Clinical presentation of a patient with SLC20A2 and THAP1 deletions: differential diagnosis of oromandibular dystonia.

Abstract

Oromandibular dystonia is a rare, focal dystonia that is characterized by forceful contractions of the face, jaw, and/or tongue [1]. These contractions cause difficulty with the opening and closing of the mouth, which leads to mastication impairment and speech problems. Idiopathic basal ganglia calcification (IBGC) is a rare, autosomal-dominant disease that is accompanied by abnormal calcium deposition in the brain [2]. IBGC is clinically characterized by dystonia, parkinsonism, tremor, ataxia, dementia, psychosis, and seizures [2]. IBGC is classified into five subgroups, IBGC1 - IBGC5, and this classification is based on causative genes/loci. Wang and colleagues [3] identified SLC20A2 mutations as a genetic cause of IBGC3. We recently discovered SLC20A2 and THAP1 deletions in a familial form of basal ganglia calcification in which dystonia was the most predominant clinical manifestation [4, 5]. We provide a video presentation of a previously reported case from this previously described family (patient III-3 in the previous report [5]) [6]. We also include a summary of the clinical features associated with the type of oromandibular dystonia that arises from known genetic causes (Table). Table 1 Neurogenetic disorders that have been associated with oromandibular dystonia A right-handed man developed abnormal movements of his trunk and arms at the age of 26 years. His initial symptoms were writer’s cramp and involuntary posturing of his shoulders and trunk; these symptoms were more prominent on his right-side. His symptoms remained stable until he was 50-years-old, which was when he developed progressive dysarthria with speech-induced involuntary jaw opening, mild short-term memory loss, and gait impairment. His family history was notable for dystonia, chorea, and postural tremor. A brain CT showed calcifications in the occipital cortex, subcortical white matter, basal ganglia, thalamus, and the cerebellum. The esupp video shows the patient during two examinations; one was conducted when he was 77-years-old, and the other was conducted when he was 80-years-old.. The patient provided written consent before filming. The video displays that the patient had speech-induced jaw opening dystonia, severe dysarthria, chorea, right shoulder postural dystonia, and writer’s cramp. His gait deteriorated between his first and second examinations. He eventually developed severe cognitive impairment and behavioral problems. He died at the age of 85 years. An autopsy identified patchy, multifocal calcifications in the periventricular regions, basal ganglia, anterior thalamus, visual cortex, and the cerebellum. Genetic testing revealed that the patient carried SLC20A2 and THAP1 deletions [4]. To date, eighteen genetic disorders with known causative gene mutations have been reported to be associated with oromandibular dystonia (Table. Of these, only neurodegeneration with brain iron accumulation 1 (NBIA1) is known to cause calcification in the brain. NBIA1 is caused by PANK2 mutations and is clinically characterized by dystonia, dysarthria, pyramidal signs, cognitive impairment, pigmentary retinopathy, dysphagia, chorea, psychiatric symptoms, developmental delay, oculomotor abnormalities, and parkinsonism. Typical symptomatic disease onset for NBIA1 usually occurs before the age of 10 years. However, a minority of patients exhibit atypical clinical features, such as a later symptomatic disease onset (between 15–40 years), prominent speech problems, psychiatric symptoms, and a more gradual disease progression. Calcifications in the brains of NBIA1 patients generally can be observed in the basal ganglia. Our patient and his family [5,6] can be clinically distinguished from NBIA1 patients based on the more extensive distribution of brain calcification in their brains. Currently,, no patients carrying SLC20A2 mutations have been reported to present with oromandibular dystonia [3]. However, oromandibular dystonia is one of the prominent features of patients with THAP1 mutations. The oromandibular dystonia seen in this case and in that of others previously reported [5,6] could presumably be caused solely by a mutation in the THAP1 gene. Additional functional studies to confirm this hypothesis are warranted. Genetic testing, especially for THAP1, should be considered in individuals that have extensive basal ganglia calcifications and a family history of dystonia.