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Last updated: 8/6/2024
Years published: 2019, 2023
NORD gratefully acknowledges Darius Ebrahimi-Fakhari, MD, PhD, Boston Children’s Hospital, and CureSPG47, for the preparation of this report.
Summary
Spastic paraplegia 52 (SPG52) is a slowly progressing neurodegenerative 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 hypotonia (low muscle tone) that may result in a “floppy” appearance. As the affected child grows older the muscular 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]
SPG52 is caused by changes (pathogenic variants) in the AP4S1 gene. Inheritance is autosomal recessive.[1][2]
Treatment is focused on alleviating the symptoms that the affected person has. There is an active investigation towards finding an effective.[1]
Spastic paraplegia 52 (SPG52) 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 SPG52 have:[1]
Other known features of SPG52 can include the following (not every child will have these features):[1][2][4]
SPG52 is caused by changes (pathogenic variants) in the AP4S1 gene. It is inherited in an autosomal recessive manner.
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.
SPG52 affects males and females of ethnic groups from around the world.
The prevalence of SPG52 is unknown. SPG52 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.
SPG52 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 SPG52 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 white matter of the brain. A definitive diagnosis is reached by genetic testing.
There is no cure for SPG52. Current treatment is focused on alleviating the 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 help with transition to adulthood.
Motor Dysfunction
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 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.
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