PP12.10 – 2930: Expansion of the spectrum of TUBB4A mutations-related phenotype in hypomyelinating leukodystophy with atrophy of basal ganglia and cerebellum

Abstract

Objective Hypomyelinating leukodystophy (HDL) with atrophy of basal ganglia (BG) and cerebellum (H-ABC or HDL6) has recently been associated with de Novo mutations of tubulin beta 4 (TUBB4A), a gene known to be involved in a dominant form of dystonia (DYT4). We propose to illustrate the large clinicoradiological spectrum of TUBB4A-gene-related mutations. Methods We report on 4 patients. Results Patient 1 presented with a classic form: nytagmus at 3 months of age, no head control; spastic tetraparesis, choreo-athetosic movements and axial dystonia were obvious before the age of 2 years. MRI showed hypomyelination with progressive BG atrophy. Patient 2 and 3 presented with predominant motor dysfunction which manifested as delayed acquisition of milestones and progressive severe spastic quadriplegia. Communication and receptive language were relatively preserved. Extrapyramidal symptomatology and cognitive dysfunction appeared after several years of evolution. MRI dysplayed hypomyelination, corpus callosum and cerebellar atrophy in patients 2 and 3, associated with cortical and BG atrophy in patient 3. Patient 4 acquired independent but unsteady walking at 12 months of age. He could run and read. He was explored for the first time at around 2 years for nystagmus and delayed acquisition of language. Motor functions deteriorated after a limb fracture (7y) in a context of very slowly progressive cerebellar syndrome, which had been evident at 3 years of age. Independent ambulation was lost at 8. MRI at 10 years showed hypomyelination and a slight atrophy of the striatum. All patients have diferent de Novo TUBB4A mutations. 2 are known, 2 are reported for the first time (patients 2, 4). Conclusion These observations illustrate a phenotypic continuum linked to TUBB4A mutations, as reported in the others HDL. This diagnosis should be discussed when HDL is associated with BG and/or cerebellum atrophy in a patient presenting with spasticity and/or progressive cerebellar symptoms.