DLG4-Related Synaptopathy: Expanding Understanding of Marfan-Like Features in a Rare Neurodevelopmental Disorder
Overview of DLG4-Related Synaptopathy
DLG4-related synaptopathy is an uncommon neurodevelopmental disorder linked to mutations in the DLG4 gene, which encodes the postsynaptic density protein 95 (PSD-95). This protein plays a critical role in synaptic function, and disruptions can lead to a diverse range of neurological and systemic symptoms.
Case Report Highlights
A recent case from Brazil detailed a 21-year-old man exhibiting a complex clinical picture that included chronic musculoskeletal pain, sensory hypersensitivity, tremors, cognitive decline, and traits consistent with autism spectrum disorder (ASD). In addition to neurological symptoms, the patient displayed marfanoid characteristics—features reminiscent of Marfan syndrome, a connective tissue disorder.
Other reported issues involved gastrointestinal symptoms such as gastroesophageal reflux, dysphagia, and constipation, as well as urinary difficulties including hesitancy and nocturnal polyuria. Visual disturbances and impaired sleep quality were also noted.
Genetic Findings and Diagnostic Challenges
Genetic testing through whole-exome sequencing identified a heterozygous missense variant (c.149A>T; p.Tyr50Phe) in the DLG4 gene. However, this variant is currently classified as one of uncertain significance (VUS), meaning its direct role in causing the patient’s symptoms remains unclear. Cytogenetic analysis showed a normal male karyotype (46,XY).
Clinical Implications and Management
This case underscores the broad and heterogeneous nature of DLG4-related synaptopathy, which can manifest with neurodevelopmental symptoms, sensory disturbances, and connective tissue-like features. The patient is receiving multidisciplinary care and symptomatic treatment with pregabalin to manage chronic pain.
What This Means for Families and Clinicians
Clinicians should be aware of DLG4-related synaptopathy as a potential diagnosis in individuals presenting with a combination of neurodevelopmental challenges and marfanoid traits. Early genetic evaluation can aid in clarifying diagnoses, guiding treatment strategies, and potentially improving outcomes.
Limitations and Future Directions
Because the identified genetic variant is of uncertain significance, definitive conclusions about genotype-phenotype correlations cannot yet be drawn. Further research and case accumulation are necessary to better understand the spectrum of symptoms and the underlying genetic mechanisms.
For more detailed information, see the original report at PubMed.
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