DLG4-related synaptopathy

DLG4-related synaptopathy is a condition that affects neurological development. This condition is characterized by delayed development and mild to moderate intellectual disabilities that typically becomes evident before age 2. Over time, many individuals with DLG4-related synaptopathy lose skills that they have learned, such as speech or motor skills. About 20 percent of people with this condition cannot speak. Affected individuals often have neurodevelopmental disorders, such as autism spectrum disorder or attention-deficit/hyperactivity disorder. About half of individuals with this condition have recurrent seizures (epilepsy) that typically begin in childhood. Brain changes can also occur. These include brain tissue loss (atrophy) and abnormalities of the tissue connecting the left and right halves of the brain (corpus callosum) or the  hippocampus, which is a region of the brain that is involved in learning and memory.

Individuals with DLG4-related synaptopathy can also have weak muscle tone (hyptonia), loose joints (joint laxity), or a spine that curves to the side (scoliosis). Movement problems, including impaired muscle coordination (ataxia), involuntary muscle coordination (dystonia), or rhythmic shaking (tremor) are common in people with this condition. Other problems can include migraine, sleep problems, or anxiety. Some people with DLG4-related synaptopathy have a distinctive body type that includes a long face, slim body, and long fingers.

Less commonly, DLG4-related synaptopathy can affect a person's vision. Affected individuals can have eyes that do not point in the same direction (strabismus), farsightedness (hyperopia), or involuntary movements of the eyes (nystagmus). Some affected individuals have blindness because the area of the brain responsible for processing vision is impaired. 

DLG4-related synaptopathy can also cause gastrointestinal difficulties that make it difficult to eat. These can include a backflow of stomach acids into the esophagus (gastroesophageal reflux disease or GERD).

DLG4-related synaptopathy is a rare disorder, although its exact prevalence is unknown. This condition has been reported in at least 100 people.

The DLG4 gene provides instructions for making a protein that plays a role in nerve cells (neurons) in the brain. The DLG4 protein is found at synapses, which are the connections between neurons where cell-to-cell communication occurs. The DLG4 protein plays roles in synaptic signaling, development, survival, and function. In particular, this protein interacts with other proteins to regulate a process called synaptic plasticity, which allows synapses to change and adapt over time in response to experience. Synaptic plasticity is critical for learning and memory.

Variants (also called mutations) in the DLG4 gene cause DLG4-related synaptopathy. Most of these variants impair the normal function of the DLG4 protein by decreasing its ability to interact with the other proteins involved in synaptic plasticity or decreasing its ability to help synapses send signals. Other variants prevent the production of any normal DLG4 protein. The signs and symptoms of DLG4-related synaptopathy are likely caused by the reduced ability of synapses to change and adapt during important periods of brain development. Movement problems seen in people with DLG4-related synaptopathy may because caused by signaling changes at certain synapses. In addition, changes that impact synapse development and activity may cause seizures in people with this condition.

Genetic Testing Information

• Genetic Testing Registry: Intellectual developmental disorder 62

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62; MRD62

Scientific Articles on PubMed

• PubMed

• Levy AM, Gomez-Puertas P, Tumer Z. Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners. Int J Mol Sci. 2022 Apr 15;23(8):4390. doi: 10.3390/ijms23084390. Citation on PubMed
• Rodriguez-Palmero A, Boerrigter MM, Gomez-Andres D, Aldinger KA, Marcos-Alcalde I, Popp B, Everman DB, Lovgren AK, Arpin S, Bahrambeigi V, Beunders G, Bisgaard AM, Bjerregaard VA, Bruel AL, Challman TD, Cogne B, Coubes C, de Man SA, Denomme-Pichon AS, Dye TJ, Elmslie F, Feuk L, Garcia-Minaur S, Gertler T, Giorgio E, Gruchy N, Haack TB, Haldeman-Englert CR, Haukanes BI, Hoyer J, Hurst ACE, Isidor B, Soller MJ, Kushary S, Kvarnung M, Landau YE, Leppig KA, Lindstrand A, Kleinendorst L, MacKenzie A, Mandrile G, Mendelsohn BA, Moghadasi S, Morton JE, Moutton S, Muller AJ, O'Leary M, Pacio-Miguez M, Palomares-Bralo M, Parikh S, Pfundt R, Pode-Shakked B, Rauch A, Repnikova E, Revah-Politi A, Ross MJ, Ruivenkamp CAL, Sarrazin E, Savatt JM, Schluter A, Schonewolf-Greulich B, Shad Z, Shaw-Smith C, Shieh JT, Shohat M, Spranger S, Thiese H, Mau-Them FT, van Bon B, van de Burgt I, van de Laar IMBH, van Drie E, van Haelst MM, van Ravenswaaij-Arts CM, Verdura E, Vitobello A, Waldmuller S, Whiting S, Zweier C, Prada CE, de Vries BBA, Dobyns WB, Reiter SF, Gomez-Puertas P, Pujol A, Tumer Z. DLG4-related synaptopathy: a new rare brain disorder. Genet Med. 2021 May;23(5):888-899. doi: 10.1038/s41436-020-01075-9. Epub 2021 Feb 17. Citation on PubMed
• Tumer Z, Dye TJ, Prada C, White-Brown AM, MacKenzie A, Levy AM. DLG4-Related Synaptopathy. 2023 Jun 22. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK592682/ Citation on PubMed