the four sub-types is extremely similar. Patients afflicted with any of the AP-4 HSP genetic disorders generally present with symptoms including global developmental delay, microcephaly, seizures, malformation of the brain, and hypotonia (low-muscle tone). The few patients that learn to walk independently tend to lose that ability a few months or a few years later as they develop hypertonia (high-muscle tone) and muscle spasticity. Of the ~300 confirmed cases of AP-4 HSP in the world at this time, most patients have progressed to loss of mobility in some or all extremities, and are severely intellectually challenged. Because of the extreme rarity of AP-4 HSP, limited research has been conducted to date, and there are very few treatments available at this time.

SPG47, SPG50, SPG51 and SPG52 are caused by mutations in the AP4B1, AP4M1, AP4E1 and AP4S1 genes respectively. Each is an autosomal recessive disorder, which means that both parents have contributed a defective recessive gene to the child. The result is that the patient is unable to correctly produce a protein required for proper functioning of the AP-4 Adaptor Complex. The area of highest expression is central motor neurons located in the hippocampus region of the brain. On a cellular level, it is now understood that AP-4 malfunction causes build-up of an autophagy compound called ATG9A, as well as an enzyme called DAGLB, inside the Trans-Golgi Network. The mis-location of DAGLB reduces 2-AG signaling in neurons, impairing their growth.

The Cure AP-4 non-profit organization was founded in 2016 by families of two of the known SPG47 patients. It was originally founded as Cure SPG47, but the mission has since expanded to include all four AP-4 related disorders due to shared natural history, goals and patient/family needs. We refuse to accept the bleak prognosis which our children face. We have decided to fight. The purpose of this organization is to study and seek a cure for all AP-4 HSP disorders. We aim to improve the quality of life for children impacted by AP-4 HSP by accelerating the research for cures and treatments and providing support for patient therapies critical to their well-being and rehabilitation.

» Download the AP-4 Associated HSP Family Education Guide

Grant/Funding Announcements:

Cure AP-4 announces with deep gratitude and appreciation that LifeArc has recently granted £470,066 (just over $600,000 USD) from its Philanthropic Fund to Dr. Mimoun Azzouz, University of Sheffield, towards furthering efforts on his AP4B1 (SPG47) gene therapy research. LifeArc is an independent medical research charity helping turn promising science into benefits for patients. The LifeArc Philanthropic Fund supports, through grants, translational rare disease research projects focused on developing an intervention (therapeutic, device or diagnostic) that will address a significant, unaddressed need for rare disease patients and on research which has a credible translational and development path to reaching those patients.

Boston Children's Hospital and Astellas Pharma Inc. (Astellas) have entered into a strategic alliance aiming to identify and fund promising research to advance novel therapeutics. Principal Investigator Dr. Darius Ebrahimi-Fakhari and his mentor Dr. Mustafa Sahin were awarded $500,000 in funding to help further AP-4-HSP drug screening research. Ebrahimi-Fahkari and Sahin were the first selected investigators for collaboration with one of Astellas' research subsidiaries Mitobridge (Cambridge, MA) which is focused on autophagy and mitochondrial pathways. Astellas is a Japan-based pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products.

The Spastic Paraplegia Foundation has generously supported the "Generation of Human Nerve Cells from Children with AP-4-Associated Hereditary Spastic Paraplegia to Support a Search for New Therapies" project under direction of Boston Children's Hospital's Dr. Darius Ebrahimi-Fakhari.

NIH/NINDS has awarded Dr. Darius Ebrahimi-Fakhari with funding for two projects: "An Unbiased Phenotypic Screen for Novel Therapeutic Targets in AP-4-associated Hereditary Spastic Paraplegia" and "Development of a Translational Research Platform to Understand and treat Defective Protein Trafficking in Childhood-Onset Hereditary Spastic Paraplegia"

The Manton Center for Orphan Disease Research has awarded Dr. Darius Ebrahimi-Fakhari with a pilot grant for "Functional Genomic Screen in a Neuronal Model of Hereditary Spastic Paraplegia". This project will test the hypothesis that an unbiased arrayed CRISPR-mediated loss-of-function screen can identify novel modulators of intracellular protein trafficking for the treatment of AP-4-associated hereditary spastic paraplegia, an ultrarare neurogenetic disease in children.

The Children's Rare Disease Cohort Initiative has selected Dr. Darius Ebrahimi-Fakhari's "The Early-onset Hereditary Spastic Paraplegia Sequencing Initiative" project.

The Tom Wahlig Foundation has awarded Dr. Darius Ebrahimi-Fakhari a grant for his "Characterization of ap4b1-/- zebrafish as a novel in vivo model of SPG47 and its application in small molecule screens" project. This project will characterize ap4b1-/- zebrafish on a morphological biochemical and behavioral level and test novel small molecule modulators of ATG9A trafficking.