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

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.

Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants

“…Mutations in TUBB4A (MIM# 602662) have been identified to cause a wide phenotypic spectrum of diseases spanning hereditary generalized dystonia with whispering dysphonia (DYT‐TUBB4A) (Hersheson et al., ; Lohmann et al., ), hereditary spastic paraplegia (HSP) (Kancheva et al., ; Sagnelli et al., ), and leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H‐ABC) (Arai‐Ichinoi et al., ; Blumkin et al., ; Hamilton et al., ; Pizzino et al., ; Simons et al., ). The causative mutation in DYT‐TUBB4A is a NM_006087.3:c.4C>G (p.R2G) substitution, whereas in another patient with spasmodic dysphonia, the mutation NM_006087.3:c.811G>A (p.A271T) was detected (Lohmann et al., ).…”

“…The causative mutation in DYT‐TUBB4A is a NM_006087.3:c.4C>G (p.R2G) substitution, whereas in another patient with spasmodic dysphonia, the mutation NM_006087.3:c.811G>A (p.A271T) was detected (Lohmann et al., ). At present, the vast majority of H‐ABC cases have been diagnosed with the NM_006087.3:c.745G>A (p.D249N) mutation in the TUBB4A gene (Hamilton et al., ; Simons et al., ; Tonduti et al., ).…”

Association Between Invisible Basal Ganglia and ZNF335 Mutations: A Case Report

“…To the best of our knowledge, hypomyelination with atrophy of the basal ganglia and cerebellum (known as H-ABC), is the only disease showing a decreased basal ganglia size in infancy. 3 Thus, it is important to consider ZNF335 mutations as a differential diagnosis when encountering infants with both microcephaly and invisible basal ganglia.…”

Epilepsy in Multigene Tubulin Family Mutations

“…Mutations in α-and β-tubulin genes are responsible for a large spectrum of overlapping brain malformations characterized by abnormal neuronal migration, organization, differentiation, and axon guidance and maintenance as cortical abnormalities (agyria-pachigyria spectrum, nodular heterotopias, polymicrogyria and schizencephaly), defects of commissural axon tracts, dysmorphisms of basal ganglia and brainstem, rare forms of leucoencephalopathy with degeneration of motor and sensor axons and, as recently described, cerebellar dysplasia [10,11,[15][16][17][18][19][20][21][22][23]. Despite this overlapping phenotype, mutation-specific phenotypes in tubulin isotypes exist, due both to the specific function of the related isotype and to the different functional areas of the protein involved leading to a genotype/phenotype correlation, based not only on the primary sequence of the protein, but also on the tertiary structure and the three-dimensional arrangement of the protein [9].…”

“…A rare form of leukoencephalopathy, chacterized by hypomielination with atrophy of the basal ganglia and cerebellum (H-ABC), has been described also associated to mutations of the TUBB4A gene [18][19][20][21], supporting the hypothesis that tubulin genes have subtle, but yet distinct roles in microtubular dynamics and functions, according to cell type and neurodevelopmental time points [9]. Despite the underlying cellular and molecular mechanisms responsible for these phenotypes remain to be defined, it has been demonstrated that this gene is expressed at low levels in developing brain, but it is highly transcripted in adult cerebellum, brainstem and striatum [30].…”