Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation.
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.
1 Department of Child Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Eline M
EM
Hamilton
1 Department of Child Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Emiel
E
Polder
2 Centre for Genetic Medicine Research, Children's National Medical Centre, 111 Michigan Avenue, DC 20010 Washington, USA.
Adeline
A
Vanderver
3 Johns Hopkins University School of Medicine, Hugo Moser Research Institute, Kennedy Krieger Institute, 707, N. Broadway, Baltimore, USA.
Sakkubai
S
Naidu
4 Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, TX 75226 Dallas, USA.
Raphael
R
Schiffmann
5 Department of Paediatrics, Western Sussex Hospitals NHS Foundation Trust, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex, BN11 2DH, UK.
Kate
K
Fisher
6 Department of Child Neurology, Clinical Hospital Mostar, Bijeli Brijeg, 88 000 Mostar, Bosnia and Herzegovina.
Ana Boban
AB
Raguž
7 Paediatric Neurology Unit, Metabolic-Neurogenetic Clinic, The E. Wolfson Medical Centre, P.O. Box 5, Holon 58100, Israel.
Luba
L
Blumkin
1 Department of Child Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Carola G M
CG
van Berkel
8 Department of Clinical Genetics, VU University Medical Centre, 1081 BT Amsterdam, The Netherlands.
Quinten
Q
Waisfisz
9 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia.
Cas
C
Simons
9 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia.
Ryan J
RJ
Taft
1 Department of Child Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Truus E M
TE
Abbink
1 Department of Child Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Nicole I
NI
Wolf
1 Department of Child Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands10 Department of Functional Genomics, Centre for Neurogenomics and Cognitive Research, VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands ms.vanderknaap@vumc.nl.
Marjo S
MS
van der Knaap
D000293:Adolescent; D000367:Age Factors; D001284:Atrophy / Q000473:pathology; D001479:Basal Ganglia / Q000473:pathology*; D002531:Cerebellum / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D056784:Leukoencephalopathies / Q000235:genetics / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D014404:Tubulin / Q000235:genetics*; D055815:Young Adult
C582076:TUBB4A protein, human; D014404:Tubulin
H-ABC; MRI pattern; TUBB4A; genotype–phenotype correlation; hypomyelination