In August, Rare Disease Report covered a story about Ruby Hoffman, a 2-year old beauty pageant winner and patient with the rare brain disorder hypermyelination with atrophy of the basal ganglia and cerebellum (H-ABC).
One of her doctors, Adeline Vanderver, MD, is an Attending Physician in the Division of Neurology, Program Director of the Leukodystrophy Center, and Jacob A. Kamens Endowed Chair in Neurologic Disorders and Neuroptherapeutics at Children’s Hospital of Philadelphia (CHOP). RDR sat down with Dr Vanderver to discuss the pathophysiology and presentation of H-ABC with the hope of learning more about the condition that plagues Ruby.
Vanderver: H-ABC – we also call it TUB4A-associated leukodystrophy, recognizing that not all patients with the mutation of this gene have the exact same clinical presentation – TUB4A-associated leukodystrophy is 1 of 30 different leukodystrophies. Leukodystrophies are genetic disorders of the white matter of the brain. They are disorders where a faulty gene results in a problem with the cells that make or maintain myelin, resulting in significant neurological problems.
Almost all patients with H-ABC and/or TUB4A-associated leukodystrophy have hypomyelination. Hypomyelination is a situation where (a patient) fails to develop normal myelin. Typically, that diagnosis is first made based on an MRI where it’s recognized that a child has not met normal developmental milestones for myelination and has not achieved an age-appropriate level of myelination. The reason why that’s important is because there are a number of children where an early MRI doesn’t detect, or the delay in myelination just isn’t recognized. A number of children are first misdiagnosed or undiagnosed because that myelination defect is not realized or not recognized, and so I think an important thing is for people who are looking at MRIs of children with neurologic disease to make sure they’re familiar with age-appropriate stages of myelination to make sure that the MRI is not read as normal despite the absence of myelination.
I think that because of that difficulty, sometimes children are misdiagnosed as having cerebral palsy or having other early disorders of development. I think that the challenge is really making sure that that category of hypomyelination leukodystrophy is recognized from the get-go.
Once you are in that diagnostic category of a hypomyelination leukodystrophy, there are really only a handful of disorders that can present in that way that are currently identified. If the clinician is well-versed in the presentation, they may recognize the disorder clinically and not need to do extensive genetic testing, but as an alternative, these are not disorders that can be picked up with any standard blood test; no enzyme tests or biochemical tests are going to give you an answer.
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