Hypomyelination with atrophy of the basal ganglia and cerebellum

Further delineation of the phenotype and genotype-phenotype correlation

Eline M. Hamilton, Emiel Polder, Adeline Vanderver, Sakkubai Naidu, Raphael Schiffmann, Kate Fisher, Ana Boban Raguž, Luba Blumkin, Carola G M Van Berkel, Quinten Waisfisz, Cas Simons, Ryan J. Taft, Truus E M Abbink, Nicole I. Wolf, Marjo S. Van Der Knaap

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1921-1930
Number of pages10
JournalBrain
Volume137
Issue number7
DOIs
StatePublished - 2014

Fingerprint

Genetic Association Studies
Basal Ganglia
Cerebellum
Atrophy
Phenotype
Mutation
Magnetic Resonance Spectroscopy
Dystonia
Magnetic Resonance Imaging
Tubulin
Genotype
Exome
Leukoencephalopathies
Mosaicism
Putamen
Genetic Testing
Ataxia
Myelin Sheath
Epilepsy

Keywords

  • genotype-phenotype correlation
  • H-ABC
  • hypomyelination
  • MRI pattern
  • TUBB4A

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Hamilton, E. M., Polder, E., Vanderver, A., Naidu, S., Schiffmann, R., Fisher, K., ... Van Der Knaap, M. 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. https://doi.org/10.1093/brain/awu110

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; Raguž, Ana Boban; Blumkin, Luba; Van Berkel, Carola G M; Waisfisz, Quinten; Simons, Cas; Taft, Ryan J.; Abbink, Truus E M; Wolf, Nicole I.; Van Der Knaap, Marjo S.

In: Brain, Vol. 137, No. 7, 2014, p. 1921-1930.

Research output: Contribution to journalArticle

Hamilton, EM, Polder, E, Vanderver, A, Naidu, S, Schiffmann, R, Fisher, K, Raguž, AB, Blumkin, L, Van Berkel, CGM, Waisfisz, Q, Simons, C, Taft, RJ, Abbink, TEM, Wolf, NI & Van Der Knaap, MS 2014, 'Hypomyelination with atrophy of the basal ganglia and cerebellum: Further delineation of the phenotype and genotype-phenotype correlation', Brain, vol. 137, no. 7, pp. 1921-1930. https://doi.org/10.1093/brain/awu110
Hamilton, Eline M. ; Polder, Emiel ; Vanderver, Adeline ; Naidu, Sakkubai ; Schiffmann, Raphael ; Fisher, Kate ; Raguž, Ana Boban ; Blumkin, Luba ; Van Berkel, Carola G M ; Waisfisz, Quinten ; Simons, Cas ; Taft, Ryan J. ; Abbink, Truus E M ; Wolf, Nicole I. ; Van Der Knaap, Marjo S. / Hypomyelination with atrophy of the basal ganglia and cerebellum : Further delineation of the phenotype and genotype-phenotype correlation. In: Brain. 2014 ; Vol. 137, No. 7. pp. 1921-1930.
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AU - Naidu, Sakkubai

AU - Schiffmann, Raphael

AU - Fisher, Kate

AU - Raguž, Ana Boban

AU - Blumkin, Luba

AU - Van Berkel, Carola G M

AU - Waisfisz, Quinten

AU - Simons, Cas

AU - Taft, Ryan J.

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AU - Van Der Knaap, Marjo S.

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N2 - 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.

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