Featuring another family recently diagnosed........

My heart shattered

Foundation to Fight H-ABC has been the guiding light that showed up right when I needed it the most. My name is Miesha and I’m a single mother battling an autoimmune disease called ankylosing spondylitis alone with my son Tilyn Sincere. He was born healthy and grew into this bright bundle of happiness. As early as one, he started showing signs that something wasn’t right. We went through years of doctors guessing treatment options or assuming he would grow out of delays and begin thriving like most children do. In the beginning of 2024 we finally were told he had a number of things going on. He was diagnosed with clonus, autism, and cerebral palsy which is a crushing blow to say the least. We had already been in therapy prior to the diagnoses but I kept seeing a decline as the months went on.

July 17th 2024 was the day that changed everything. I had found a new neurologist and hoped that she could explain what was going on to make my life a little easier. My answer was a rare condition called hypomyelinating leukodystrophy disorder that often can be fatal, but it will cause his brain and body to slowly lose communication, thus impairing his body to operate as it should. My heart shattered in an instance, what mother can bear being told that your child will live as long as his body will allow, there is no cure, and we will only be able to manage his quality of life. I FREAKED OUT there was nothing I could do to stop it and I had no one to help me navigate what was to come.

Struggling to grasp this new reality I went looking for answers and I found the Foundation to Fight H-ABC. I found my lighthouse; they provided me with mental comfort, emotional support, and resources to navigate these rough waters. Everything is still brand new but with this foundation we have been able to see the steps to start this journey. Tilyn is already on a path others waited years to be on and it was all possible with the support of this foundation. With rough seas ahead of us, Tilyn and I won't have to navigate this alone with our new family of H-ABC fighters

Testimony directly from one of our Leukodystrophy patients!

It is unusual to meet a Tubb4a patient who is so articulate! Killian does a fantastic job of telling us more about his leukodystrophy on Utube, and what better timing than during September Leukodystrophy Awareness Month! Thank you Killian, you are an amazing young man!

https://youtu.be/hGTRVM21Sdo?feature=shared

*** September is Leukodystrophy Awareness Month ***

H-abc/Tubb4a is one of many leukodystrophies. Leukodystrophy describes a group of more than 50 inherited neurological disorders. These diseases affect myelin, the protective covering on nerve cells in the brain and spine. Leukodystrophies cause a progressive loss of neurological function in infants, children and sometimes adults. Leukodystrophies affect about 1 in 7,000 live births. As we progress through the month of September we will provide more details on H-abc and leukodystrophies and what they mean for our families waiting for a cure. If you wish to donate to our efforts to help families and find a cure, use the QR code in the image!

National H-abc/Tubb4a Awareness Day

May 2 is now the official National Tubb4a Awareness Day! Thanks to Sarah Marta, one of our patient moms who pursued the appropriate approvals. This day was chosen as it represents the first official day that the tubb4a mutuation was announced as the cause of the condition!

First clinical trial for H-abc/Tubb4a Leukodystrophy

Very excited to announce the first individualized clinical trial for Tubb4a! This is an interventional study to evaluate the safety and efficacy of treatment with an individualized antisense oligonucleotide (ASO) treatment in a single pediatric participant with a de novo pathogenic gain of function TUBB4A mutation associated with severe leukodystrophy with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC. This is great news for our community, and we pray it will be successful

https://www.clinicaltrials.gov/study/NCT06369974?cond=TUBB4A-Related%20Leukodystrophy&aggFilters=status:not%20rec&rank=1

New Scientific Advisor

We are very pleased to announce the addition of Dr. Wendy Chung as a scientific advisor to the Foundation. Dr. Chung is a clinical and molecular geneticist and the Chief of the Department of Pediatrics at Boston Children’s Hospital and Harvard Medical School. Dr. Chung directs NIH funded research programs in human genetics and is a national leader in the ethical, legal, and social implications of genomics. She was the recipient of the Rare Impact Award from the National Organization of Rare Disorders, and is a member of the National Academy of Medicine and the American Academy of Physicians. Dr. Chung received her B.A. in biochemistry from Cornell University, her M.D. from Cornell University Medical College, and her Ph.D. from The Rockefeller University in genetics.

Remembering Alice

Alice's mom reached out recently checking in on our progress. Gwen shared her beautiful rock art, this picture is the first she did to commemorate her beautiful daughter Alice. I asked Gwen if she could share her story about Alice, this is what she had to share:

In 2010, my then-wife Lonnie Hardage and I wanted to add to our large family of birth-kids and adopted-kids. Our adoption worker showed us a picture of a brother and sister. ages 6 and 4, who needed a forever family. When we met these dear children they were both developmentally delayed and the little girl had some balance issues that looked to me like cerebral palsy (I am a pediatric OT and SLP). I thought, "We can certainly handle this, and she'll have company, because one of our other kids has CP."

Alice and her brother came home and she blossomed, learning to walk with less falling, starting to talk, feeding herself, and almost being toilet trained. Then suddenly, at age seven, she started losing ground in her abilities. Lonnie took her to a neurologist who hospitalized her for tests; the next day the verdict came: not CP, but rather TUBB4A leukodystrophy, H-ABC. Shattering news, although at that point we could only find record of about 14 other children who had this (the founding families of the H-ABC Facebook group) so it seemed as though there must be things doctors didn't know yet; they couldn't possibly have formed rigid conclusions with such a small sample of children. We did not want our hope to be dashed. Gradually Alice lost skills. She needed a walker and we pulled her out of the first grade class at the Waldorf charter school without ADA-compliant ramps to her classroom. Soon she needed a wheelchair. Her ability to talk was nearly gone, so we tried first a fancy AAC speech-generating device with "robust capabilities for language"-- but it was more than she could understand. We ended up using a paper communication book of PODD (Pragmatic Organization, Dynamic Display), which Alice and I became really good at using together; she could even make up stories with it. Unfortunately, not many other adults came to enjoy using it well, so Alice had limited conversation partners.

Alice had surgery to get a g-tube (which we combined with a reduction of her salivary glands, hoping she would drool less). In hindsight I would not have done that, because the remaining salivary glands seemed to overcompensate, and much drool soon continued. She joined a special day class at the local public school. Through all these changes Alice maintained her joyful attitude toward life and her wish to love and be loved. She was the queen of hugs and loved to be playfully mischievous or involved in a marathon of "hide and seek." She had a crush on the teenage boy across the street. If she cried and I made her laugh about something, she would seem to forget that she had been sad or mad. At first I worried this was not fair for her emotional development, but as she lost ground I decided it wouldn't be detrimental to relieve her discomfort with a tickle or silly face. Lonnie and Alice attended a gathering of families coping with H-ABC in Philadelphia in October, 2014, where she was thrilled to meet other children like her and where she had a consult with Dr. van der Knaap. There was hope, research was beginning, and more and more children with H-ABC were being identified.

Alice loved her social life at school and hated to miss a day. Even when she began to develop intractable body pain she wanted to go to school. Lonnie was on the phone with doctors daily, getting stronger pain medicine that still didn't reduce the aching in her body. On her last week of life she attended school on Monday and Tuesday, stayed home sick Wednesday, and went to the ER on Thursday where they finally gave her a sedative strong enough to let her sleep. She did not wake up from this sleep. Alice died Friday, August 30, 2019 at age 13. My belief is that her body wore out from fighting the pain.

Rest in peace, Angel Alice. And may the search for treatment for H-ABC continue until an accessible, affordable, internationally available cure is found!

Updates on Preclinical Trial Readiness

Below is a summary from Children's Hospital of Philadelphia (CHOP) on their work in preparation for the ASO clinical trail. CHOP is working alongside SynaptixBio.

Impact of Disease: This work includes interviews and surveys conducted with families, focusing on the impact of TUBB4A on children and their families. Parents provided feedback on the topic and expressed priorities for factors that could potentially improve overall quality of life. The project has ended, and a manuscript is currently under revision. Once available, I will be happy to share the link to the manuscript for easier access.

The Natural History of Variable Subtypes in Pediatric-Onset TUBB4A-Related Leukodystrophy: We are concluding a project involving more than 200 children with TUBB4A-related leukodystrophies (both U.S.-based and international). In this work, we explore medical events occurring in this population and aim to identify early predictors of disease progression. The manuscript is currently being prepared and will be submitted for peer review soon. Once accepted and published, we will share the link to the manuscript as well.

**** Clinical Trial Readiness in TUBB4A-Related Leukodystrophy:**** In alignment with recent FDA guidelines on Patient-Focused Drug Development (PFDD) (https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical), we are working on creating the infrastructure and developing a methodology to comply with this process.

Retrospective and Prospective Natural History Studies in TUBB4A-Related Leukodystrophy: We continue our efforts to understand the natural trajectories of TUBB4A-related leukodystrophies by enrolling children in our research protocol. Interested participants can consent to our research protocol and share information about their children, as well as participate in our prospective study through assessments focused on capturing gross and fine motor functions, cognitive abilities, and adaptive behavior. This is a fundamental step in identifying potential clinical trial endpoints.

Mira's Story

Mira is 5 years and has been the light in Chloe's life ever since. Mira loves Fuggler teddys and watching cartoons on her IPad. Mira first started showing signs when she was 3 months old and with much investigation and through genetic Testing mom and dad got the diagnosis in May 2022 and it flipped their whole world upside down. There wasn't much if any information until they found the Foundation to Fight H-ABC who been helping them understand what to expect in future. It was hard at first especially when they discovered there is no current cure but Mira hasn't let anything stop her smile!

Mira is constantly fighting and gives us all hope and our biggest hope is that in the future there is a cure!

How Microtubules work and what causes the disruption in the Tubb4a gene causing H-abc/Tubb4A related leukodystrophy

The video is available at https://youtu.be/MZ47-G4XKDw. You can see microtubules being assembled from 1:06-1:10, then disassembled from 1:11-1:15. The next sequence (1:15-1:26) is of a kinesin protein "walking" along a microtubule filament while pulling a vesicle.

Here is a longer (and narrated!) version of this video available at https://youtu.be/FzcTgrxMzZk. Its long but may provide some useful scientific context.

The "vesicle pulling" clip represents intracellular transport. The microtubules basically serve as "molecular highways" for molecular motors that haul protein cargo to different parts of the cell. Variants in TUBB4A gene result in misfolded tubulin proteins, which interfere with the ability of those microtubules to assemble properly - the process in the video - or prevent those molecular motors from attaching correctly, leading to disruptions in those intercellular transport mechanisms.