TUBB4A Gene Omnibus

As of 2019,there arefewer than 200documentedcases of H-ABChave been identified,the majority of which are children. However, that number is on the riseas patientshave access to better clinical diagnosis.H-abccan present similarly to other conditions,such as Cerebral Palsy, and therefore misdiagnosis is common

H-ABC is caused by a mutation in the TUBB4A gene.Unlike other genetic disorders, H-ABC is usually not inherited from a parent. Instead, ittypically emerges as a random mutation(de novo)in the affected individual

The symptoms tied to H-ABC usually begin in infancy or early childhood and vary inseverity. Each child is affected differently; however, here are some symptoms observed atearly onset: Usually children affectedstartmissingmilestones at infant or toddler stage. Developmental delaysare common first signs. Other symptoms include: Low muscle tone(dystonia) Poor coordination Speech problems Difficulty eating Involuntary movements Rigidity Deafness Poor vision Seizures Muscle and limb stiffness Learning difficulties Problems paying attention Loss of balance Immobility (initial or over time)

H-ABC is diagnosed basedona combination ofgenetic testing,physical symptomsandbrain imaging(using MRI). Magnetic resonance imaging (MRI) of the brain is a key part of the process, as it candetect brain tissuemorphologythat are characteristic of H-ABC. However, genetictesting(by whole exome or whole genome sequencing)is the only meansof accuratediagnosis of H-ABC through identificationmutationin the TUBB4A gene.

Currently, there is no known cure for this disablingand life-threatening condition. For those affected by H-ABC, some treatmentssuch asphysical therapy and certainmedicationmay alleviate symptoms and improve quality of life.

The good news is that research is currentlyunderway. Children's Hospital ofPhiladelphia (CHOP), for example, has already started exploring gene therapy, which isthe wave of the future in curing manygeneticdiseases.Gene therapy can take on manyforms. In particular,Antisense Oligos (ASOs)therapy has gained traction in treatingneurological disease. ASOsare short, synthetic, single-stranded oligodeoxynucleotidesthat can alter gene expression (RNA) and reduce, restore, or modify protein expression. By targeting the source of the pathogenesis,ASO-mediated therapies have a higherchance of success than therapies targeting downstream pathway. Two ASO-mediatedtherapies havealreadyreceived approval from the US Food and Drug Administration(FDA)for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscularatrophy (SMA). Researchinto the mechanismsof the disease ismaking significant progress. Precisetargeting of TUBB4A requires meticulous ASO design to ensure that it does not bind other related members of the Tubulin gene family. CHOP is currently screening ASOpanels in both human cell lines and mouse models to find the best candidates. Once that stage is completed,the team will need to obtain FDA approvalfor a clinical trial to proceed.

The children don’t have much time. Their condition is deteriorating by the day. We need all the help we can get to accelerate the research for this treatment to reach clinic as fast as possible. If you know someone who has been diagnosed with H-abc or Tubb4a please ask them to enrol on the natural history study at CHOP using the link below. This will facilitate understanding of theprogression of the disease which also play a role in defining our clinical protocols. Equally,if you know anyone whose child has an unknown diagnosis which might fit the symptoms described here, do not hesitate to approach your clinicianto request for a clinical genetic test. Raising funds and awareness is vital, please contact us using the contact page if youwould like to jointhe mission.