Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation

Hamilton, Eline M., Polder, Emiel, Vanderver, Adeline, Naidu, Sakkubai, Schiffmann, Raphael, Fisher, Kate, Raguz, Ana Boban, Blumkin, Luba, H-ABC Research Group, van Berkel, Carola G. M., Waisfisz, Quinten, Simons, Cas, Taft, Ryan J., Abbink, Truus E. M., Wolf, Nicole I. and van der Knapp, Marjo S. (2014) Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation. Brain, 137 7: 1921-1930. doi:10.1093/brain/awu110


Author Hamilton, Eline M.
Polder, Emiel
Vanderver, Adeline
Naidu, Sakkubai
Schiffmann, Raphael
Fisher, Kate
Raguz, Ana Boban
Blumkin, Luba
H-ABC Research Group
van Berkel, Carola G. M.
Waisfisz, Quinten
Simons, Cas
Taft, Ryan J.
Abbink, Truus E. M.
Wolf, Nicole I.
van der Knapp, Marjo S.
Total Author Count Override 16
Title Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation
Journal name Brain   Check publisher's open access policy
ISSN 0006-8950
1460-2156
Publication date 2014-04-30
Year available 2014
Sub-type Article (original research)
DOI 10.1093/brain/awu110
Open Access Status
Volume 137
Issue 7
Start page 1921
End page 1930
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2015
Language eng
Formatted abstract
Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation in TUBB4A, which encodes tubulin β-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin β-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients’ magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype–phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated with TUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable. 
Keyword H-ABC
TUBB4A
Hypomyelination
Genotype–phenotype correlation
MRI pattern
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 30 April 2014.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 24 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 21 May 2014, 12:39:23 EST by Susan Allen on behalf of Institute for Molecular Bioscience