By: Sofia Arreguin
Dup15q Gene Mutation and Epilepsy
What is Dup15q?
Chromosomes are essential building blocks of living organisms, containing the DNA, genes, and proteins that define the characteristics of a human body. Humans have 46 chromosomes in each cell, half inherited from the mother and the other half inherited from the father, and each strand is paired with another to create 23 pairs of chromosomes (National Library of Medicine, 2024). However, abnormalities in chromosomal structures can alter how the human body develops; deletions, rearrangements, and duplications are possible occurrences that can result in syndromes.
Chromosome 15q11.2-13.1 Duplication Syndrome (Dup15q syndrome) is a rare genetic disorder that results from duplications on chromosome 15, a nucleotide, or fundamental unit, that accounts for more than three percent of DNA (National Library of Medicine, 2024). For this condition to manifest and become classified as Dup15q syndrome, at least one copy of 15q11.2-13.1, a section that contributes to human development within the long arm (q) of chromosome 15, must be duplicated and inherited from the mother; this parent-specific gene activation is identified as genomic imprinting (National Organization for Rare Disorders [NORD], 2024; National Library of Medicine, 2019). The duplications must include the Prader-Willi/Angelman critical region (PWACR), a segment within 15q11.2-13.1 that contains genes essential to development, and can occur in two ways: isodicentric 15 chromosome (idic(15)) or interstitial duplication 15 (int dup(15)). Idic(15), the most common form, contains a unique chromosome that offers a mirror image of DNA segments and possesses two centromeres, unlike typical one-centromere chromosomes (NORD, 2024). Here, a phenomenon known as tetrasomy for 15q11.2-13.1 occurs, where the standard two copies of a chromosome are present alongside an additional two copies of 15q11.2-13.1, resulting in four copies of the region (NORD, 2024). During a typical cell division, sister chromatids each hold one centromere, which is then pulled by spindle fibers into opposing directions to different cells; however, when sister chromatids each have two centromeres, spindle fibers will attach to each centromere on a single chromatid and continue to pull in opposing directions (Warburton, 2001). As a result, the chromatid becomes stretched out and takes on the shape of a bridge, which is eventually broken and leads to unstable connections with other chromosomes, ultimately causing changes to DNA sequences, such as duplications. The less common form of manifestation is the int dup(15), where a phenomenon known as trisomy occurs, in which one additional copy of 15q11.2-q13.1 appears on one of the two chromosome 15s, forming three copies of the region (NORD, 2024). Such mutations or genetic alterations disrupt normal bodily development.
Dup15q Related Epilepsy
The overexpression of the UBE3A gene in the 15q11.2-q13.1 chromosomal region prompts the expression of seizures, a symptom experienced by many affected individuals (Thodeson et al., 2026). Studies found that UBE3A overexpression can lessen the likelihood of glutamatergic synaptic transmission, a process that releases the excitatory neurotransmitter glutamate (Smith et al., 2011). Typically, seizures occur as a result of too much glutamate in the brain, producing hyperexcitable neurons and excessive neuronal electrical charges; however, low glutamate release can also impact seizure susceptibility. The inhibitory neurotransmitter, GABA, works to calm the excitable energy produced by glutamate; glutamate initiates the release of GABA to reduce the likelihood of overexcitability. When there are low glutamate levels, there is no trigger for the release of GABA, resulting in low levels of GABA in the brain. From this deficiency, surrounding neurons may begin to fire electrical signals repeatedly and simultaneously, eventually causing a seizure.
Seizure types include infantile spasms, myoclonic, focal, absence, or tonic-clonic seizures that initially develop from six months to nine years of age. Infantile spasms, or muscle contractions, typically occur before the age of one, and can be dangerous for and harmful to the developing brain of a baby. These spasms can grow into Lennox-Gastaut syndrome, involving drug-resistant and difficult-to-manage seizures (National Library of Medicine, 2019). Patients may also experience myoclonic seizures, which often involve the involuntary movement of the limbs, or focal seizures, which affect one side of the brain and also cause involuntary, or jerky, limb movements, changes to the senses, and emotional shifts. Tonic-clonic seizures, characterized by loss of consciousness, rigidity, and jerky movements, may also manifest, as can absence seizures, which involve “staring spells,” described as a blank stare at a fixed point, and unresponsiveness from the affected patient (National Library of Medicine, 2019). Such seizures can lead to a fatal condition known as sudden unexpected death in epilepsy (SUDEP), wherein individuals with epilepsy, especially teenagers and young adults, die during their sleep (NORD, 2024). The brain, pulmonary, and cardiac systems cease to function, resulting in a decline in respiration and pulse rate, and, therefore, death.
Dup15q syndrome imposes other symptoms on patients, as well, including low muscle tone (hypotonia), developmental or speech delays, autism spectrum disorder (ASD), and intellectual disability (NORD, 2024).
Hypotonia. Low muscle tone is most common in infants and presents certain complications in motor development. Newborns typically experience difficulty with feeding, specifically with latching and swallowing, as a result of their weak facial muscles. As they reach the ages of two and three, the children begin to develop the ability to walk independently; however, their walking pattern (gait) deviates from a steady or smooth gait and is often described as unsteady (ataxic) or as a staggering walk, involving wide stances to maintain balance and multiple missteps or stumbles due to low muscle tone in the legs (National Library of Medicine, 2019). Delays in sitting, crawling, weak cries, and drooling are additional symptoms that can be seen in infants. Individuals can even experience joint hyperextensibility, where joint muscles move beyond typical muscle flexibility, which may lead to joint dislocations or chronic pain in the future (Kalsner & Chamberlain, 2015).
Speech Delays. Abnormal speech patterns normally present in affected patients include echolalia, a form of repetitive speech of phrases, words, or sounds heard from their surroundings; reverse pronouns, where an individual may use the term “you” to describe themselves; and limited speech, or the absence of functional speech (NORD, 2024).
Autism Spectrum Disorder (ASD). Most patients experience difficulty with socially engaging and communicating with others, oftentimes avoiding bodily contact with others or showing a disinterest in peers. Many exhibit behavioral issues, such as displaying tantrums and aggressiveness, or engage in stereotypies, such as hand clapping or flapping, repeated spinning, or wringing fingers (Kalsner & Chamberlain, 2015). Difficulty with changes to routine, anxiety or frustration, mood disorders, or hyperactivity are also features that can manifest within patients.
Physical characteristics. Individuals possess a flattened nasal bridge with an upturned nose, nostrils that face upward (anteverted nostrils), a wide expanse between the nose and lips (philtrum), full lips, a small jaw (micrognathia), downslanted outer corners of the eyes (downslanting palpebral fissures), flattened back of the skull (occiput), low-set ears, and strabismus, a condition where the eyes look in opposing directions (National Library of Medicine, 2019).
Additional symptoms include: scoliosis, eczema, overeating, excessive weight gain, eye problems, reduced ability to feel pain, hearing loss, sleep problems, cardiac issues, respiratory infections, early puberty or irregularity in menses for females, genital abnormalities for males, and, in rare cases, psychosis (NORD, 2024).
Treatment and Research
Although there is no existing cure for Dup15q syndrome, there are treatment and therapy options to help manage symptoms. Medical professionals should consider performing a physical examination on the patient to detect any irregularities in the body, such as feeding difficulties in infants. Neurological examinations should also be conducted to discover abnormalities in brain activity, such as increased electrical activity or structural damage. Meeting with specialists is also recommended to support the development of the individual, manage seizure frequency, and slow the decline of speech, mobility, and cognition. The team of specialists can include speech therapists to improve communication skills, occupational or physical therapists to refine motor function, and applied behavioral analysis (ABA) specialists to regulate behavioral reactions and help patients achieve greater independence (NORD, 2024).
Other recommendations include monitoring one’s caloric intake to prevent excessive weight gain, increasing melatonin levels to address sleep problems, and the administration of serotonin reuptake inhibitors to manage behavioral issues (Kalsner & Chamberlain, 2015). Serotonin is a neurotransmitter associated with impulse and emotional control; preventing its reuptake, or removal, allows it to remain in the brain longer to exert its effects. In the event that a female experiences a loss of menstruation (amenorrhea) or develops irregular menstrual cycles (oligomenorrhea), obtaining low dosages of estrogen, or a combination of estrogen and progesterone, are viable treatment options (Kalsner & Chamberlain, 2015). For males who experience hypogonadism, a deficiency of testosterone or sex hormones, human chorionic gonadotropin (hCG) can be administered to increase testosterone production (Kalsner & Chamberlain, 2015).
Medications are typically prescribed to help regulate seizure frequency, including valproic acid, clonazepam, lamotrigine, and clobazam, and avoidance of seizure triggers, such as stress or sleep deprivation, is often recommended to further manage the onset of seizures (Kalsner & Chamberlain, 2015). For the management of infantile spasms, the adrenocorticotropic hormone (ACTH) can be provided to prevent the occurrence of seizures or abnormal neuronal activity. Once these spasms evolve into Lennox-Gastaut syndrome, medications normally used to treat epilepsy can be used, including carbamazepine, rufinamide, valproic acid, zonisamide, and lamotrigine (Kalsner & Chamberlain, 2015). For those unresponsive to medication, it is recommended that they participate in the ketogenic diet, a low-carbohydrate program that produces ketones to help calm excessive neuronal excitability.
Consulting a medical professional about any signs and difficulties is the best way to find the most efficient treatment option to treat or manage symptoms. Emotional support from family members or people close to the affected patient is also beneficial to help provide a supportive and comforting environment in their journey of gaining better control over their symptoms.
References
Kalsner, L., & Chamberlain, S. J. (2015). Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes. Pediatric Clinics of North America, 62(3), 587–606. https://doi.org/10.1016/j.pcl.2015.03.004
National Library of Medicine. (2019, January 1). 15q11-q13 duplication syndrome. MedlinePlus. https://medlineplus.gov/genetics/condition/15q11-q13-duplication-syndrome/
National Library of Medicine. (2024, April 26). Chromosome 15. MedlinePlus. https://medlineplus.gov/genetics/chromosome/15/#conditions
National Organization for Rare Diseases. (2024, September). Dup15q syndrome. https://rarediseases.org/rare-diseases/dup15q-syndrome/
Smith, S. E., Zhou, Y. D., Zhang, G., Jin, Z., Stoppel, D. C., & Anderson, M. P. (2011). Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Science Translational Medicine, 3(103), Article 103ra97. https://doi.org/10.1126/scitranslmed
Thodeson, D., Lockard, T., & Koh, S. (2026). Genomics of Complex Neurodevelopmental Disorders with Variable Epilepsy Phenotypes: A Clinical Review of Dup15q Syndrome. Genes, 17(2), 163. https://doi.org/10.3390/genes17020163
Warburton, P. E. (2001). Epigenetic analysis of kinetochore assembly on variant human centromeres. Trends in Genetics, 17(5), 243-247. https://doi.org/10.1016/S0168-9525(01)02283-1
