Última actualización:
December 13, 2019
Años publicados: 2016, 2019
NORD gratefully acknowledges John M Graham, Jr MD, ScD, Consulting Pediatrician, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center Professor Emeritus, Department of Pediatrics, David Geffen School of Medicine at UCLA, and Neda Zadeh, MD, FACMG, Medical Geneticist, CHOC Children’s Hospital, Associate Director, Molecular Diagnostic Laboratory at Genetics Center, for assistance in the preparation of this report.
Summary
KCNK9 imprinting syndrome is an extremely rare genetic disorder characterized by a variety of symptoms including distinctive facial features, varying degrees of the intellectual disability, and low muscle tone at birth (hypotonia). The specific symptoms and severity of the disorder can vary from one person to another. Because so few people with this disorder have been reported in the medical literature, researchers do not yet have a complete understanding of the symptoms potentially associated with the disorder. The KCNK9 imprinting syndrome is caused by an alteration in the maternal copy of the KCNK9 gene. An alteration in the paternal copy of the KCNK9 gene is not believed to be associated with disease.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and other factors prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below or may have symptoms that are not discussed. Every case is unique and the disorder can be different in one child when compared to another.
Affected children may have a head that is longer than would be expected (dolichocephaly). As infants and children age, distinctive facial features may become noticeable including an elongated face with a narrow bitemporal diameter, which means that the distance between the two temporal sutures (on the sides of the skull) is more narrow than normal. Additional facial features include full eyebrows that are arched and flared upward, a short groove or depression that runs from the nose to the upper lip (short philtrum), a tented upper lip, abnormalities of the roof of the mouth (cleft palate in 42% of known cases), and a small lower jaw (micrognathia) that is set back or recessed farther than normal (retrognathia) so that the upper and lower jaws don’t meet when the mouth is closed. The bridge of the nose may be narrow and high and the tip of the nose may be broad.
Severe generalized low muscle tone (hypotonia) may be present at birth (congenital). These children may be described as being ‘floppy.’ Infants may have low blood sugar after birth that eventually goes away on its own (transient neonatal hypoglycemia). Some infants experience severe difficulties with feeding because of a poor ability to suck. Children may have difficulty swallowing (dysphagia) liquids, and some children may require the placement of a gastrostomy tube to aid with feeding. They may also have difficulty speaking (dysphonia) and a muffled-sounding voice into early adulthood.
Older children have exhibited intellectual disability that has ranged from moderate to severe, delays in reaching developmental milestones, weakness of the muscles closest to the body (proximal muscles) such as those of the upper legs or upper arms, and reduced facial movements. Muscle weakness and hypotonia may eventually progress to cause contractures, which is when a joint becomes fixed, and this may be alleviated by physical therapy. Some children will develop seizures.
KCNK9 imprinting syndrome is caused by an alteration in the maternal copy of the KCNK9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
To date, a specific amino acid change (p.G236R) has been detected in the KCNK9 gene most likely as a recurrent de novo event in families. Recently, a single patient with a p.Ala237Asp alteration has also been described. The alteration in the KCNK9 gene that causes the disorder is a de novo alteration in the maternal copy of the gene. This means that the change in the gene occurred randomly and was not passed on from a parent. The likelihood of another child in the family having the disorder is extremely low.
This disorder involves a normal process called genetic imprinting. Everyone has two copies of every gene – one received from the father and one received from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders. With the KCNK9 gene, the copy received from the father is turned off or silenced. An alteration in this gene from the father is not associated with any consequences to the child, but it can be passed to his daughters, who would then be at risk to have affected children. The copy received from the mother is normally turned on. An alteration to the maternal copy of this gene leads to KCNK9 imprinting syndrome.
The KCNK9 gene contains instructions for producing (encoding) a specialized protein. This protein is important for the proper health and function of the TASK3 ion channel. Ion channels are pores in cell membranes that regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium ions) into various cells including nerve cells (neurons). These ions carry electrical impulses necessary for the normal function of the cells involved. TASK3 ion channels are found throughout the body, particularly in the brain. Alterations in maternal copy of the KCNK9 gene result in abnormal functioning (i.e. lack of activity) of this ion channel and, in turn, affect the proper function and development of nerve cells (neurons).
KCNK9 imprinting syndrome is an extremely rare disorder that has been described in only several families worldwide. The incidence and prevalence of the disorder is unknown. It is likely that people with this disorder go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of KCNK9 imprinting syndrome in the general population.
A diagnosis of KCNK9 imprinting syndrome is almost always made through molecular testing and confirmed by identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation with specialized tests to rule out other causes of congenital hypotonia. Molecular genetic testing looks for changes (mutations) in the KCNK9 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Most cases are diagnosed by whole exome sequencing, when a specific amino acid change (p.G236R) is detected in the KCNK9 gene.
Whole exome sequencing is a test that looks for genetic changes (mutations) in a small portion of the human genome called the exome. The human genome is a person’s complete set of DNA, including all of his or her genes. The exome is the part of the genome that contains the coding portions of the genes (exons) that code for the various amino acids that make up individual proteins. These proteins have wide and varied responsibilities in the body. Up to 84% of genetic disorders occur because of a change or alteration in these coding exons of the gene. Whole exome sequencing can identify a diagnosis of KCNK9 imprinting syndrome by detecting a specific mutation (p.G236R) in the KCNK9 gene that is known to cause this disorder.
Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the KCNK9 imprinting syndrome, there are no treatment trials that have been tested on a large group of patients. Based on research in mouse models, specific nonsteroidal inflammatory drugs (flufenamic acid and mefenamic acid) have been used to treat children with KCNK9 imprinting syndrome due to the G236R variant. There are anecdotal reports that a few children have shown a favorable response to these drugs with no adverse effects.
In general, treatment of KCNK9 imprinting syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, speech pathologists, specialists who diagnose and treat disorders of the stomach and intestines (gastroenterologists), psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.
Seizures may be treated with drugs that work to stop or reduce seizures (anticonvulsants). Children may benefit from occupational, physical and speech therapy. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well. Additional therapies for KCNK9 imprinting syndrome depend upon the specific abnormalities present.
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 NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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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, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Šedivá M, Laššuthová P, Zámečník J, Sedláčková L, Seeman P, Haberlová J, Novel variant in the KCNK9 gene in a girl with Birk Barel syndrome. European Journal of Medical Genetics 2019; Jan 25. pii: S1769-7212(18)30486-5. doi: 10.1016/j.ejmg.2019.01.009. ub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30690205
Graham JM Jr, Zadeh N, Kelley M, Tan ES, Liew W, Tan V, Deardoff MA, Wilson GN, Sagi-Dain L, Shalev SA. KCNK9 imprinting syndrome—further delineation of a possible treatable disorder. Am J Med Genet – Part A 2016;170(10):2632-2637. https://www.ncbi.nlm.nih.gov/pubmed/27151206
Veale EL, Hassan M, Walsh Y, Al-Moubarak E, Mathie A. Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol Pharmacol. 2014;85:397-407. https://www.ncbi.nlm.nih.gov/pubmed/24342771
Barel O, Shalev SA, Ofir R, et al. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J Med Genet. 2008;38:193-199. https://www.ncbi.nlm.nih.gov/pubmed/18678320
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Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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