Last updated:
9/26/2024
Years published: 2019, 2023
NORD gratefully acknowledges Darius Ebrahimi-Fakhari, MD, PhD, Amy Tam, BSc, and Vicente Quiroz, MD, Boston Children’s Hospital, for the preparation of this report.
Summary
AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a group of neurodevelopmental and slowly progressive neurological 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).
AP-4-associated HSP are inherited in an autosomal recessive manner. There are four genes that encode subunits of the AP-4 complex, AP4B1, AP4E1, AP4M1, and AP4S1.
There is no cure or specific treatment. Treatment focused on managing the symptoms.
Most children with AP-4-associated hereditary spastic paraplegia (AP-4-HSP) have:
• a “floppy” appearance in infancy due to low muscle tone
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• delayed motor development
• poor or absent speech development
• moderate to severe intellectual disability
• microcephaly
• seizures including frequent seizures in the setting of fever
Other known features of AP-4-HSP can include the following (not every child will have these features):
• short stature
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
AP-4-associated hereditary spastic paraplegia (AP-4-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.
Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
AP-4-associated hereditary spastic paraplegia (AP-4-HSP) affects males and females of many 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 hereditary spastic paraplegia (AP-4-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.
Management of Symptoms
There is still no cure or specific treatment for AP-4-associated hereditary spastic paraplegia (AP-4-HSP). The following management recommendations can be useful for people affected with these conditions:
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 the age of 12 years. Developmental pediatricians can help with transition to adulthood.
Motor Dysfunction
Gross motor dysfunction
• Physical therapy is recommended to maximize mobility.
• Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics and adaptive strollers).
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.
Multidisciplinary Care
Care should be provided by a multidisciplinary care team that includes input from neurology, physiatry, orthopedics, developmental medicine and others is recommended.
Dr. Darius Ebrahimi-Fakhari at Boston Children’s Hospital has initiated the first International Registry and Natural History Study for Adaptor-Protein 4 (AP-4)-associated Hereditary Spastic Paraplegia (ClinicalTrials.gov: NCT04712812).
Participant enrollment entails:
• Informed consent conversation with study staff (in person or via phone)
• Written consent and medical record release paperwork
• Clinical history questionnaire
• Possible blood sample collection
There is no cost to participate, and travel to Boston is not required. Enrollment can be completed remotely. If you think you or your child may be eligible for this study, and you are interested in learning more please contact:
HSP Research Coordinator
Boston Children’s Hospital
Phone: +1 (617) 355-2698
Email: [email protected]
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:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
INTERNET
Ebrahimi-Fakhari D, Behne R, Davies AK, et al. AP-4-Associated Hereditary Spastic Paraplegia. 2018 Dec 13. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535153/ Accessed Sept 13, 2023.
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