Last updated:
1/23/2024
Years published: 2024
NORD gratefully acknowledges Madison Webster and Kali King, MD Candidates, Creighton University School of Medicine and Eric Marsh MD, PhD, Division of Neurology, Children’s Hospital of Philadelphia, for the preparation of this report.
Summary
IQSEC2-related disorder is a genetic condition that causes intellectual disability and sometimes other physical, neurological or psychiatric symptoms. Intellectual disability is noted in early development when a child does not meet motor, social or language milestones at a typical age. Characteristic symptoms include developmental delay in language, difficulties with social communication, abnormal hand movements and low muscle tone. This condition is caused by changes (variants or mutations) in the IQSEC2 gene located on the X chromosome that are not inherited. Males are more likely be affected but females can also be affected. Females tend to have milder symptoms. Patients described in the medical literature have been diagnosed as early as 8 months of age, with seizures occurring between 8 months to 4 years of age.
Introduction
In developed countries, around 2% of the population is affected by intellectual disabilities and there are over 100 known genetic causes. The IQSEC2 gene was first considered as a cause of neurologic disorders in 2008. As of 2024, over seventy distinct variants in the IQSEC2 gene have been identified. Several case series presenting children with intellectual disability and epilepsy with variants of the IQSEC2 gene have been published in the medical literature.
Patients with IQSEC2-related disorder have a range of intellectual disabilities. Some patients can live independently with minimal support, and others require 24-hour care and in-depth support for daily activities. Many are unable to walk independently and have minimal ability to talk or respond to commands. Most children also have some level of cognitive impairment, such as an inability to name body parts and common objects. Children with ISEC2-related disorder often have autistic features such as difficulty with communication, restricted interests, repetitive behaviors and lack of interest in other children. Associated mental health disorders may develop including anxiety, depression and schizophrenia.
Physical features may include a flattened head shape (plagiocephaly), a very small head (microcephaly), reduced muscle tone (hypotonia) and crossed eyes (strabismus).
Seizures typically present at an early age and often persist despite anti-seizure treatments. Many different types of seizures have been reported, including becoming limp (atonic), brief jerking (myoclonic), brief flexion or extension of a body part (epileptic spasms), blank staring (absence) and rhythmic jerking of the arms and legs (generalized tonic-clonic). MRI findings of the brain often show nonspecific white matter changes, thinning of the corpus callosum (nerve fibers joining the two hemispheres of the brain) and mild overall atrophy (structures smaller than usual).
Specific symptoms depend on the IQSEC2 gene variant (mutation). However, a precise relationship between the specific gene variant and physical characteristics has yet to be identified. Missense mutations (point changes causing a different amino acid to be added), nonsense mutations (early termination of the DNA reading), splice site mutations (change in DNA sequence at the processing site), deletions, duplications and structural variants in the IQSEC2 gene have all been described.
IQSEC2-related disorder is a genetic condition caused by variants in the IQSEC2 gene that are not inherited. The variant occurs spontaneously in the affected person (de novo variant). The gene change is not known to be caused by environmental exposures or events during pregnancy.
Variants in the IQSEC2 gene can result in a protein product that does not function normally. The IQSEC2 gene encodes for a protein called guanine nucleotide exchange factor (GEF) which activates cell signaling pathways. These pathways are important for conducting nerve impulses and the overall structure of a nerve. Excitation of nerves is necessary to form connections in the brain, which furthers development. Disorganized excitatory nerve pathways are likely responsible for the seizure activity in these children. It is these seizures that are thought to contribute to autism-like features.
As learning occurs in early childhood, new areas where excitatory nerves connect and communicate (synapses) in the brain develop. This results in an increased number of projections coming off a nerve. However, as time goes on and cognition becomes more refined, a process called “pruning” occurs, where extra projections are removed to increase the strength of communication between nerves (synaptic efficiency). Pruning is a part of normal brain maturation. It is hypothesized that individuals with IQSEC2-related disorder undergo less pruning and have nerve projections that do not mature properly.
The IQSEC2 gene is located on the X chromosome so IQSEC2-related disorder is an X-linked genetic disorder. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
It is estimated that fewer than 1,000 people in the U.S. have this disorder. There have been no studies to identify ethnic groups, regions or environmental factors that influence this disorder. Since IQSEC2-related disorder is an X-linked genetic disorder, more males are affected than females.
Physical examination and developmental assessments are not enough to make a diagnosis of IQSEC2-related disorder. If a child has intellectual disability and seizures, consultation with a genetic counselor and DNA testing is warranted. Identification of a pathogenic variant in the IQSEC2 gene confirms the diagnosis.
Patients should see a neurologist and start antiepileptic medication if they have frequent recurrent seizures. It is recommended to continue care with a neurologist to monitor dosage and maintain seizure control, as specific dosage can change over time. Unfortunately, most male children with IQSEC2 gene variants have drug resistant seizures.
A cure or treatment specific to IQSEC2-related disorder is not currently available. However, symptomatic treatment and supportive therapies can improve quality of life. Antiepileptic drugs can provide reduction in seizures. One study showed that in resource-limited settings, steroids may be considered for seizure control. Early intervention and education programs can assist with language development and learning. Physical therapy and occupational therapy can help with walking and performing daily activities.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Shoubridge C, Dudding-Byth T, Pasquier L, Goel H, Yap P, McConnell V. IQSEC2-related encephalopathy in males due to missense variants in the pleckstrin homology domain. Clin Genet. 2022;102(1):72-77. doi:10.1111/cge.14136
Jada R, Zag L, Borisov V, et al. Housing of A350V IQSEC2 pups at 37 °C ambient temperature prevents seizures and permits the development of social vocalizations in adulthood. Int J Hyperthermia. 2021;38(1):1495-1501. doi:10.1080/02656736.2021.1988730
Levy AP, Levy NS, Heyman E, Schertz M, Genizi J. Reduction in seizure burden in a child with a A350V IQSEC2 mutation using heat therapy with a Jacuzzi. Clin Case Rep. 2021;9(9):e04734. Published 2021 Aug 30. doi:10.1002/ccr3.4734
Nagabushana D, Chatterjee A, Kenchaiah R, Asranna A, Arunachal G, Mundlamuri RC. Response to steroids in IQSEC2-related encephalopathy presenting with rett-like phenotype and infantile spasms. J Pediatr Genet. 2020;12(1):76-80. Published 2020 Dec 7. doi:10.1055/s-0040-1721371
Accogli A, Eric Jarvis G, Schiavetto A, et al. Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder. J Genet. 2020;99:47.
Levy NS, Umanah GKE, Rogers EJ, Jada R, Lache O, Levy AP. IQSEC2-associated intellectual disability and autism. Int J Mol Sci. 2019;20(12):3038. Published 2019 Jun 21. doi:10.3390/ijms20123038
Shoubridge C, Harvey RJ, Dudding-Byth T. IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy. Hum Mutat. 2019;40(1):5-24. doi:10.1002/humu.23670
Mignot C, McMahon AC, Bar C, et al. IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients [published correction appears in Genet Med. 2018 Oct 2]. Genet Med. 2019;21(4):837-849. doi:10.1038/s41436-018-0268-1
Zipper R, Baine SD, Genizi J, Maoz H, Levy NS, Levy AP. Developmental progression of intellectual disability, autism, and epilepsy in a child with an IQSEC2 gene mutation. Clin Case Rep. 2017;5(10):1639-1643. Published 2017 Aug 24. doi:10.1002/ccr3.1139
Zerem A, Haginoya K, Lev D, et al. The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia. 2016;57(11):1858-1869. doi:10.1111/epi.13560
Alexander-Bloch AF, McDougle CJ, Ullman Z, Sweetser DA. IQSEC2 and X-linked syndromal intellectual disability. Psychiatr Genet. 2016;26(3):101-108. doi:10.1097/YPG.0000000000000128
INTERNET
Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome. Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=397933 Accessed Jan 17, 2024.
IQSEC2. Human Disease Genes – Clinical Characteristics. Updated 3/14/23. Accessed Jan 17, 2024.
IQSEC2- related disorder Unique. 2019.https://rarechromo.org/media/information/Chromosome_X/IQSEC2-related%20disorder%20FTNW.pdf Accessed Jan 17, 2024.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/