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DLG4-related synaptopathy
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

DLG4-related synaptopathy

DLG4-related synaptopathy is a rare genetic condition affecting neurological development, characterized by delayed development, intellectual disability, and potential loss of learned skills.

Overview

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 become 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, including:

  • Brain tissue loss (atrophy)
  • Abnormalities of the tissue connecting the left and right halves of the brain (corpus callosum)
  • Abnormalities of the hippocampus, a region of the brain involved in learning and memory

Symptoms

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 are common in people with this condition, including:

  • Impaired muscle coordination (ataxia)
  • Involuntary muscle coordination (dystonia)
  • Rhythmic shaking (tremor)

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.

Vision and Gastrointestinal Issues

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)
  • 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 (GERD).

Frequency

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

Causes

The DLG4 gene provides instructions for making a protein that plays a role in nerve cells 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 be caused by signaling changes at certain synapses. In addition, changes that impact synapse development and activity may cause seizures in people with this condition.

Inheritance

This condition is inherited in an autosomal dominant manner, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These affected individuals have no history of the disorder in their family.

Other Names for This Condition

  • Intellectual developmental disorder 62
  • Intellectual developmental disorder, autosomal dominant 62
  • SHINE syndrome
  • Sleep disturbances, hypotonia, intellectual disability, neurologic disorder, and epilepsy syndrome

Frequently Asked Questions

Skill regression, especially in speech and fine motor abilities, is a recognized feature of DLG4‑related synaptopathy and often begins after the age of 2. Early intervention with speech‑language therapy, augmentative communication devices, and consistent home practice can help maintain function longer, although some decline may still occur. Regular monitoring by a developmental pediatrician is essential to adjust therapy plans as needed.
targeted single‑gene test or a comprehensive neurodevelopmental gene panel that includes DLG4 is appropriate. Testing can be done via blood or saliva DNA. If the pathogenic variant is identified, the sibling should have baseline neurodevelopmental assessment, EEG, and brain MRI even if asymptomatic, because early detection allows prompt therapy and surveillance for seizures or skill regression.
Yes, ocular misalignment (strabismus) and migraine are reported in a minority of patients. An ophthalmologist should evaluate the strabismus for possible corrective lenses, patching, or surgery. For migraines, a pediatric neurologist can recommend lifestyle triggers, acute abortive agents (e.g., ibuprofen or triptans if appropriate), and preventive medication if attacks are frequent. Treating these comorbidities improves overall quality of life.
Seizures occur in about half of affected individuals. Management follows standard epilepsy protocols: obtain a baseline EEG, start a first‑line antiseizure medication (e.g., levetiracetam or valproic acid) and titrate to seizure control while monitoring side effects. Because DLG4 mutations can affect brain structure, periodic neuroimaging is advised to rule out progressive atrophy that might influence drug choice. A neurologist experienced in genetic epilepsies should oversee care.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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