Last updated:
8/5/2024
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
Spastic paraplegia 47 (SPG47) is 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. Other symptoms include low muscle tone (hypotonia) that may result in a “floppy” appearance. As the affected child grows older, the muscle tone increases (hypertonia) and may result in spasticity of the legs that leads to the inability to walk (non-ambulation) and the need for a wheelchair. A partial or total loss of use of all four limbs and torso (tetraplegia) may also develop.[1]
SPG47 is caused by changes (pathogenic variants) in the AP4B1 gene. Inheritance is autosomal recessive.[1][2]
Treatment is directed towards alleviating the symptoms that the affected person has. There is an active investigation towards finding an effective treatment.[1]
Spastic paraplegia 47 (SPG47) is part of a group of diseases called “AP4 deficiency syndrome” (also called “AP-4-associated hereditary spastic paraplegia” or “severe intellectual disability and progressive spastic paraparesis” characterized by spastic paraplegia complex and progressive that typically begins in infants or young children.[1][3]
Most children with SPG47 have:[1]
Other known features of SPG47 can include the following (not every child will have these features):[1][2][4]
SPG47 is caused by variants in the AP4B1 gene and is inherited in an autosomal recessive manner. [1][2]
Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant 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.
SPG47 affects males and females of many ethnic groups from around the world.
The prevalence of SPG47 is unknown. SPG47 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and without genetic testing, many patients may be misdiagnosed as having cerebral palsy.
SPG47 is part of the AP-4-associated disorders. To date about 80 individuals affected with AP-4 are known.[1][3]
Since many of the initial clinical manifestations of SPG47 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.[1]
There is no cure for SPG47. Treatment is focused on improving the symptoms. It may include:[1]
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 children 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 determine 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, 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.
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/
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report