Patient with ALS with a novel TBK1 mutation, widespread brain involvement, behaviour changes and metabolic dysfunction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by the presence of upper and lower motor neuron dysfunction. Clinical presentation and disease progression are variable between patients with ALS, with psychosocial, neuropsychological, nutritional and genetic factors all related to ALS outcome. We present a detailed characterisation of a patient with familial ALS with a novel TBK1 mutation with coexistent brain atrophy, behavioural changes and metabolic dysfunction. This male patient was first seen at age 62 years with a 3-month history of gait unsteadiness, weakness of the right arm and emotional lability. There was a history of depression. His father had died of ALS at age 67 years. At first assessment, there was weakness of the right upper limb, ALS Functional Rating Scale-Revised (ALSFRS-R) was 39 and his weight was 72 kg. After 6 months, there was onset of dysphagia. He had tongue fasciculations, brisk jaw jerk, weakness, wasting, brisk reflexes and fasciculations of upper and lower limbs. The ALSFRS-R was 34 and weight had further declined to 65 kg. Three months later, he had deteriorated further with severe weakness, nausea, anorexia and depression. ALSFRS-R was 25 and weight was 54 kg. His respiratory function declined from FVC of 4.57 L to 1.05 L over 6 months. He died ~16 months after the onset of symptoms. The patient participated in a series of neuropsychological, imaging and metabolic studies of unselected consenting patients with ALS enrolled from our clinic.1 Neuropsychological assessment results for this patient are presented in online supplementary table 1. Comparison of his individual results with those of other patients with ALS is presented in online supplementary tables 2 to 4. Genetic assessment was done by massively parallel sequencing using a custom-designed neuromuscular gene capture panel that tests for 66 genes known to be associated …