NORD gratefully acknowledges Natacha Esber, MD, Director, Research and Scientific Committee, KAT6A Foundation, for assistance in the preparation of this report.
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 (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 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 are still trying 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 of 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. Most children experience delays in reaching developmental milestones like sitting up or crawling. Speech delays are also common, and can be significant. Most children have better receptive language skills, which means that they can understand more information spoken to them than they are able to speak themselves (express language skills). Some children will improve and may develop normal language skills, but others may remain relatively 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 difficulties feeding 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.
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. According to the KAT6A 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. Additional symptoms that have also 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.
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 particular 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. These types of enzyme are 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.
In cases where a variation in KAT6A is disease causing, the disorder 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. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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 regardless of the sex of the resulting child.
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 KAT6A Foundation, as of October 2018, there are 150 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 underdiagnosed and one estimate 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 a 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 similar to 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 particular organs and bodily tissues. An MRI of the brain can reveal degeneration or damage to the brain. An echocardiogram is 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.
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. Pediatricians, surgeons, physicians who specialize in diagnosing and treating heart disorders (cardiologists), physicians who specialize in diagnosing and treating eye disorders (ophthalmologists), physicians who specialize in diagnosing and treating digestive disorders (gastroenterologists), speech therapies, physical therapies, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is also recommended.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with KAT6A syndrome.
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 have required surgery. Regular examination of the eyes is recommendation 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 sign language and various communication devices. Periodic reassessments and adjustment of services should be provided with all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.
According to a poster presented at David W. Smith Workshop on Morphology and Morphogenesis in August 2018, some affected children have metabolic abnormalities consistent with mitochondrial disease. Mitochondria, found by the hundreds within virtually every cell of the body, generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The poster notes that several severely-affected patients were treated with an antioxidant cocktail (a combination of antioxidants) and some mildly-affected patients were treated with carnitine and pantothenic acid. Most patients showed improved motor and cognitive abilities and a decreased number of infections. See poster abstract below:
KAT6A Syndrome: Deficiency of a Histone Acetyltransferase as the Cause of Mild to Severe Mitochondrial Disease. R.I. Kelley, MD, PhD. Department of Genetics and Genomics, Boston Children’s Hospital, Boston, MA.
After the referral of several children with KAT6A syndrome beginning in 2016, a standardized set of laboratory tests was established and used in the evaluation of 28 children and adults with KAT6A. These tests included plasma amino acid levels measured at 4 to 5 hours fasting; plasma levels of vitamin E, Coenzyme Q10, total homocysteine, and lactate; and routine CBCs and chemistry profiles. Amino acid levels were converted into normalized ratios-to-mean for analysis. By definition, the mean normalized ratio-to-mean is 1.00, with most diagnostically important amino acids having standard deviations of 0.12 to 0.16, as determined in 180 controls.
The most common amino acid abnormalities were increased levels of citrulline (16/28; mean 1.28) and asparagine (10/28, mean 1.24), with variably increased or decreased levels of other amino acids associated with mitochondrial diseases. However, whereas only 1 of 23 subjects under age 10 had amino acid levels and other metabolic abnormalities diagnostic of mitochondrial disease, 4 of 5 subjects over age 10 had moderately severe mitochondrial disease, suggesting cumulative, age-related oxidative damage. Treatment with a mitochondrial antioxidant cocktail in severely affected patients or only carnitine + pantothenic acid (to augment complex I activity) in several more mildly affected patients led to improved motor and cognitive abilities and a decreased number of infections in most treated subjects. In addition, despite having normal absolute plasma methionine levels, 3 of 6 subjects with low normalized methionine levels had other evidence of systemic methionine deficiency (anemia, low total homocysteine level, high MCV).
Both histone acetylation and methylation are dynamic processes that respond to and affect mitochondrial function, among other aspects of cellular metabolism. Although quantifying gene expression is a standard way to study gene regulatory effects in disorders of histone modification, the results reported here show the utility, including immediate clinical benefits, of planned metabolic studies to find the causes of clinical disease in syndromes whose clinical problems are often attributed to their associated prenatal developmental abnormalities.
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Kennedy J, Goudie D, Blair E, et al. KAT6A syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. Genet Med. 2018;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30245513
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/
Unique. KAT6A Syndrome. 2017. Available at: https://www.rarechromo.org/media/information/Chromosome%20%208/KAT6A%20Syndrome%20FTNW.pdf Accessed October 30, 2018.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:616268; Last Update:03/23/2015. Available at: https://www.omim.org/entry/616268 Accessed October 30, 2018.
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