Ayelet Zerem,Dorit Lev, Benjamin Glick, Ayelet halevy, Esther Leshinsky-Silver, Tally Lerman-Sagie, Lubov Blumkin
To describe 3 patients from our Metabolic-Neurogenetic clinic representing the wide phenotype of TUBB4A-related disorders.
Mutations in the TUBB4A gene have been described in two main clinical phenotypes: childhood-onset hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and late-onset dystonia (DYT4) also called whispering dysphonia. Recently, the spectrum of the neurodegenerative diseases associated with TUBB4A mutations has expanded.
TUBB4A encodes a beta-tubulin which constitutes a component of the microtubules in the cells cytoskeleton and is highly expressed in the cerebellum, putamen and white matter.
Patient 1: an 8 year old girl with a classic clinical and radiologic picture of H-ABC. She presented with delayed motor development and gait instability by the end of her first year of life, followed by very slowly progressive motor deterioration and extrapyramidal signs. She has moderate intellectual disability and severe dysarthria. Her half brother suffered from a similar disease and died from aspiration.
Patient 2: a 3 year old girl with hypomyelination but without atrophy of the basal ganglia or cerebellum. Presented with congenital nystagmus, generalized dystonia, postnatal microcephaly and global developmental delay.
Patient 3: a 9.5 year old boy with gait instability from the second year of life, followed by slowly progressive spastic paraparesis, segmental dystonia, mild intellectual disability, severe behavioral problems, and evidence of regional hypomyelination associated with progressive cerebellar atrophy.
Sequence analysis of the TUBB4A gene in the first patient's DNA and whole exome sequencing in the other 2 patients were performed.
3 different de novo mutations in the TUBB4A gene were detected.
The first patient and her half brother were found to carry the common D249N mutation known in H-ABC, suggesting germline mosaicism.
Dystonia, intellectual disability and hypomyelination are key features in TUBB4A-related disorders, even though the phenotypic variations are wide.