Última actualización:
8/23/2023
Años publicados: 2016, 2019, 2023
NORD gratefully acknowledges the KCNQ2 CURE Alliance and Kristen Park, MD, Associate Professor, Department of Pediatrics, University of Colorado School of Medicine, Associate Program Director for the Epilepsy Fellowship at Children’s Hospital of Colorado, for assistance in the preparation of this report.
Summary
Children with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) typically present with seizures in the first week of life. Seizures appear as stiffening of the body (tonic) often associated with jerking and changes in breathing or heart rate. The seizures are usually quite frequent (many per day) and often difficult to treat. Typically, the seizures are associated with abnormal brain wave patterns on EEG during this time. The seizures often resolve within months to years, but children have some degree of developmental impairment involving one or more domains (motor, social, language, cognition). This can range from mild to severe depending on several different factors. Some children may also have autism or other neurobehavioral issues. Other, less common presentations have also been reported including later onset seizures, intellectual disability without seizures, infantile spasms and sudden twitching (myoclonus).
The story of KCNQ2-DEE begins with the identification and characterization of another related disorder, benign familial neonatal seizures (BFNS) now called SLFNE (self-limited familial neonatal epilepsy). This condition was initially described as a syndrome in 1964 by Rett and Teubel. They reported a family with eight affected individuals over 3 generations. The youngest infant had the onset of seizures at three days of age described as tonic-clonic events occurring multiple times per day. The EEG was normal in between seizures and the children developed appropriately after the seizures stopped later in infancy. Over the next twenty years, additional families with similar stories were described. In a few instances, seizures persisted into later life, but outcomes were otherwise favorable. The pattern of inheritance was determined to be autosomal dominant (see the Affected Populations section for further explanation) and genetic testing linked the disorder to the long arm of chromosome 20 (see the Causes section for further definition). In 1998, researchers identified a gene in the region that appeared similar in structure to a potassium channel within the heart. This new gene was named, according to convention, KCNQ2. Subsequently, several families were identified in which the outcome was not benign having either persistent seizures that did not respond to medication, developmental impairment or both. This prompted a group of researchers to screen patients with severe neonatal epilepsy syndromes for changes (variants or mutations) in KCNQ2. Eight children were identified from the group of 80 patients and the children shared many characteristics. Since that initial paper in 2012, many more individuals have been diagnosed and the syndrome has been defined further. Approximately 200 individuals with KCNQ2-DEE have been reported in the medical literature.
The gene that is altered in patients with KCNQ2-DEE is the gene for a potassium channel within the brain.
KCNQ2 belongs to a family of other ion channel genes and is sometimes abbreviated Kv7.2 to reflect that it is the 7th out of 12 different subgroups containing more than 40 genes. Ion channels are pores in the cell membrane that allow charged atoms (ions) to flow into and out of cells and play a key role in a cell’s ability to generate and transmit electrical signals. Electrical signals are one of the main mechanisms of neuronal communication but also control heartbeat and muscular contractions.
These ion channel genes share important properties and are named to reflect them. “K” is the chemical symbol for potassium which is a positively charged atom. CN is an abbreviation for channel. This gene is the 2nd member of the Q subfamily which indicates that the channel is voltage gated. This means that the channel opens according to the charge in its cellular environment. Variants in the KCNQ2 gene cause a spectrum of disease that ranges from self-limited seizures in infancy to epileptic encephalopathy likely based on the degree of dysfunction in this channel and whether variants cause it to work poorly (loss of function) or be overactive (gain of function). Those that cause encephalopathy are typically located in several areas including the pore and voltage sensor; however, recent literature suggests that distinguishing presentations based on location may be more complex than initially thought. Much research is being done to determine how to accurately classify a gene variant as causative of disease (pathogenicity) and predict whether it causes a severe or milder presentation. Current testing and analysis allow for accurate pathogenicity assessments in about 90% of patients but are not yet able to reliably determine severity.
Epilepsy is estimated to affect 1 in 26 people during their lifetime with an incidence of approximately 44/100,000 people. The incidence is highest in young children and older adults with children often having the most severe types of epilepsies. The incidence of epilepsy in children under 2 years of age is estimated to be 70.1 per 100,000 based on a recent population-based study conducted in North London. In this research, severe epilepsies associated with abnormal development and EEG (epileptic encephalopathies) were identified in 22 (39%) of 57 infants and were associated with several genetic causes.
KCNQ2-DEE affects males and females in equal numbers. Estimates of incidence are difficult for rare diseases but two recent studies using population data and novel genetic methodologies suggest KCNQ2-DEE occurs in 1/17,000 births or ~6/100,000. Patients can go undiagnosed or misdiagnosed, often due to the accessibility of genetic testing, making it difficult to determine the disorder’s true frequency in the general population.
KCNQ2-DEE is considered an autosomal dominant disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual (de novo). Most children with KCNQ2-DEE have a de novo gene variant in contrast to SLFNE which frequently runs in families. A small number of patients with KCNQ2-DEE have a gene variant inherited from an unaffected or mildly affected parent in a pattern called mosaicism. This means that only some cells in the parent’s body contain a copy of the altered gene and they may have mild or no symptoms. Sometimes, the gene variant is found only in egg or sperm cells which is called germline mosaicism. In such situations, the risk of having another affected child is estimated at 1-2%.
The diagnosis of KCNQ2-DEE is made by molecular genetic testing. This can be done by examining only the potassium channel gene or by testing that looks for changes in several genes associated with epilepsy in infancy or childhood. Most children with KCNQ2-DEE have a single letter misspelling in the gene but some have a deletion of some or part of the gene (10%).
Clinical Testing and Work-up
One of the first steps in the evaluation of new onset seizures in an infant is to characterize the patterns of brain activity associated with the seizures. This is done by performing an electroencephalogram or EEG. This is a painless and non-invasive means of recording the patterns of electrical activity of the brain. Electrodes placed on the scalp pick up and record the electrical waves during periods of activity, sleep and during seizures. KCNQ2-DEE is often associated with a burst-suppression pattern on EEG but may have other epileptiform abnormalities and is typically not normal between seizures, in contrast to SLFNE.
When seizures are present in infancy, there are several potential causes that may need to be excluded before genetic testing is pursued. This often depends on the presentation and other clinical factors. Tests that may be performed include evaluations for infection, electrolyte disturbances, metabolic disorders and structural problems in the brain. Magnetic resonance imaging (MRI) is a radiological technique that produces detailed images of cross-sections or slices of the brain by using a magnetic field. The images can provide information concerning any malformation of the brain structures or other types of lesions commonly seen in epilepsy.
Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, developmental pediatricians and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.
In some children, it is possible that treatment with anticonvulsant drugs may help reduce or control various types of seizure activity associated with KCNQ2-DEE. Anticonvulsant medications have many different mechanisms of action, and it is not entirely clear which medications are best for patients with KCNQ2-DEE. Some reports suggest that children respond best to medications which affect how sodium or potassium flow into nerve cells; however, the number of children reported may be too small to draw these conclusions. If seizures fail to respond to medication, other treatments including specialized diets, devices and surgeries may be considered.
Information on current clinical trials is posted on the Internet at www.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 National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about KCNQ2E:
Kristen Park, MD
Children’s Hospital of Colorado
Associate Professor of Pediatrics
University of Colorado School of Medicine
720-777-6895
[email protected]
TEXTBOOK
Miceli F, et al. KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism. EBioMedicine 2022; 81:104130.
Bureau M, Genton P, Dravet C, Delgado-Escueta AV, Tassinari CA, Thomas P and Wolf P. Epileptic Syndromes in Infancy, Childhood and Adolescence. (5th ed.). Paris, FR: John Libbey Eurotext; 2012.
JOURNAL ARTICLES
Ritter DM, Horn PS, Holland KD. In silico predictions of KCNQ variant pathogenicity in epilepsy. Pediatr Neurol 2021; 118:48-54.
López-Rivera JA, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain 2020; 143(4):1099-1105.
Millichap, J.J., et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurology Genetics 2016 Oct; 2(5): e96.
Eltze, C. M., et al. A population-based study of newly diagnosed epilepsy in infants. Epilepsia 2013;54(3): 437-445.
Kato, M., et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia 2013;54(7): 1282-1287.
Weckhuysen, S., et al. Extending the KCNQ2 encephalopathy spectrum: Clinical and neuroimaging findings in 17 patients. Neurology 2013;81(19): 1697-1703.
Weckhuysen, S., et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012;71(1): 15-25.
Nabbout, R. and O. Dulac. Epileptic encephalopathies: a brief overview. J Clin Neurophysiol 2003;20(6): 393-397.
INTERNET
KCNQ2 Gene. MedlinePlus. April 1, 2013. Available from https://medlineplus.gov/genetics/gene/kcnq2/ Accessed August 15, 2023.
Developmental and Epileptic Encephalopathy 7; DEE7. Online Mendelian Inheritance in Man (OMIM). MIM Number: 613720. Last edited 10/13/2020. https://www.omim.org/entry/613720#:~:text=Entry%20%2D%20%23613720%20%2D%20DEVELOPMENTAL%20AND,EPILEPTIC%20ENCEPHALOPATHY%207%3B%20DEE7%20%2D%20OMIM Accessed August 15, 2023.
Miceli F, Soldovieri MV, Weckhuysen S, et al. KCNQ2-Related Disorders. 2010 Apr 27 [Updated 2022 May 19]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK32534/ Accessed August 15, 2023.
RIKEE – Rational Intervention for KCNQ2/3 Epileptic Encephalopathy
https://www.rikee.org/ Accessed August 15, 2023.
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
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