I live in New York, USA. My son, Peter, was diagnosed with severe autism and global developmental delay at the age of 18 months. We didn’t have a KAT6A diagnosis till the age of 8 years old. After many online research, after talking with multiple geneticists around the country and talking to other families with the same diagnosis, I started giving Peter the mitochondrial cocktail following Dr Richard Kelley recommendations.

Here’s my experience with the mitochondrial cocktail:

– At 4 weeks after the start of the cocktail, Peter became potty-trained during the day without any training. He pulled his pull up off, refused to put it back on.

-At 2 months, Peter started riding his bike with no training wheels and playing soccer. He became able to kick the ball and run after it till he scores.

-At 2.5 months, he started skiing independently. I used to try to teach how to ski since he was 3yo. I used to spend hours and hours picking him up off the snow with no result. I tried different kind of reinforcers (food,..) with no result. After the cocktail, he just went down the hill by himself, He can ski independently now and knows how to make turns.

-At 2-3 months, I started noticing an increased strength in playing ice hockey and street hockey with a better understanding of the game. His typing ability improved too, he used to have severe apraxia while typing (type the letter next to the letter he wants to type…).

-At 3-4 months, Peter’s fingers on the piano became stronger, he became able to play harder songs with less training and less frustration. I also noticed an increase in “common sense” like for example putting his backpack in the car instead of throwing it on the floor next to the car and riding the car without his backpack. Another example, when we go to the public library, he knows by himself that he has to go to the children section, and walks independently without showing him directions to the play area inside the children section. In the past, he used to grab books the time he enters the library, throw a tantrum on the floor. The most important milestone is that Peter started to say few words that I can understand.

-At 11 months, Peter became potty-trained at night. His speech is slowly getting clearer. His fine and gross motor skills are still getting better.

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Jack was born at full term in February 2016. As soon as Jack came into the world, he decided to give his parents a run for their money. He was born with Sagittal Synostosis, a heart murmur, Laryngomalacia, and undescended testicles. In the first year of Jack’s life he had 3 surgeries: a Cranial Vault Reconstruction to fix the Synostosis, a Supraglottoplasty to help with the Laryngomalacia, and a double Orchiopexy, which also resulted in a hernia repair. At that time, we also had a gastronomy tube placed because Jack had stopped eating by mouth around 6 months and was losing weight. Throughout all of this, Jack was a trooper. He was strong and happy and was often found smiling in post-op… the nurses and doctors easily fell in love.

Jack began receiving PT, OT, and Speech Therapy services through Birth to Three at 4 months old. Now 21 months, he continues to receive these services in addition to a private Speech Therapist, who focuses on feeding therapy since Jack is still primarily fed through a g-tube, and an Aquatic Physical Therapist. We are hoping that within the next year and a half Jack will be able to eat solely by mouth and we can remove the g-tube. Jack attends a special needs program for children under the age of 3. He goes 2 days a week for 3 hours a day. He has a one-to-one aide, and it’s the best thing we could have found for him. He’s challenged and content, and we’ve seen major muscular and cognitive developments since he started in September 2017.

Last winter Jack spent more than 23 days in Yale’s PICU for Rhinovirus and Parainfluenza. The first time we brought him to the ER was the most traumatic. He had been sick for a few days after Thanksgiving. We found him in his crib one morning grey and struggling to breathe. He was intubated upon arrival at the hospital and remained so for 9 days. Although Rhinovirus is a common virus for children to contract, Jack struggled overcoming the illness because of his abnormal airway obstruction, which is simply a part of his anatomy. The next 2 hospital stays were for the same reason. Although the doctors discussed putting in a trach to avoid future dangerously low oxygen levels, we decided to hold off to see whether or not Jack can overcome this on his own as he grows bigger and stronger.

In addition to being followed by 12 specialists, Jack works with Dr. Richard Kelley, an expert in metabolic diseases and biochemistry, and Vicki Kobliner, a nutritionist. Dr. Kelley created a mitochondrial ‘cocktail’ for Jack based off of his metabolic abnormalities, and we’ve seen great improvements in Jack’s development since he began taking it. Vicki helped create a blenderized diet for Jack, so he eats a well balanced nutritious meal 3 times a day, all through his g-tube. He probably eats a healthier diet than most people I know!

It has definitely been a journey thus far with our little man. He brings us so much happiness everyday despite all that we’ve been through with him. Watching Jack hit milestones brings tears of joy to our eyes. His most recent accomplishment is sitting up by himself! We can only hope that he’ll continue to develop and thrive, and we can’t wait to see what he achieves next!

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Life for us living with this has been a challenge some days. Izzy was a preemie of 2lbs 10 oz. She was in the NICU for 5 weeks. She is not our biological daughter but came to live with us 2 weeks post NICU. From the start she vomited most of her feedings. She grew very slowly at first and at 5 months old was hospitalized with pneumonia from aspirating her spit up. They did a swallow study and diagnosed her with GERD. We then started feeding her 1-2 oz of severely thickened formula every 2 hours….slowly increasing until we were at 3-4. She never ate more than 4oz until she was over 2. Needless to say, I was exhausted!

As she has aged, we experienced slightly delayed walking and talking. She had a tough time potty training but by 4.5…she had it down for the most part. Today she is 6.5 and in kindergarten. We are seeing learning delays by about 2 yrs but she is so happy and brightens any room! We are finishing testing with neuropsych and occupational therapy and will have an appointment with the school for an IEP soon.

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Ma plus belle histoire d’amour. ..

Ma plus grande bataille…

Mon étoile de l espoir…

Mon trèfle à quatre feuilles, unique, extraordinaire…

Toi!!!

Ma guerrière Chloé

-Poème de Carine (la mère de Chloé)

English Translation:

My most beautiful love story. ..

My biggest battle …

My star of hope …

My four leaf clover, unique, extraordinary …

You!!!

My warrior Chloe

-Poem by Carine (Chloe’s mother)

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Bonjour voilà nous avons eu le diagnostic du KAT6A le 13 septembre dernier notre petite Lysie âgé de 3 ans. Ce qui engendre des retard psychomoteur intellectuelle et des acquisitions elle est hypotonique . Je vais essayer de vous expliquer au mieux le parcours de notre princesse. Dès la naissance Lysie ne s’alimenter pour bcp à la maternité il nous disais que c’était normal qu’elle avais avaler du liquide amniotique. Lui donner le biberon était un combats Lysie pleurer beaucoup on avais l’impression qu’elle souffrait o était impuissant.

Même les geste du quotidien était difficile la promener en poussette ou en voiture était un calvaire que des pleure même les courses impossible jusqu’à à peut près 1 Mois sa va mieux Lysie commence et être un peut plus poser. Au niveau repas la a etait le gros problème Lysie vommisser énormément elle manger pas de morceau il a fallu tout broyer dans son lait à l’aide d’un robot puissant le Thermomix ce qu’il lui a permis de commencer à prendre un peut de poid il y avait plus aucun morceau . En janvier dernier j’ai réduit fortement mon activité professionnelle pour m’occuper de Lysie je n’est pas lâcher prise j’ai insister surtout sur le repas à je vous dis pas Lysie a énormément vomi mais nous avons eu une victoire Lysie mange normalement de tout et de régale c’est un plaisir de la voir manger .

Sur le développement Lysie a marcher tard à 20 mois la piscine la beaucoup aider elle a tenu assise à 10 mois à peut près. Actuellement Lysie ne joue pas vraiment avec ces jouet elle jette plutôt impossible de la tenir sur une activité plus de 10 min nous travaillons sur cela a l’aide d’une éducatrice spécialisée elle est tjr frustrer et a peur de tout. Elle met encore tout à la bouche et croque dans tout à en avoir des morceau en bouche . Elle a des problèmes ophtalmologique on a rdv prochainement ,une malformation aux oreilles petites oreilles donc très petit conduit. Lysie marche mais tombe facilement et se fatigue vite. Elle a une malformation au cœur également . Pour notre part elle n’est pas constipée elle a un rythme régulier une a deux fois par jour à la selle .

Voilà j’espère avoir pu vous faire partager la vie de lysie vraiment pas facile pour moi d’expliquer.

bonne réception amicalement

Séverine

English Translation:

Hello,
Here we have received the diagnostic of KAT6A last September 13 for our little Lysie 3 years old. This generates intellectual psychomotor delay and acquisitions. She is hypotonic. I will try to explain the best course of our Princess. From birth she did not nurse well. They said it was normal since she had swallowed amniotic fluid. The bottle was a fight. Lysie cried a lot. We had the impression that she was suffering or was helpless.

Even the gesture of daily life was difficult. To walk her in a stroller or car was an ordeal. Her crying made it impossible until close to 1 month where she seemed better. Mealtime was a big problem. She vomited a lot and everything had to be ground into her milk using a powerful robot Thermomix which allowed her to start gaining a bit of weight. In January I strongly reduced my professional activity to take care of Lysie. I did not let go. I continued to insist particularly on the meal. I tell you that Lysie threw up a lot but we had a victory. Lysie now eats normally of anything. It is a pleasure to see her eat.

Developmentally Lysie walked at 20 months. The pool was a big help. She sat up at about 10 months.
Currently Lysie does not really play with her toys. She just throws them. Impossible to keep her interested in an activity longer than 10 minutes. We are working on this with the help of an education specialist. She is frustrated and scared of everything. She still puts everything in her mouth and bites everything to have a piece in her mouth. She has problems with her eyes. We have an appointment soon. She also has a malformation to her small ears so she has very small ducts. Lysie walks but falls easily and gets tired fast. She also has a heart defect. For our part, she is not constipated. She has a steady pace of one to two times a day in the bathroom.

Here, I hope to have been able to share the life of Lysie. Really not easy for me to explain.
Your friend,
Severine

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Here is some of Kristen’s story….diagnosed with KAT6A at age 28, she is 29 1/2 now.  She is a beautiful young woman who has endured more medical challenges than anyone I have ever known.  She is a twin (fraternal), was a preemie, and born hypotonic on the short end of placental discordance.  We never stopped searching for answers as to why she struggled so much and her twin sister never did.

One particularly difficult area of development for Kristen was her speech and language. Kristen did not make any sounds as a baby, deafness was ruled out, speech therapy started at 11 months.  A larenoscopy showed vocal cords were weak and inconsistently responded to sound stimulus.  Oral motor therapy shortly followed. Teaching Kristen to use her tongue and try different food textures (eating had been a struggle since birth.  At birth she lacked the oral motor strength to suck a bottle) was important in helping her develop more oral motor strength needed for speech.  A special pre school with daily OT, PT, and speech therapy was next at age 2.5. Diagnosed then with apraxia of speech.  We taught her sign language to communicate while never giving up on speech.  Kristen entered kindergarten (a special day class for language impaired children)with two words, neither was her name.  Daily speech therapy at school and we continued private therapy twice a week.  The progress was slow, but progress was there.  Kristen eventually learned more words, mumbles at first, articulation poor. Over the years it continued to improve, albeit it very slow.  By the time Kristen left elementary school she spoke short sentences, not necessarily grammatically correct but she was able to communicate verbally her needs and wants (with a little patience getting those thoughts out).  That continued to improve, and private therapy continued, and continues to this day.  Articulation became somewhat clearer, word finding is still an issue, but for the most part Kristen can communicate to even strangers and have them understand her. Will her speech and language ever be normal, no, but her growth still continues to this day at age 29, as does her therapy and her will to communicate with those around her.

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Parents and caregivers of children or adults with KAT6 disorders are the first to recognize whether the person they care for is in distress.  Those continually looking after the person’s needs are the best ones to intervene and advocate for medical care when it appears that a problem is present and getting worse.  But what are we looking for and when might it call for emergency care?

INTESTINAL BLOCKAGE

Gastrointestinal issues are common with KAT6 disorders.  Low muscle tone throughout the body may mean low motility in the gut — weak contraction of the muscles that mix and propel contents in the gastrointestinal tract.  When there is a temporary lack of normal muscle contractions of the intestines this is known as ileus — not a blockage, but a stoppage.  (Think of a blockage as a train wreck, preventing any other train from passing through, and think of a stoppage as merely a train sitting on the tracks and failing to move along.)

When the contents of the upper or lower bowel cease to move, the resulting mass can become enlarged and can harden as it dries out, stretching the part of the intestine where the mass occurs.  Regular contractions can return and eventually move it along, but if the contents sit too long they can begin to ferment and decay, with potentially serious results.  Vomiting and diarrhea, for example, are normal consequences once the body applies its other resources to the obstruction.

If it does not eventually start moving on its own it may respond to non-invasive treatments such as stimulants taken orally or a rectal enema, depending on proper assessment of the location of the problem.  But if there is a physical barrier to continued movement of intestinal contents, the problem can quickly become life-threatening.

MALROTATION AND VOLVULUS

Around the tenth week of gestation, as the intestinal tract is developing, it normally moves from the base of the umbilical cord into the abdominal cavity.  As the intestine descends into the abdomen, it makes two rotations and settles into its normal position.  When a portion of the intestine, or even the entire intestinal tract, fails to lie properly in this space, it ls known as a malrotation.

A malrotation may cause immediate symptoms and problems after a baby is born or may lead only to intermittent trouble, or it may cause no problems at all.  In some people it is not discovered until well into adulthood or perhaps never discovered at all.  In others, it can be the source of repeated obstructions.  The point is, a malrotation is an anatomical defect and one that must be suspected if problems arise, especially in early childhood.  It can lead either to continuous or intermittent problems but is not necessarily dangerous.

When a loop of intestine and the membrane that holds it in place twist around each other like sausage links or a kinked garden hose, this causes a bowel obstruction called a volvulus.  A certain kind of volvulus in a horse is commonly called a torsion.  It is not going to clear and open back up on its own, and normal muscle contractions in the gut are not going to force a trapped mass of intestinal contents to move past it.

The trapped material, already partially digested, continues to break down, though, and some contents may be ejected as diarrhea or gas, while most of it will remain and swell the gut.  A person suffering a volvulus, who enters emergency surgery soon enough, may still lose part of the intestinal tract in surgery.  Without emergency surgery a volvulus is almost certain to be fatal.

If a volvulus is suspected in an emergency room, a buildup of gas in the intestine may show up on a series of x-rays, which must be taken at intervals long enough for changes to appear but no so long that surgery comes too late.

OTHER GI ISSUES

The esophageal sphincter is the valve between the esophagus and the stomach.  When the muscle that keeps this valve closed is weak, a blast of burning stomach acid may rise as far as the throat.  This is acid reflux.  A baby with KAT6A or KAT6B can be resting quietly in a baby seat, alert and cheerful, and suddenly scream in pain and terror.  If this happens with any frequency, reflux should be suspected when nothing else is likely.

Dumping syndrome is a group of symptoms, such as diarrhea, nausea, and feeling light-headed or tired after a meal, that are caused by rapid gastric emptying, a condition in which food moves too quickly from the stomach to the duodenum.  This can become an issue after a person has undergone GI surgery.  Adjustments in diet or medicine can resolve things, and, if surgery was involved, time may be the best healer.

OUR NEED TO REMAIN VIGILANT

Communication problems are common with the KAT6 population as well as an apparent high tolerance for pain.  Children and adults with KAT6 disorders, especially those who can’t tell us that something hurts or where it hurts, need to be monitored continually for lack of gut movement.  Constipation, (a general term for any disruption of intestinal activity that leads to pain and irregularity of bowel movements), can make a normally cheerful person irritable.

A volvulus is a rare occurrence in the general population, but among the KAT6 population it seems common enough to be of serious concern.  Although we are still studying the matter and don’t have statistics, it appears that untreated bowel obstructions are the leading cause of death among children affected by KAT6 disorders.

Many of those with KAT6 disorders are tube-fed through a gastrostomy.  For some, this is their only source of nutrition, and so variations in gastrointestinal activity are less likely to be caused by daily changes in diet.

What is the person’s normal frequency of bowel movements?  Has it been a day longer than normal?  Two days?  Is she also becoming irritable, combative, unable to sleep?  Does this happen in repeating cycles?  What does her blood work show?  What does a gastroenterologist say?  Do cycles of irritability correlate with cycles of unusual toilet contents?  Someone close to the patient needs to be asking these questions and insisting on answers.

People with KAT6 disorders may show no signs of a bowel obstruction until it has progressed to a serious degree.  They may quietly tolerate the increasing pain until it has become severe.  An obstruction can go from bad to dangerous quickly.  It is hard to differentiate an obstruction from other gastro-intestinal issues.  Obstructions can happen again and again and can strike at any age.

While it is probably more likely to become an issue early in a child’s life, an affected person who has a KAT6 disorder can seem to be OK for years, perhaps irritable at times for no apparent reason.  Just because it hasn’t been diagnosed at an early age it could be that a complete obstruction simply hasn’t happened yet.  The best prevention of complications is be on top of it all of the time.  Not all doctors understand that, with a bowel blockage, you can still pass diarrhea — the assumption seems to be that if they’re passing anything at all then there’s no obstruction.

Medical services vary from country to country, and while another country may have excellent hospitals and perfectly competent doctors, they may also have different approaches to parent involvement, different protocols for intervention, and different standards for what can and should be treated.

Compounding the danger, a doctor may not consider an intestinal obstruction if a parent or caregiver hasn’t suggested it, and so a doctor wants to ascribe a change in behavior to anxiety, a virus, a food allergy, and so on.  Meanwhile the child has mere hours to get the problem resolved or else irreversible damage has been done with a high potential for fatal results.

LIVING WITH IT

We aren’t supposed to tell people about our poop or ask others about theirs.  With KAT6 in a family we could save a life if we get beyond that taboo.  In our own experience, Beth and I share in all phases of the care of our son, Sam, who is now 32 years old.  He is one of the more severely disabled individuals with KAT6A syndrome, and so we must pay constant attention to all the signs he gives us.  We “read” his behavior, we both examine his bowel movements daily or at least describe to each other what he has done.  (He even has an “I POOPED TODAY” T-shirt.)

Sam has had a gastrostomy and feeding tube since he was a baby and receives all medicine and sustenance through the tube.  He had a nissen fundoplication during his first surgery as a baby, so he cannot burp or vomit.  He had a malrotation of the duodenum at birth (corrected by surgery), reflux as a baby, a volvulus before he was two (indicated by changes in a gas pocket on successive x-rays), a second near-fatal obstruction due to adhesions, and numerous instances of ileus and other partial obstructions requiring hospital stays.  As an adult he is now treated for ulcerative colitis.  He does not walk and can’t speak.  But he is engaging and even mischievous, affectionate, enthusiastic, and popular.  When he hurts, his only ways to show it are in withdrawal, resistance, and restlessness.

We are fortunate that Sam has had doctors who care about him as a person and who listen to us, his parents.  His doctors, though, need to trust what we are telling them, and so our information must be reliable.  By educating ourselves, paying close attention to the signs that Sam gives us, and making sure we communicate consistently and accurately with medical providers, we have been Sam’s best advocates.

Many parents have observed GI benefits from a mitochondrial cocktail and other supplements, such as Cytra-3. Learn more about these supplements by watching Dr. Richard Kelley’s presentation from our 2022 Conference. It is essential to consult your child’s physician before starting anything new.

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On March 24, 2022, The KAT6A Foundation hosted the second KAT6A and KAT6B Virtual Symposium.  The event was designed to solidify the KAT6A and KAT6B research network of clinicians and researchers through identification of research gaps, opportunities and collaborations. The symposium series aims to drive patient- centered and collaborative research to improve outcomes for individuals with KAT6A and KAT6B syndromes. The symposium series also aims to spark new collaborations among the KAT6A and KAT6B research groups and healthcare communities.The first KAT6A and KAT6B symposium, conducted in 2021, discussed a range of neurodevelopmental challenges faced by children with KAT6A and KAT6B gene variations. The second symposium expanded on the stakeholder representation to include parents of children with KAT6A and KAT6B gene variations along with health care professionals, clinicians, and researchers. This symposium focused on understanding the impact of KAT6A and KAT6B gene variations on speech and language development, a domain that is most commonly affected in this population of children.10 speakers and nearly 60 members of the KAT6 community attended the the symposium. The symposium ran for three hours and was organized in two sessions: the first session provided an overview of the KAT6A Foundation’s goal to empower patient-centered research and initiatives led by the Foundation to support research. The second session focused on understanding the pathophysiology of KAT6A and KAT6B related speech and language disorders.

Please read the symposium recap pdf for a complete summary of each presentation. The next virtual symposium is tentatively scheduled in September 2022. This symposium will focus on unraveling the range of gastrointestinal difficulties faced by individuals diagnosed with KAT6A and KAT6B syndromes.

The KAT6 Foundation is honored to receive a third year of funding from the Chan Zuckerberg Initiative (CZI), in the amount of US$150,000. The grant supports the expansion of the KAT6A/KAT6B Research Network and accelerates our work to find treatments or a cure for KAT6A and KAT6B syndromes.

“We are so grateful to the Chan Zuckerberg Initiative for their continued support of the KAT6 Foundation and the rare disease community. Their continued support recognizes the great progress our foundation has made in developing and organizing the community of researchers seeking to understand and treat KAT6A and KAT6B syndromes. We look forward to continuing to develop new research opportunities and collaborations as we seek future sustaining funding opportunities,” shared Jordan Muller, chairperson of the KAT6 Foundation.

In February 2020, The KAT6 Foundation was selected as one of thirty patient-led organizations for CZI’s Rare as One Project and was awarded a grant of US$450,000 to be used over 30 months. This grant has enabled the foundation to expand its Research Network by funding a science director, research coordinator, and patient registry coordinator, which helped facilitate the first KAT6A & KAT6B Virtual Symposium in 2021. This was the first collaborative research event organized by the KAT6 Foundation in which 16 speakers presented their research related to KAT6A or KAT6B genes. This conference provided researchers an opportunity to discuss their findings, ask questions and receive feedback while strengthening collaboration. In June 2022, these funds will allow us to host the 3^rd International KAT6A & KAT6B Conference so that we can bring families, researchers, and medical doctors together for the first time since 2019. Furthermore, the CZI grant has been critical in helping us improve fundraising and awareness initiatives by supporting marketing and communications costs.

As we move forward, we will continue CZI’s mentorship program, which has provided us with the valuable opportunity to collaborate and learn from other rare disease organizations. This additional funding will foster greater collaboration between all the researchers currently working or interested in KAT6 through subsequent meetings in the KAT6A and KAT6B Virtual Symposium series. The opportunity CZI has provided us to strengthen our Research Network has allowed us to be a driving force in international KAT6A and KAT6B research. It is an honor to serve the KAT6 patient community as we move forward in our mission to ensure equity in access to testing, knowledge, and therapies for KAT6 patients around the world. Thank you for your continued support.

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KAT6A Families,On March 1, 2018, Dr. Francis Collins, the Director of the National Institutes of Health (NIH) dedicated his blog posting to Dr. Valerie Arboleda’s research on KAT6A.  This blog post provides great visibility for our community and the KAT6A Foundation, and is a very good summary of her research plan. https://directorsblog.nih.gov/…/creative-minds-looking-fo…/…

I also wanted to recognize and thank all of the families who supported the Children’s National Race For Every Child over the past several years. It was funds you raised for those events that supported her initial research. This research provided the early findings that helped her win the NIH grant that will help sustain this research going forward. So congratulations to all of you for helping further KAT6A research. And thank you for your continued support of our new KAT6A Foundation as we continue to raise funds to support future research.

Jordan Muller

Chairperson of the KAT6A Foundation

On February 3, 2018, the first KAT6A clinic was held in Baltimore, Maryland, at the Kennedy Krieger Institute. Nineteen families attended and several more followed the clinic by livestream.

We were pleased to have in attendance and as speakers Jacqueline Harris, M.D., Ph.D., Pediatric Neurologist from the Kennedy Krieger Institute in Baltimore, Hans Thomas Bjornsson, M.D., Ph.D., Director of Epigenetic and Chromatin Clinic and Assistant Professor of Pediatrics at Johns Hopkins Hospital in Baltimore, Jill Fahrner, M.D., Ph.D., Assistant Residency Program Director at Johns Hopkins Genetic Medicine Residency Program and Assistant Professor of Pediatrics at Johns Hopkins Hospital in Baltimore, and Richard Kelley, M.D., Ph.D., former Director of Division of Metabolism at Kennedy Krieger Institute in Baltimore and current researcher at the Division of Genetics and Boston Children’s Hospital.

After a welcome by KAT6A Communications Director Brittany Green, Dr. Jacqueline Harris presented an overview of the KAT6A clinical syndrome. She explained that KAT6A is a histone modifier epigenetic disorder. This means that the gene function is changed, not the gene sequence, and it is influenced by the histone machinery. It is most often de novo, which means that the genetic change happens in the child and is not inherited from either parent. She reported that there are only a few documented cases, so not much is known about KAT6A syndrome. Researchers need more cases to study. However, there seem to be some features that are nearly universal and some features that seem to be related. Some of the universal features include hypotonia, feeding problems, congenital heart disease, eye or vision problems, skull abnormalities, distinctive facial features, and global developmental delay. Less common but probably associated features are small birth size, perinatal complications, seizures, specific behavioral features, sleep disturbances, immune system irregularities, dental abnormalities, hand abnormalities, and brain MRI abnormalities. She concluded by stating that current researchers learn most from the patients and their families and by drawing from information from other similar epigenetic syndromes.

Next, Dr. Kelley spoke about mitochondrial dysfunction in KAT6A. KAT6A affects metabolic protein absorption, and children with this disorder often have abnormal levels of certain plasma amino acids. Some that he mentioned were citrate, asparagine, and phenylalanine. Using common lab standards, amino acid levels often seem within normal range but a doctor who specializes in mitochondrial disorders uses a conversion scale to determine whether there is a mitochondrial disorder. Dr. Kelley has been working with several families to analyze plasma amino acid levels and then recommending parts or all of a mitochondrial cocktail that he has developed as treatment. Carnitine has been shown to potentiate chromatin opening, and Vitamin B5 helps the body break down carnitine, so these are often helpful to children with KAT6A. Several parents have documented developmental progress in their children who are taking carnitine and vitamin B5. Dr. Kelley is quite confident that carnitine is very beneficial to individuals with KAT6A.

Dr. Bjornsson was the last speaker and he spoke about mendelian disorders of the epigenetic machinery and therapeutic possibilities. He has been studying a disorder very similar to KAT6A called Kabuki Syndrome. They are both epigenetic disorders of the histone machinery. Dr. Bjornsson is studying a mouse model of Kabuki syndrome and has been able to gain much needed information, including some effects that can be reversed using drugs targeting the epigenetic machinery. He also feels that carnitine is likely a good therapeutic treatment for KAT6A. He would like to be able to build KAT6A related data based on seeing more patients with KAT6A. He summarized by emphasizing how rare KAT6A is and that in order to assist in further research, the KAT6A Foundation needs to participate in research by donating results, samples and joining studies, as well as promote research by raising funds to help any interested lab get preliminary data to attract NIH funding. We can also continue to organize meetings and clinics such as this one and continue to increase awareness about KAT6A in the world.

The meeting concluded with some time for the families to meet, share information, and speak individually with the doctors. For those present as well as those families who were listening to the live feed, this first get-together was stimulating, rejuvenating, and gave us hope for our children’s future.

You can view the full presentations by the medical specialist on our KAT6A Foundation Youtube channel.

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Biomarker discovery in KAT6A for translation into clinical trials

For KAT6A syndrome and other neurodevelopmental disorders, researchers are starting to understand the dysregulated cellular processes affecting neurons and their supporting cells. The Chromatin Disorders Research Team at Murdoch Children’s Research Institute is currently using a mouse model, alongside human cortical neurons to study gene expression and metabolomics KAT6A syndrome, in collaboration with Professor Anne Voss at the Walter and Eliza Hall Institute of Medical Research. This work is being led by PhD student Dr Sarah Donoghue and supervised by Professor David Amor and Professor Paul Lockhart. The goal of this project is to understand the differences in brain development that occur in KAT6A syndrome, and to identify biomarkers that may show response to treatment in clinical trials.  

The team is looking to extend their work on blood biomarkers in KAT6A mice to children and adults with KAT6A syndrome. In this project, they will measure a range of molecular compounds in blood samples from human participants with KAT6A syndrome, using untargeted metabolomic and proteomic analyses. They will compare the plasma profile of 50 KAT6A syndrome participants to the plasma samples of 20 participants without KAT6A syndrome. The aim is to identify biomarkers that are detectable in the plasma of participants with KAT6A syndrome, with the hope that these can be translated for use in clinical trials, as an objective measure of treatment efficacy as the community proceeds to clinical trials.

For more information about this research, please contact Sarah Donoghue at sarah.donoghue@mcri.edu.au.

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ATTENTION RESEARCHERS:

The KAT6 Foundation is addressing a critical research priority raised by families—gastrointestinal challenges faced by children with KAT6A and KAT6B. This population experiences a concerning increase in mortality due to poor GI motility and perforation. Tragically, we recently lost another child to GI perforation, which has heightened anxiety and urgency within the community.

We are keen to better understand the factors that contribute to susceptibility to poor motility, bowel obstruction, and the risk of perforation in children with KAT6A and KAT6B. Equally important is identifying effective treatment strategies to address these serious issues.If you are interested in collaborating on this important challenge, please email the KAT6 Foundation at support@kat6a.org.

Learn more about Bowel Obstructions in the KAT6 Population.

We are proud to report that research led by Dr. José A. Sánchez-Alcázar and his team was published by Genes on November 15, 2022 in an article titled Pantothenate and L-carnitine Supplementation Corrects Pathological Alterations in Cellular Models of KAT6A Syndrome. This is an important milestone for our Foundation as it is the first research project that we directly funded to reach publication, and is an important step forward on the path to finding a treatment for KAT6 individuals. Development of surrogate models simulating KAT6A gene variation is the first step towards understanding the pathophysiological alterations caused by this gene variation. By outlining pathophysiological pathways, treatment model(s) addressing alterations in these pathways can be developed for testing.

Three individuals with KAT6A gene variation participated in the study conducted at Universidad Pablo de Olavide in Spain. An initial series of experiments generated evidence supporting the use of patient-derived fibroblast to study KAT6A gene variation. The team identified four critical pathophysiological processes altered by KAT6A gene variation: 1) Coenzyme A (CoA) metabolism, 2) Iron metabolism, 3) Enzymatic antioxidant system and 4) Mitochondrial function. Two compounds were identified to have a positive impact on the altered physiological pathways. These compounds are: 1) Pantothenate and 2) L-carnitine. Pantothenate is a CoA metabolism activator and L-carnitine is a mitochondrial boosting agent. Supplementation with pantothenate and L-carnitine supported the survival of the KAT6A fibroblast in a stress inducing medium. The concentration of pantothenate and L-carnitine varied in all three KAT6A cell lines suggesting that different type of mutations respond differently to these positive compounds. The KAT6A gene plays a significant role in histone acetylation which is a key process involved in cell progression and differentiation. Supplementation with pantothenate and L-carnitine resulted in significant increase in histone acetylation, recovery of gene expression patterns and expression levels of proteins affected due to the KAT6A gene variation.

We want to extend our sincere thanks to Dr. José A. Sánchez-Alcázar and his entire team for their professionalism and commitment to rare disease research and the KAT6 community. We look forward to building upon this partnership in the future.

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The Gastrointestinal Health and Beyond in Children with Rare Genetic Variations was a 2-hour long, patient-centered, collaborative event organized by the KAT6 Foundation. It was designed to fuel conversation about the gastrointestinal challenges faced by children with KAT6A and KAT6B gene variations and enable open dialogue between families, clinicians, and researchers. The webinar provided a platform for the KAT6 community to expand its network and build connections with new researchers and experts working on tackling GI and GI related issues. More than 90 individuals registered for this event. On the day of the webinar, 20 families and 35 scientists attended the event. With some international representation, the majority of the families and researchers were based in the USA.

Dr. Tanya Tripathi, research coordinator of the KAT6 Foundation moderated three scientific presentations by renowned scientists – Dr. Sarkis Mazmanian, Dr. Gustavo Mostoslavsky and Dr. Richard I Kelley. Please read the summary of the presentations here.

On March 24, 2022, The KAT6A Foundation hosted the second KAT6A and KAT6B Virtual Symposium.  The event was designed to solidify the KAT6A and KAT6B research network of clinicians and researchers through identification of research gaps, opportunities and collaborations. The symposium series aims to drive patient- centered and collaborative research to improve outcomes for individuals with KAT6A and KAT6B syndromes. The symposium series also aims to spark new collaborations among the KAT6A and KAT6B research groups and healthcare communities.The first KAT6A and KAT6B symposium, conducted in 2021, discussed a range of neurodevelopmental challenges faced by children with KAT6A and KAT6B gene variations. The second symposium expanded on the stakeholder representation to include parents of children with KAT6A and KAT6B gene variations along with health care professionals, clinicians, and researchers. This symposium focused on understanding the impact of KAT6A and KAT6B gene variations on speech and language development, a domain that is most commonly affected in this population of children.10 speakers and nearly 60 members of the KAT6 community attended the the symposium. The symposium ran for three hours and was organized in two sessions: the first session provided an overview of the KAT6A Foundation’s goal to empower patient-centered research and initiatives led by the Foundation to support research. The second session focused on understanding the pathophysiology of KAT6A and KAT6B related speech and language disorders.

Please read the symposium recap pdf for a complete summary of each presentation. The next virtual symposium is tentatively scheduled in September 2022. This symposium will focus on unraveling the range of gastrointestinal difficulties faced by individuals diagnosed with KAT6A and KAT6B syndromes.