TUBB4A de novo mutations cause isolated hypomyelination

We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations. Patients in 2 large institutional review board-approved leukodystrophy bioregistries at Children's National Medical Center and Montreal Children's Hospital with similar MRI features had whole-exome sequencing performed. MRIs and clinical information were reviewed. Five patients who presented with hypomyelination without the classic basal ganglia abnormalities were found to have novel TUBB4A mutations through whole-exome sequencing. Clinical and imaging characteristics were reviewed suggesting a spectrum of clinical manifestations. Hypomyelinating leukodystrophies remain a diagnostic challenge with a large percentage of unresolved cases. This finding expands the phenotype of TUBB4A-related hypomyelinating conditions beyond hypomyelination with atrophy of the basal ganglia and cerebellum. TUBB4A mutation screening should be considered in cases of isolated hypomyelination or hypomyelination with nonspecific cerebellar atrophy