PP12.9 – 2524: Clinical spectrum of TUBB4A-related disorders: Three patients with different phenotypes and course

Abstract

Objective To describe 3 patients representing the wide phenotypic spectrum of TUBB4A-related disorders. Methods The setting: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Israel. The subjects: Patient 1: An 8 year old girl with a classic clinical and radiologic picture of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). She presented with delayed motor development and gait instability by the end of her first year of life, followed by slowly progressive motor deterioration and extrapyramidal signs. She has mild intellectual disability and severe dysarthria. Her half-brother suffered from a similar disease and died in the second decade. 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 regional hypomyelination 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. Results The first patient and her half-brother were found to carry the common D249N mutation known in H-ABC. Their mother is negative for the mutation, suggesting germline mosaicism. A novel de-novo mutation, V179L was found in the second patient and a de-novo E410K mutation was found in the third patient. Conclusions Mutations in the TUBB4A gene have been described in association with two main clinical phenotypes: childhood-onset hypomyelination with atrophy of the basal ganglia and cerebellum, and late-onset dystonia. Our cases demonstrate that the spectrum of TUBB4A-related disorders also includes: familial cases due to germline mosaicism, lack of cerebellar atrophy on neuroimaging, regional hypomyelination and a clinical phenotype consistent with complicated spastic paraparesis.