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.
Spastic paraplegia 50 (SPG50) is both a neurodevelopmental and a slowly progressive neurological disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to 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 SPG50 have:
• a “floppy” appearance in infancy due to low muscle tone
• delayed motor development
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• intellectual disability
• poor or absent speech development
Other known features of SPG50 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
The gene that is involved in SPG50 is called AP4M1, and SPG50 is inherited in an autosomal recessive manner. 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.
SPG50 affects males and females of many ethnic groups from around the world.
The prevalence of SPG50 is unknown. SPG50 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be misdiagnosed as having cerebral palsy.
Since many of the initial clinical manifestations of SPG50 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures, 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.
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 the age of 12 years. Developmental pediatricians can help with transition to adulthood.
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, 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 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.
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.
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
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
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, 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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