AP-4-Associated Hereditary Spastic Paraplegia (AP-4-HSP)

AP-4 hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of slowly progressing neurodegenerative disorders. Children with these disorders may have developmental delays, moderate to severe intellectual disability, impaired or absent speech, small head size (microcephaly), seizures, and progressive motor symptoms.

Most children born with AP-4-HSP have low muscle tone (hypotonia) in infancy that develops into high muscle tone (hypertonia) in early childhood. This causes spasticity of the legs that leads to the inability to walk and reliance on a wheelchair. Spasticity may also progress to the arms and hands, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).

HSP includes four subtypes: SPG47, SPG50, SPG51, and SPG52. Each of these subtypes is associated with a defective autosomal recessive gene, which causes a failure in the AP-4 adaptor complex. The phenotype and prognosis for each of the four sub-types is very similar.

SPG47, SPG50, SPG51, and SPG52 are caused by mutations in the AP4B1, AP4M1, AP4E1, and AP4S1 genes respectively. Each is an autosomal recessive disorder. This means each parent has passed a defective recessive gene to the child. This gene prevents the child from being able to correctly produce a protein required for proper functioning of the AP-4 adaptor complex.

Most children with HSP have:

• A “floppy” appearance in infancy because of 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 (small head size)
• Seizures, including frequent seizures when they have a fever

Other symptoms of AP-4-HSP can include the following (not every child will have these):

• Short stature
• Dystonia (involuntary muscle contractions)
• Ataxia (impaired balance and coordination)

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 clubfeet

There is no cure for AP-4-HSP. Treatment involves management of symptoms, which may include referrals to the following programs and services.

• Birth to 3 years. Children with AP-4-HSP should be referred to an early intervention (EI) program for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators, and sensory-impairment specialists.
• Ages 3 to 5 years. At this age, children should be enrolled in developmental preschool through their local public school district. Before placement, an evaluation will determine which services and therapies the child needs. An individualized education plan (IEP) is developed for those who qualify, based on the child’s level of motor, language, social, or cognitive delays. The early intervention program typically assists with this transition.
• Ages 5 to 21 years. The child’s local public school district should develop an IEP based on the child’s level of function. The IEP will specify which instruction or related services the individual needs. Discussion about transition plans, including financial and medical arrangements, should begin at age 12. Developmental pediatricians can help with transitioning to adulthood.

Children with AP-4-HSP often lose their ability to walk independently and will eventually need to use a walker or cane. Many need to use a wheelchair before their teen years. Others can walk with a waddling gait. Some children with AP-4-HSP have reached their early 20s, but long-term life expectancy for this condition is still unclear, as it was only first recognized in 2011. However, many children with hereditary spastic paraplegias in general have a normal life expectancy.

Of the approximately 150 confirmed cases of AP-4 HSP in the world at this time, most patients have progressed to loss of mobility in some or all extremities, and are severely intellectually challenged.

Since AP-4-HSP is a recessive disorder, parents each carrying the same AP-4-mutated gene have a 25 percent chance of having a child with HSP, a 50 percent chance of having a child without the condition who is a carrier for the condition, and a 25 percent chance of having a child who does not have the condition and does not carry a mutated gene. Genetic counseling is often helpful if you are planning to have more children.

At Boston Children’s Hospital, we care for patients with AP-4-HSP in the Department of Neurology, the Neuromuscular Center, the Cerebral Palsy Program, and the Clinical Genetics program. Learn more from our Patient Education Guide.