What are the other Names for this Condition? (Also known as/Synonyms)

• KAT6A Gene Syndrome

What is KAT6A Syndrome? (Definition/Background Information)

• KAT6A Syndrome is a rare genetic abnormality that involves the KAT6A gene located on chromosome 8. In this disorder, either the gene function is disrupted, or the gene is missing, resulting in a set of neurodevelopmental signs and symptoms
• This chromosomal anomaly may develop from sporadic mutations (in many cases), or it may be inherited from one’s parents (in some rare cases). KAT6A Syndrome may be diagnosed through specialized genetic testing. In some children, the condition may be mild and hence can also remain undiagnosed. Features that often occur include feeding difficulties, developmental delays, seizures, recurrent infections, speech and language challenges, and abnormal facial features
• Following a diagnosis, the condition may be managed based on the presenting symptoms and extent of involvement of the body systems. The treatment may involve physician experts from several specialties, and can include the use of speech and language therapy, physiotherapy, and seizure control, as needed
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with KAT6A Syndrome are able to cope well through adequate treatment and supportive care. Some of the signs and symptoms associated with the condition are known to improve with time

Who gets KAT6A Syndrome? (Age and Sex Distribution)

• The incidence of KAT6A Syndrome is presently unknown. It is a rare disorder with less than 200 cases reported in the medical literature
• In many cases, individuals with mild signs and symptoms may be undiagnosed in their lifetime. Hence, a true incidence of the disorder may be difficult to estimate
• KAT6A Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for KAT6A Syndrome? (Predisposing Factors)

In a majority of cases, there are no identified risk factors for KAT6A Syndrome.

• In some rare cases, a positive family history is noted that may be an important risk factor for KAT6A Syndrome
• Currently, no environmental and lifestyle (including dietary) factors have been implicated
• The syndrome is not caused by what the expectant mother does or does not do, either prior to or during pregnancy

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of KAT6A Syndrome? (Etiology)

KAT6A Syndrome is caused by abnormalities involving the KAT6A gene. In a majority of cases, this disorder is caused by abnormal changes/mutations to the KAT6A gene that is located on the short arm (p) of chromosome 8, at location p11.21.

• The changes result in abnormal functioning of one of the two copies of the gene leading to associated signs and symptoms. In some cases, one copy of the gene on chromosome 10 may be missing or absent
• The KAT6A gene, or K (lysine) acetyltransferase 6A gene, is responsible for controlling the expression of several other genes and for production of hematopoietic stem cells
  • The gene is known to undergo several forms of genetic alterations, notably stop gains or frameshift mutations, resulting in a shortened form of the protein (that the gene encodes for)
  • In some cases, the disorder arises from what is known as a “missense” mutation, wherein there is a misplacement of building blocks causing faulty gene function

There are two chromosomes numbered 8. Children with KAT6A Syndrome typically will have one (chromosome 8) in normal condition, while the other may be abnormal. The abnormality is characterized by a loss of chromosomal material.

• A vast majority of the cases develop sporadically (de novo) during embryonic development. This means that no deletion of genetic material at 8p is observed in either of the parents
• However, KAT6A Syndrome can also be inherited, even though presently no such cases are recorded in the medical literature (probably attributed to a lack of adequate testing/diagnosis)

It is important to note that a child’s development and future is not only influenced by the chromosome material duplicated/deleted and genes involved, but also by other factors such as one’s environment, involvement of other genes, and unique personality.

Additional (general) information on chromosomes, which is helpful in understanding the disorder:

Chromosomes are microscopic thread-like protein structures present in each cell nucleus that carry genetic information in the form of DNA (deoxyribonucleic acid). DNAs are nucleic acids that encodes the genetic information of any organisms; a basic unit of the DNA is termed a gene with a specific set of instructions and a defined function. Each chromosome is “X” shaped with a center, called the centromere, and two short arms (termed p arms) and two long arms (termed q arms).

Humans have 46 chromosomes in the cell nucleus, in 23 pairs, of which one pair is named the sex chromosome. In males, it is designated XY, for chromosome X and chromosome Y; while, in females, it is designated XX, for a pair of chromosome X. The other 22 pairs of chromosomes are numbered chromosome 1 through 22, approximately according to size (with chromosome 1 being the largest; chromosome 21 being the smallest) and are referred to as autosomes or somatic chromosomes. During conception, the embryo inherits one copy of each chromosome from each parent (i.e., mother and father). Any alteration in the chromosome numbers or structure, such as via addition or deletion of chromosomal material, can result in mild to severe genetic abnormalities that may manifest as birth defects, growth delays, and intellectual disabilities.

What are the Signs and Symptoms of KAT6A Syndrome?

The signs and symptoms of KAT6A Syndrome may be significantly different from one individual to another. The degree of signs and symptoms are often related to the amount of chromosome material deleted and the number of genes affected.

The commonly noted signs and symptoms of KAT6A Syndrome that involve the eyes, brain, and lymphatic systems include:

• Feeding problems (sucking and swallowing) leading to small and underweight children
• Constipation is observed in many children
• Developmental delays are known to affect all children with the syndrome
• Poor muscle tone, or hypotonia, leading to floppy babies
• Seizures are noted in a few cases
• Learning disabilities and speech delays
• Language challenges are observed in nearly all cases
• Presence of small-sized head (microcephaly) - noted in some children
• Abnormal facial features may be mild and include large and prominent nose, thin upper lip, and droopy eyelids (ptosis)
• Congenital heart anomalies that may include valve defects and persistent ductus arteriosus (PDA)
• Eye defects may include strabismus (squint) and refractive errors resulting in poor vision
• Behavioral issues, such as anxiety, frustration, or repetitive behavior, have been observed in a few children
• Some children report sleep disturbances

How is KAT6A Syndrome Diagnosed?

Children can have varying signs and symptoms. Some children with mild signs and symptoms may go undiagnosed in their lifetimes. Given the rarity of the condition, the healthcare provider should have a high index of suspicion to consider KAT6A Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

KAT6A Syndrome is diagnosed on the basis of the following information:

• Complete physical examination and thorough medical history evaluation, including family medical history
• Assessment of the presenting signs and symptoms, including evaluation of body systems such as vision, hearing, muscles, heart, kidneys, central nervous system, genitalia, and immune system
• Hearing and vision assessment through various tests
• Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
• Radiological studies of the affected regions, as needed
• Assessment of cardiac function
• Neurological examination that involves the central nervous system (brain and spinal cord)
• Behavioral studies
• Prenatal studies including abdominal ultrasonography
• Specialized genetic testing techniques are often required to confirm the diagnosis. This may include:
  • Fluorescence in situ hybridization (FISH) testing
  • Array comparative genomic hybridization (array-CGH)
  • DNA sequencing

Often, karyotyping of the chromosome is not adequate to diagnose the condition, since individuals with this condition can have normal karyotype chromosomal studies.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of KAT6A Syndrome?

The complications of KAT6A Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Delayed milestone achievement; children tend to take longer to roll, sit, and walk (mean age at walking is about 28 months)
• Cortical visual impairment
• Recurrent infections that involve the ear, chest, and urinary tract; some infections may be severe
• Severe communication difficulties
• Reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is KAT6A Syndrome Treated?

There is no cure for KAT6A Syndrome since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. It also depends on the severity of the signs and symptoms and the body systems affected. Individuals with mild signs and symptoms may require periodic monitoring without significant medical intervention. Often, a multidisciplinary team of specialists including pediatricians, ophthalmologists, otolaryngologists, neurologists, internists, cardiologists, endocrinologists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for KAT6A Syndrome may involve:

• Speech and language therapy; the use of sign language may be beneficial
• For feeding difficulties, use of feeding tubes (temporary nasogastric or gastrostomy tubes), medications, feed thickeners, bottle-feeding expressed milk, including special diets and nutritional supplements
• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet: Seizure control is important to ensure that the child’s learning ability is not significantly affected
• Special education: Employing suitable learning strategies via music therapy, visual and tactile books, touch screen computers, etc.
• Physiotherapy for weakened muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, and other adapted activities; use of specially-designed toys and daily-used items (such as spoons and cups)
• Use of walking aids
• Heart abnormalities may require surgical correction in some cases; some defects, such as patent ductus arteriosus, tend to improve over time without any invasive procedures
• Use of suitable glasses and/or surgical correction of vision defects
• Sleep disorders may require medication
• Antibiotic therapy for infections including prophylactic treatment
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary

Regular medical screening at periodic intervals with tests and physical examinations are necessary and highly recommended.

How can KAT6A Syndrome be Prevented?

KAT6A Syndrome may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. Also, some cases are sporadic occurrences, which means there is no family history of the condition.

In many cases, the condition is familial, meaning they occur within families. In expecting parents with a familial history:

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

It is important to note that the chances of both the parents with normal chromosomes having another child with KAT6A Syndrome is highly unlikely. This may be confirmed via specialized prenatal testing and preimplantation genetic diagnosis (PGD), if needed. Prenatal tests may include chorionic villus sampling (CVS) and amniocentesis.

What is the Prognosis of KAT6A Syndrome? (Outcomes/Resolutions)

The prognosis of KAT6A Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any. It may be assessed on a case-by-case basis, but it is generally difficult to predict the long-term outlook.

• Children with mild conditions are generally able to cope well via appropriate treatment and adaptive behaviors as they get older
• Some children may require extended medical support and care

Presently, there are no recorded cases of malignancy (blood cancers)in children with KAT6A Syndrome.

Additional and Relevant Useful Information for KAT6A Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/