Differences in TUB4A-Associated Leukodystrophy Presentations

Adeline Vanderver, MD

Yesterday, Rare Disease Report posted an interview with Adeline Vanderver, MD, about the pathophysiology and presentation of the rare brain disorder hypermyelination with atrophy of the basal ganglia and cerebellum (H-ABC).

Dr Vanderver 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).

One of her patients, Ruby Hoffman, is a 2-year old beauty pageant winner and has also been the subject of coverage from RDR. In this video, Dr Vanderver discusses the differences in presentations of TUB4A-associated leukodystrophy.

Vanderver: (CHOP) follows about 50 children with TUB4A-associated leukodystrophy; we know of probably about 100 others in one of our larger datasets. The way children with this genetic change present are most easily grouped into 3 big groups. Some children present with the typical H-ABC, and those children typically have normal initial, or only mildly-delayed initial development. (Those children) will often learn to walk or at least acquire early milestones within the first year of life. Somewhere after 6 months, and usually around the toddler years – 2 or 3 – they will present with motor problems, including walking problems, and sometimes problems called hemidystonia, where there’s sort of a torsion type of problem with one side. Those children will often progress and lose motor skills over time, such that, usually by the teenage years, they are confined to a wheelchair with a lot less independent mobility.

Those children present that present with the classic presentation are more likely to have a common mutation called D249N, and are also more likely to have the classic radiologic presentation over time. There are other types of presentations: one is a child who presents very early on, typically before 6 months of life, with an early onset of cephalopathy, or for non-medical personnel, a lack of acquisition of cognitive and awareness milestones, and also very significant motor milestone delay, including severe hypotonia. Some of those children also have as complications seizures. Those children are paradoxically less likely to develop the full classical radiological features of H-ABC which doesn’t make a lot of sense because you would think that those things would be more severe, and they’re also less likely to have the common mutation.

At the other end of the spectrum, there’s a presentation where children tend to present later, mainly because of spastic paraparesis, and have much more reserved cognitive and motor function. At the very tail end of that spectrum, there’s something called whispering dysphonia, which is an adult-onset presentation which has been documented in a couple families. In it, people have completely normal development, and it’s not until adulthood that they start having problems with their voices and with the production of sounds, and not being able to loud sounds with their voices.
For more from Dr Vanderver regarding rare leukodystrophies, follow RDR on Facebook and Twitter.
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