SLC35A2-congenital disorder of glycosylation

SLC35A2-congenital disorder of glycosylation (SLC35A2-CDG) is a multisystem neurodevelopmental condition caused by pathogenic variants in the SLC35A2 gene, which encodes a transporter needed for proper protein glycosylation. Disruption of this pathway alters the structure and function of many proteins, leading to early-onset neurological problems and characteristic facial features. Because the gene is located on the X chromosome, most individuals diagnosed are females, although males can be affected in rare circumstances. Symptoms usually begin in infancy, and the disorder is considered very rare, affecting fewer than one person in a million worldwide.

Severity and symptoms vary widely between individuals. The earliest signs often emerge in the first months of life and include epileptic spasms that can progress to an epileptic encephalopathy, along with generalized hypotonia that makes feeding and motor development challenging. Children typically show profound global developmental delay with absent or extremely limited speech. Distinctive facial characteristics such as thick eyebrows, a broad nasal bridge, coarse facial appearance, thick lips, mandibular prognathia, and an open mouth posture help clinicians recognize the disorder. Neurological involvement extends beyond seizures; many children experience intellectual disability, behavioral differences, and abnormalities seen on brain MRI such as cerebral atrophy or a thin corpus callosum. Other body systems can also be involved. Some individuals have cardiac findings such as an atrial septal defect, ocular anomalies, short stature from intra-uterine growth restriction, dental issues including fused teeth or enamel hypoplasia, and hypertension. Not all individuals experience all features, and severity can differ considerably even among people with the same diagnosis.

SLC35A2-CDG results from disease-causing variants in the SLC35A2 gene on the X chromosome. The SLC35A2 protein transports UDP-galactose into the Golgi apparatus, a key step required for attaching sugar chains to newly made proteins. When the transporter does not function properly, many proteins are inappropriately glycosylated, disrupting normal development and organ function. The condition is usually described as X-linked. Because females have two X chromosomes, they may be variably affected depending on which X chromosome is active in each cell, while males, who have only one X chromosome, can be more severely affected if they survive to birth. Many diagnosed cases appear to arise sporadically with no previous family history, but an affected individual can pass the variant to future children. Families are therefore encouraged to meet with a genetic counselor to discuss testing options, reproductive planning, and the possibility that mildly affected or asymptomatic relatives could carry the variant.

Currently, management focuses on supportive care and symptom management. Seizures often require antiepileptic medications, and some families explore ketogenic or modified diets under medical supervision. Early intervention services, physical therapy, occupational therapy, and speech therapy aim to maximize developmental potential and address hypotonia and absent speech. Given the multisystem nature of the disorder, long-term care is coordinated by a multidisciplinary team that may include neurology, cardiology, ophthalmology, dentistry, and nutrition specialists. Regular surveillance is an essential part of long-term care, helping to identify potential complications such as cardiac defects, hypertension, or progressive cortical changes before they become serious. Treatment plans are highly individualized, and families should work closely with their healthcare team to determine which interventions are most appropriate. Genetic counseling is recommended for relatives who may be at risk and for parents considering future pregnancies.

Outcomes depend on many factors including the severity of epilepsy, the extent of developmental delays, and access to specialized care. Some children achieve better seizure control and make incremental developmental gains, while others continue to experience frequent seizures and profound cognitive challenges. Feeding difficulties, respiratory issues related to hypotonia, and medical complications from organ involvement can affect overall health and quality of life. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with expert clinicians and patient support networks to share practical strategies and remain informed about emerging research.

Clinical trials are underway exploring new treatment approaches, including therapies aimed at improving glycosylation or controlling seizures more effectively. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.