autism spectrum disorder - epilepsy - arthrogryposis syndrome

Autism spectrum disorder-epilepsy-arthrogryposis syndrome, also called SLC35A3-CDG, is a congenital disorder of glycosylation that affects both the nervous and musculoskeletal systems. It arises when both copies of the SLC35A3 gene are altered, disrupting a transporter needed for proper sugar attachment to many proteins. Symptoms usually begin in infancy or early childhood and involve developmental, orthopedic, and neurological challenges. Fewer than one in a million people worldwide are thought to have this condition, making it exceptionally uncommon.

The condition presents a distinctive combination of joint and neurological features. Early signs often include muscle hypotonia that makes infants feel "floppy," along with mild finger contractures and deviation of the finger tips, collectively described as distal arthrogryposis. Many children have acetabular or hip dysplasia that may lead to hip or knee dislocation if untreated. Neurological involvement is central. All reported individuals show autistic behavior with challenges in speech, social interaction, and repetitive activities. Cognitive development is variably affected: some children have mild intellectual disability while others have moderate or, less commonly, severe difficulties. Focal motor or absence seizures typically start in childhood and may require long-term management. Parents sometimes notice microcephaly (a smaller-than-average head size) as growth progresses. Orthopedic concerns can evolve over time. Camptodactyly, hammertoes, and scoliosis may become more apparent with growth spurts, and joint contractures can limit range of motion. Because growth of the jaw is reduced, retromicrognathia may affect feeding or breathing. Not all individuals experience every feature, and severity varies considerably. Families should be aware that cognitive, behavioral, and orthopedic needs can change as the child grows, and early supportive therapies can make a meaningful difference.

The syndrome is caused by pathogenic variants in the SLC35A3 gene. SLC35A3 encodes a transporter that moves nucleotide-sugars into the Golgi apparatus so that many proteins receive correct sugar chains. When the transporter does not work properly, multiple organ systems are affected, particularly developing joints and the brain. The condition follows an autosomal recessive inheritance pattern, meaning a child must receive one altered copy of the gene from each parent to be affected. Parents who each carry one altered copy are usually healthy but have a 25 percent chance with every pregnancy of having an affected child. This condition is more common when parents share a common ancestor because the likelihood that both carry the same rare genetic change is higher. Carrier testing and genetic counseling are strongly recommended for family members who may be planning future pregnancies.

Currently, management focuses on supportive care and symptom control tailored to each individual. Early involvement of a multidisciplinary team—including neurologists, developmental pediatricians, orthopedic surgeons, physical and occupational therapists, and speech-language specialists—helps address the broad range of needs. Seizures are treated with standard anti-seizure medications selected by a neurologist. Physical therapy and, when necessary, orthopedic surgery aim to maintain joint mobility and correct dislocations. Speech and behavioral therapies support communication and social development. Regular surveillance is an essential part of long-term care, helping to identify potential complications such as scoliosis or worsening contractures before they become serious. Genetic counseling provides families with information about recurrence risk and emerging research. Patients should discuss all management options with their healthcare team to determine which approaches are most appropriate for their specific situation.

Outcomes vary widely between individuals and depend on the severity of orthopedic issues, seizure control, and the degree of intellectual or behavioral challenges. With early intervention, many children make developmental gains, though most will require ongoing educational and therapeutic support throughout life. Life span data are limited because the condition is so uncommon, but there is no evidence that it shortens life expectancy when complications are well managed. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with expert centers and genetic counselors to stay updated on best practices and research opportunities.