H-ABC
WHAT IS H-ABC
H-ABC stands for “Hypomyelination with atrophy of the basal ganglia and cerebellum,” because of the key injury to the myelin of the brain, the basal ganglia and the cerebellum.
Myelin is a part of the brain that may also be called “white matter.” When an individual does not have enough myelin, they are said to have “hypomyelination,” where “hypo” means less than expected. Myelin is to neurons in the brain like the insulation around the electrical cords in your house. It enhances the efficiency of communications between cells in the brain, and supports the health of cells in the brain. Myelin is made by cells called oligodendrocytes. In H-ABC, researchers think these special cells do not do their job properly, leading to insufficient development of myelin
The basal ganglia, also called deep gray nuclei, are collections of neurons deep in the brain. They help coordinate how smoothly movements are executed, their coordination and their speed. In H-ABC, researchers think these special cells get sick and die, leading to atrophy of these structures.
The cerebellum is a structure at the base of the brain, that helps regulate information coming from the brain as it exits to the spinal cord. It helps regulate balance and the smoothness of movements. In H-ABC, researchers think these special cells get sick and die, leading to atrophy of this structure.
H-ABC is due to mutations in a gene called TUBB4A, and is part of a larger disease group called TUBB4A related leukoencephalopathy. TUBB4A makes a special structural protein called tubulin, and tubulins come together to build microtubules. Microtubules serve to provide structure to cells and to move cellular components in the cell.
Individuals with deleterious changes to one of the copies of the TUBB4A gene are thought to make an abnormal copy of the normal tubulin protein, interfering with normal microtubule function.
People with TUBB4A related leukoencephalopathy and H-ABC frequently have problems with motor skills, which can extend to walking, sitting, using their hands, but also speech and swallowing.
SIGNS & SYMPTOMS
The symptoms and the progress of H-ABC differ depending on when the disease first appears.
When symptoms begin in the first few months of life, the effect of the disease tends to be severe and its progress more rapid. In these cases, symptoms may include:
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A small head (microcephaly)
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Uncontrolled, jerky eye movements (nystagmus) and poor vision
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Problems with swallowing and speech
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Delays in reaching developmental milestones for movement
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Low muscle tone (hypotonia)
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Poor coordination or clumsiness (ataxia)
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Muscle and limb stiffness (spasticity)
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Involuntary movements, including twisting, writhing and abnormal postures (dystonia and choreoathetosis)
When symptoms begin later, in early childhood, the effect of the disease tends to be milder and its progress slower. In these cases, the primary symptom is progressively greater trouble with movement, including:
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Stiffness of the arms and legs (spasticity)
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Gait problems, and other problems with coordination (ataxia)
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Involuntary movements, including twisting, writhing and abnormal postures (eg. dystonia)
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Rigidity
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Learning difficulties and attention problems
In some cases, the symptoms can be very mild and begin in later in childhood or adolescence, or even in adulthood.
TREATMENT
Currently there is no cure for H-ABC, but treatment is available to manage symptoms and improve the quality of life for individuals affected by the disease. There are neurologists specialising in hypomyelination disorders and centres of excellence across Europe and US that offer treatment.
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HOW MANY PEOPLE HAVE H-ABC?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
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WHAT IS THE CAUSE OF H-ABC?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
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WHAT ARE THE SYMPTOMS OF H-ABC?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)
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HOW IS THIS CONDITION DIAGNOSED?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.
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IS THERE A CURE FOR H-ABC?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.
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WHAT IS BEING DONE TO FIND A CURE?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.
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HOW CAN I GET INVOLVED?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.
