NORD gratefully acknowledges Darius Ebrahimi-Fakhari, MD, PhD, Boston Children's Hospital, and CureAP4, for the preparation of this report.
AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a group of slowly-progressing neurodegenerative disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures, and progressive motor symptoms. Low muscle tone (hypotonia) in infancy develops into high muscle tone (hypertonia), resulting in spasticity of the legs that leads to the inability to walk (non-ambulation) and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).
Most children with AP-4-associated HSP have:
Other known features of AP-4-HSP can include the following (not every child will have these features):
Some children may also have facial differences that can include:
AP-4-associated HSP are inherited in an autosomal recessive manner. The four genes that encode subunits of the AP-4 complex are AP4B1, AP4E1, AP4M1, and AP4S1. Parents each carrying a mutated gene have a 25% chance of having an affected child, a 50% chance of having an unaffected carrier child and a 25% chance of having a child who is unaffected and does not carry a mutated gene.
AP-4-associated HSP affects males and females of ethnic groups from around the world. The prevalence of AP-4-HSP is unknown. AP-4-HSP is likely under-recognized since the symptoms (phenotypic spectrum) largely overlap with that of cerebral palsy and, in the absence of genetic testing, patients may be misdiagnosed as having cerebral palsy.
The diagnosis of AP-4-associated HSP is based on clinical characteristics and testing that may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
Treatment: management of symptoms
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators, and sensory-impairment specialists.
Ages 3-5 years. In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, and/or cognitive delay. The early intervention program typically assists with this transition.
Ages 5-21 years. In the United States, an IEP based on the individual’s level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Gross motor dysfunction
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral-motor dysfunction. Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained.
Communication issues. Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
Dr. Darius Ebrahimi-Fakhari of Boston Children’s Hospital is pursuing a drug screening experiment on cells derived from AP-4-associated HSP patients. The process begins with obtaining skin cells from the patient and the same gender parent. IPSC stem cells are developed from these skin cells, and then differentiated into neurons, which can be maintained and studied in a lab. The goal of the project is to test whether various compounds which are FDA-approved for other disorders might offer some benefit to the cells affected by AP-4 associated HSPs. Potentially, the drug screening research may help identify a treatment which benefits all of four of these diseases.
Additionally, Cure AP4 has engaged Dr. Mimoun Azzouz of the University of Sheffield to develop an AP4B1 gene therapy proof-of-concept. His team has developed an AAV9 viral vector capable of delivering a good, working copy of the AP4B1 gene to the central motor neurons of a knockout mouse as well as fibroblasts derived from SPG47 patients. If successful, this research will provide the basis for pursuing human clinical trials in the coming years. Early proof-of-concept research looks promising thus far.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/.
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Ebrahimi-Fakhari D, Behne R, Davies AK, et al. AP-4-Associated Hereditary Spastic Paraplegia. 2018 Dec 13. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.Available from: https://www.ncbi.nlm.nih.gov/books/NBK535153/ Accessed May 13, 2019.
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