LAUSR

Mutations affecting TBC1D24 are associated with an expanding spectrum of phenotypes including developmental delay, hearing impairment, Deafness, onychodystrophy, osteodystrophy and mental retardation syndrome (DOORS) syndrome (Mendelian Inerhitance in Man but now used almost exclusively as an acronym, not usual to expand (MIM) 220500), and a range of epilepsies. Different movement disorders, including ataxia, spasticity, and episodic dystonia, have also been reported, including, most recently, exercise-induced dystonia. Here we report 2 unrelated patients with biallelic TBC1D24 variants in whom exercise-induced dystonia was a major disease feature. Patient 1, now 13 years old, had episodic dystonia from infancy: while being fed in her highchair, she would arch her back or tilt her neck to 1 side. When she began to walk, walking induced episodes of truncal dystonia (Video S1). Her family recognized that exercise and repetitive physical activities frequently provoked episodes of dystonic posturing. Swimming lessons in particular were a reliable trigger and had to be discontinued, whereas singing and tongue protrusion were specifically associated with episodes of orofacial dyskinesia (Video S2). Paroxysmal episodes occurred several times each week during early childhood but over time became less frequent with effective trigger avoidance. Clinical examination between episodes revealed gait ataxia, dysarthria, intention tremor with distal myoclonus, mild dysmetria, dysdiadochokinesis, mildly impaired fine motor skills, and brisk lower limb deep tendon reflexes. She had normal saccades and smooth pursuit, although horizontal nystagmus was evident on lateral eye gaze. Speech and language skills were delayed, and cognitive testing at age 8 confirmed a mild learning disability. She had 3 generalized tonic-clonic seizures between the ages of 6 and 7 years, but became seizure free on carbamazepine monotherapy from the age of 8. It is possible that carbamazepine (in combination with trigger avoidance) may have also benefited her paroxysmal movement disorder. Brain magnetic resonance imaging on 2 occasions showed mild nonprogressive pontocerebellar hypoplasia. Whole-exome sequencing identified compound heterozygous TBC1D24 variants, 1 novel nonsense mutation, predicted to cause protein truncation and nonsense-mediated decay (NM_001199107.1: c.901C>T; p.Gln301*), and 1 previously reported as possibly pathogenic (NM_001199107.1:c.605C>T; p.Ser202Leu [rs796053400]), with 1 inherited from each parent. Patient 2, a 3-year-old girl, presented at 1 month old with episodic behavioral arrest. By 3 months, paroxysmal whole-body stiffening, upper limb flexion, and lower limb scissoring were evident. These episodes continued and, once verbal, she was able to alert her parents that one was about to begin. Her parents noticed that “playing hard” or other forms of physical exertion would reliably induce an episode, characterized by lateral flexion of the trunk and sometimes dystonic posturing of the limbs and/or tongue. Other triggers included heat, emotional stress, and prolonged computer use. Similar to patient 1, she also developed epilepsy manifesting as focal motor seizures with secondary generalization, currently well controlled with a combination of carbamazepine, topiramate, and clonazepam. To date, the attainment of neurodevelopmental milestones has been normal. Between episodes, clinical examination is normal bar subtle dystonic posturing of the hands. Whole-exome sequencing revealed 2 previously reported TBC1D24 variants, NM_001199107.1: c.475delC; p.Leu159Trpfs*10 (rs796053403) and NM_00119 9107.1c.680G > T; p.Arg227Leu (rs756181906), with 1 inherited from each parent. Our cases illustrate that not all paroxysmal events in TBC1D24-related disorders are epileptic in nature. Indeed, TBC1D24-related disease should be considered as part of the differential diagnosis of paroxysmal exercise-induced movement disorders, particularly in patients with early-onset complex neurological phenotypes.