congenital brain dysgenesis due to glutamine synthetase deficiency

Congenital brain dysgenesis due to glutamine synthetase deficiency is a severe multisystem condition primarily affecting the central nervous system and other organ systems. It is caused by pathogenic variants in the GLUL gene, which encodes the enzyme glutamine synthetase, important for glutamine production. Affected individuals present in the neonatal period with respiratory distress and distinct neurological findings along with metabolic abnormalities. This condition is very rare, affecting fewer than 1 in 1,000,000 people.

The clinical presentation is marked by several characteristic features. Neurologically, there is severe global developmental delay, seizures, and brain atrophy, with structural abnormalities such as hypoplasia of the corpus callosum and decreased cerebrospinal fluid glutamine concentration being consistently observed. Many affected children experience generalized hypotonia, lower limb hyperreflexia, and episodes of apnea, all of which contribute to significant developmental challenges. In addition, respiratory issues such as neonatal respiratory distress and recurrent respiratory infections are common, while various dysmorphic features including low-set ears, short nose, and depressed nasal bridge may be present in a subset of individuals. Not all individuals experience all features, and severity varies considerably.

This condition is caused by pathogenic variants in the GLUL gene, which encodes glutamine synthetase, a protein vital for maintaining adequate glutamine levels in the brain and body. Its deficiency disrupts normal brain development and metabolic balance, leading to features such as hypoglutaminemia and hyperammonemia. The condition is inherited in an autosomal recessive pattern, meaning that both parents must carry a copy of the altered gene. It is more common when parents share a common ancestor, which increases the likelihood that both carry the same rare variant. Genetic counseling is recommended to help families understand these inheritance implications.

Currently, management focuses on supportive care and symptom management, with treatment tailored to the individual’s needs. There are no treatments specifically approved for this condition, so a multidisciplinary team approach is recommended to address both neurological and systemic symptoms. Supportive strategies may include respiratory support, physical and occupational therapy, and other interventions aimed at improving quality of life. Regular surveillance is an essential part of long-term care to identify potential complications early, and genetic counseling is advised for affected families.

The clinical course is complex and variable, with affected individuals facing significant neurodevelopmental challenges from an early age. Outcomes vary depending on the severity of symptoms, age at diagnosis, and access to specialized care. With current standards of care, many individuals benefit from a multidisciplinary approach and regular monitoring, although the condition remains lifelong with potential periods of stabilization interspersed with challenges in motor function and respiratory health. Outcomes described in medical literature continue to evolve as standards of care improve, and families often find it helpful to connect with specialists familiar with this condition.

Clinical trials are underway exploring new treatment approaches for this condition. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.