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Last updated:
6/15/2023
Years published: 2018, 2023
NORD gratefully acknowledges Natacha Esber, MD, Director, Research and Scientific Committee, KAT6A Foundation, for assistance in the preparation of this report.
Summary
KAT6A syndrome is an extremely rare genetic neurodevelopmental disorder in which there is a variation (mutation) in the KAT6A gene. Variations in the KAT6A gene can potentially cause a wide variety of signs and symptoms; how the disorder affects one child can be very different from how it affects another. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common symptoms include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), delays in being able to speak and communicate (speech delays) and diminished muscle tone (hypotonia). Additional symptoms including abnormalities affecting the heart, eyes and gastrointestinal system can also occur. In most instances, variations in the KAT6A gene occur spontaneously and there is no family history of the disorder (de novo variations). Treatment is based on the specific symptoms present in each individual.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about KAT6A syndrome is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of additional genes, environmental factors, or other factors influencing the disorder have prevented physicians and researchers from developing a complete picture of associated symptoms and prognosis.
The potential symptoms associated with a variation in the KAT6A gene are numerous and highly variable. With genetic disorders, the specific type of variation (e.g., type of mutation, or location in the gene) can be associated more often with specific symptoms. This is called genotype-phenotype correlation. Researchers continue to determine whether there are any specific genotype-phenotype correlations in KAT6A syndrome. It is important to note that every child is unique and that affected individuals may not have all the symptoms discussed below. How the disorder affects one child can be very different from how it affects another child.
Almost all children with KAT6A syndrome have intellectual disability. Intellectual disability can range from mild to severe. The degree of intellectual disability may be hard to determine at first, because other symptoms may make evaluation difficult. Standardized measures used to assess intellectual functions often rely on speech and communication abilities. With delays in these abilities, it is challenging to fully map out the neuropsychological profile of children with KAT6A gene variation. Most children experience delays in reaching developmental milestones like sitting up or crawling.
Severe speech, language and communication difficulties are present in KAT6A syndrome. Most children are minimally verbal and alternative/augmentative communication approaches are required for many into adult life. Receptive language skills are relatively better than expressive language skills, which means that children with KAT6A gene variation can understand more information spoken to them than they are able to speak themselves. Some children may improve language skills, more in the receptive domain compared to the expressive, but others may remain relatively limited in their speech abilities or nonverbal through adulthood.
Affected infants may have microcephaly, a condition in which the circumference of the head is smaller than would otherwise be expected based on age and gender. Less often, affected infants have craniosynostosis, which is a general term for the improper development of the bones of the skull, which can result in an abnormal head shape in affected individuals. Craniosynostosis refers to the premature fusion of the fibrous joints (sutures) between certain bones of the skull. The severity of primary craniosynostosis can vary from one person to another.
As affected infants age, they may experience feeding difficulties because of problems with the movements of the muscles of the face (oromotor dysfunction). Some children have difficulty swallowing (dysphagia), and there can be a risk of food, liquid or other foreign material accidentally going into the lungs (aspiration). Infants can have additional symptoms involving the gastrointestinal tract including backflow of the contents of the stomach into the esophagus (gastroesophageal reflux), constipation, and abnormally twisting or rotation of the intestines (intestinal malrotation), which can cause pain and bowel obstruction. Bowel obstruction can be life-threating if not treated promptly. Based on a parent report published on the KAT6 Foundation’s page, untreated bowel obstructions are the leading cause of death among children affected by the KAT6A gene variation.
Some affected individuals have heart defects that are present from birth (congenital heart defects). These can include atrial and ventricular septal defects. Septal defects are when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles, or in the membrane that separates the two upper chambers of the heart, called the atria. The size of these ‘holes will determine whether any symptoms are present, and how severe these symptoms may be. Additional congenital heart defects can include an abnormal opening between the main artery of the lungs (pulmonary artery) and the aorta (patent ductus arteriosus), and patent foreman ovale, in which the normal hole between the two atria that allows blood to bypass the fetal lungs, fails to close as it normally should.
Some infants and children have distinctive facial features. This can include a broad tip of the nose, which can become more pronounced as a child grows older. Additional features include a thin upper lip, low-set ears, a prominent bridge of the nose, and narrowing of the temporal bones that make up the sides and base of the skull. Additional features include a droopy eyelid (ptosis), downturned corners of the mouth and an abnormally small jaw (micrognathia). The eyes can be misaligned (strabismus), and sometimes vision may be reduced because the eye and brain are not working together properly (amblyopia). Less often, additional eye symptoms can occur including nearsightedness (myopia), farsightedness (hypermetropia), and rapid, involuntary eye movements (nystagmus). Teeth abnormalities are common and include peg-shaped teeth, abnormally small teeth, extra (supernumerary) teeth, and crowding of the teeth.
Behavioral issues are common in KAT6A syndrome. Some children display some of the signs and symptoms that are seen in children on the autism spectrum. Such behavioral issues can include temper tantrums, hand flapping and other repetitive behaviors, inappropriate laughing, frustration, and anxiety. Coping with everyday demands that includes self-care and interacting with others can be challenging for children with KAT6A gene variation. According to the KAT6 Foundation and the medical literature, many parents have reported that their children are happy, sociable and good natured.
Many affected individuals have difficulties with sleep such as difficult falling asleep and remaining asleep. A few individuals have developed obstructive sleep apnea. Sleep apnea is a condition characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms include frequent interruptions of sleep at night and excessive sleepiness during the day. To manage sleep issues, parents of children with KAT6A gene variation often seek medical advice and rely on medications.
Additional symptoms that have been reported include cleft palate and weakened cartilage of the walls of the bronchial tubes (bronchomalacia). Some individuals experience recurrent infections, including repeated middle ear infections (otitis media) or respiratory infections. Some individuals have developed seizures, complex movement disorders, or an excessive startle reaction. There are also a few children who have had pinkies that are fixed or “locked” in a bent or curved position (clinodactyly) or abnormally short fingers (brachydactyly). In boys, there may be a delay or failure of the testes to descend into the scrotum (cryptorchidism).
There are several different symptoms that have been identified in only one or a few individuals. Researchers are not sure yet whether these are potential symptoms of KAT6A syndrome, or coincidental findings resulting from another cause. Such symptoms include food allergy or intolerance, short stature and abnormalities associated with the pituitary gland. Deficiency or abnormality of the immune system, which can contribute to repeated infections, has been suspected in some individuals, but is unproven.
It is not necessary for the KAT6A syndrome’s clinical features to have a strong association with the type or location of the gene variation. However, for core features such as intellectual disability, speech and communication delays, microcephaly, cardiac anomalies and gastrointestinal complications, studies on genotype-phenotype correlations have shown that these core features are more prevalent in late truncating mutations.
KAT6A syndrome is caused by a variation (mutation) in the KAT6A gene. This gene is also known as the MOZ or MYST3 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.
The KAT6A gene contains instructions for creating (encoding) a protein (or enzyme) that is vitally important to the body. This enzyme is believed to have multiple jobs in the body. It is classified as a type of histone acetyltransferase. These enzymes modify histones, which are structural proteins that bind to DNA and help to give chromosomes their normal shape. The KAT6A enzyme helps to control the expression of other genes and the activity and expression of other proteins in the body. This enzyme helps to regulate a wide variety of chemical processes in the body. Consequently, this enzyme is involved in various aspects of health and development, and a variation in the KAT6A gene can lead to a wide variety of issues.
The variation in the KAT6A gene almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent.
If a person with KAT6A syndrome were to have a child, they could pass the altered KAT6A gene on to their children through autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy.
KAT6A syndrome is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to the KAT6 Foundation, as of December 2022, there are 350 individuals known to have the disorder. Rare disorders like KAT6A syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. KAT6A syndrome is often underdiagnosed, and a 2015 report suggests that the disorder may account for as much as 1% of undiagnosed individuals with syndromic developmental delay.
A diagnosis of KAT6A syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. A diagnosis is confirmed through molecular genetic testing.
Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variations in the KAT6A gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having KAT6A syndrome and the sample will undergo whole exome sequencing (WES). WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the KAT6A gene that are known to cause disease, or variations in other genes known to cause symptoms like this syndrome.
Affected individuals may undergo additional tests to assess the extent of the disease. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An MRI of the brain can reveal degeneration or damage to the brain. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects sometimes associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with KAT6A syndrome.
Neurologic examination is important for individuals with the symptoms of KAT6A syndrome. Neurologic examination helps identify the specific features affecting a person. Laboratory tests, neurophysiologic testing, and neuroimaging; routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions); and analysis of cerebrospinal fluid (obtained by “spinal tap”) may be conducted to help exclude alternate and co-existing diagnoses.
Treatment
Infants with KAT6A syndrome should be evaluated for feeding issues and treated with standard methods if necessary. This can include insertion of a nasogastric feeding tube, which is a thin tube that delivers food to the stomach via the nose and esophagus. Constipation can be severe and may result in multiple hospital admissions. About 50% of children with congenital heart disease require surgery. Regular examination of the eyes is recommended to detect potential eye complications such as misalignment (strabismus).
Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Speech therapy is required. Affected children have benefited from the use of augmentative and alternative communication strategies such as sign language, picture boards, smart phone applications and speech-generating devices. Periodic reassessments and adjustment of services should be provided to all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.
The treatment of KAT6A syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including, but not limited to, surgeons, cardiologists, ophthalmologists, gastroenterologists, speech therapists and physical therapists. A metabolic genetic specialist has an important role in managing the overall care of the patient, communicating with all the specialists and providing genetic counseling to the affected individuals and their families. Psychosocial support for the entire family is also recommended.
The KAT6 Foundation is working with researchers around the world to develop more surrogate models (e.g., induced pluripotent stem cells) with the goal of better understanding the pathophysiology of the gene mutation and for drug repurposing trials. The Foundation is also collaborating with clinicians with the goal of starting clinical trials on individuals affected with the KAT6A Syndrome.
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:
Toll-free: (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
Munuera-Cabeza M, Álvarez-Córdoba M, Suárez-Rivero JM, et al. Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome. Genes (Basel). 2022;13(12):2300. Published 2022 Dec 6. doi:10.3390/genes13122300
St John M, Amor DJ, Morgan AT. Speech and language development and genotype-phenotype correlation in 49 individuals with KAT6A syndrome. Am J Med Genet A. 2022;188(12):3389-3400. doi:10.1002/ajmg.a.62899
Smith C, Harris J. Sleep, Behavior, and Adaptive Function in KAT6A Syndrome. Brain Sci. 2021;11(8):966. Published 2021 Jul 23. doi:10.3390/brainsci11080966
Kennedy J, Goudie D, Blair E, et al. KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. Genet Med. 2019; 850-860. https://doi.org/10.1038/s41436-018-0259-2
Efthymiou S, Salpietro V, Bettencourt C, Houlden H. Paroxysmal movement disorder and epilepsy caused by a de novo truncating mutation in KAT6A. J Pediatr Genet. 2018;114-116. https://www.ncbi.nlm.nih.gov/pubmed/30105118
Trinh J, Huning I, Yuksel Z, et al. A KAT6A variant in a family with autosomal dominantly inherited microcephaly and developmental delay. J Hum Genet. 2018;63:997-1001. https://www.ncbi.nlm.nih.gov/pubmed/29899504
Murray CR, Abel SN, McClure MB, et al. Novel causative variants in DYRK1A, KARS, and KAT6A associated with intellectual disability and additional phenotypic features. J Pediatr Genet. 2017;6:77-83. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423827/
Yan K, Rousseau J, Littlejohn RO, et al. Mutations in the chromatin regulator gene BRPF1 cause syndromic intellectual disability and deficient histone acetylation. Am J Hum Genet. 2017;100:91-104. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223032/
Zwaveling-Soonawala N, Maas SM, Alders M, et al. Variants in KAT6A and pituitary anomalies. Am J Med Genet A. 2017;173:2562-2565. https://www.ncbi.nlm.nih.gov/pubmed/28636259
Elenius V, Lahdesmaki T, Hietala M, Jartti T. Food allergy in a child with do novo KAT6A mutation. Clin Transl Allergy. 2017;7:19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480172/
Tham E, Lindstrand A, Santani A, et al. Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features. Am J Hum Genet. 2015;96:507-513. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375419/
Arboleda VA, Lee H, Dorrani N, et al. De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay. Am J Hum Genet. 2015;96:498-506. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375619/
ABSTRACT
Kelley RI. KAT6A Syndrome: Deficiency of a Histone Acetyltransferase as the Cause of Mild to Severe Mitochondrial Disease. 39th Annual
David W. Smith Workshop on Malformations and Morphogenesis. https://kat6a.org/wp-content/uploads/2022/07/Kelley-DWSmith-2018-Poster-1.pdf PMID 30724471, page 729, 2018.
INTERNET
Unique. KAT6A Syndrome. 2017. Available at: https://www.rarechromo.org/media/information/Chromosome%20%208/KAT6A%20Syndrome%20FTNW.pdf Accessed June 14, 2023.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:616268; Last Update: 05/13/2021. Available at: https://www.omim.org/entry/616268 Accessed June 14, 2023.
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