NORD gratefully acknowledges Darius Ebrahimi-Fakhari, MD, PhD, Boston Children's Hospital, and CureSPG47, for the preparation of this report.
Most children with SPG51 have:
• a “floppy” appearance in infancy due to low muscle tone
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• intellectual disability
• delayed motor development
• poor or absent speech development
Other known features of SPG51 can include the following (not every child will have these features):
• short stature
• late walking and later loss of the ability to walk independently
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of fever
Some children may also have facial differences that can include:
• high palate
• wide nasal bridge
• bulbous nose
• wide mouth
• protruding tongue
• short philtrum (the groove between the bottom of the nose and top of the lips)
• narrow forehead
• flat feet or club feet
SPG51 is inherited in an autosomal recessive manner. The gene that is involved is AP4E1. A gene with a disease-causing (pathogenic) mutation must be inherited from each parent to result in manifestations of symptoms. Parents 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.
SPG51 affects males and females of ethnic groups from around the world.
The prevalence of SPG51 is unknown. SPG51 is likely under-recognized since the phenotypic spectrum largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be labeled as having cerebral palsy.
Since many of the initial clinical manifestations of SPG51 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability, and seizure, the diagnosis is often only made after further diagnostic testing. This 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
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, 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.
At Boston Children’s Hospital’s Dr. Darius Ebrahimi-Fakhari, along with the Translational Neuroscience Center and the Manton Center for Orphan Diseases, has initiated the first International Registry and Natural History Study for Adaptor-Protein 4 (AP-4)-associated Hereditary Spastic Paraplegia.
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. All enrollment can be completed remotely. If you believe you or your child may be eligible for this study and you are interested in learning more:
Please contact: Translational Neuroscience Center
Boston Children’s Hospital
Phone: +1 (617) 919-4599
Fax: +1 (617) 730-0450
email: [email protected]
Dr. Darius Ebrahimi-Fakhari of Boston Children’s Hospital is pursuing a drug screening experiment on cells derived from AP-4-related HSP patients. The process begins with obtaining skin cells from the patient and the same gender parent. IPSC stem cells are developed from the tissue, 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 related HSPs. Potentially, the drug screening research may help identify a treatment which benefits all of four of these diseases.
Additionally, Cure SPG47 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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