The emerging neurological spectrum of AARS2-associated disorders.

BACKGROUND: The AARS2 gene encodes a mitochondrial alanyl-transfer RNA synthetase. Defects in this gene have been linked with autosomal recessive inheritance of a variety of different clinical phenotypes. CASE: A 13 year-old boy developed behavioral and psychiatric problems following a mild head injury. At age 21 he developed tremor, parkinsonism, and eye nystagmus. MRI revealed white matter changes consistent with a leukoencephalopathy. Genetic studies revealed two pathogenic mutations in the AARS2 gene (c.647dupG and c.595C > T). LITERATURE REVIEW: Only 47 cases of AARS2-associated disorders have been reported, with equal numbers of males and females, and age at onset ranging from infancy to 44 years. The most common clinical problems include movement disorders (71%), cognitive impairment (67%), corticospinal signs (64%), behavioral or psychiatric features (46%), and eye signs (34%). Imaging evidence suggestive of leukoencephalopathy is common, but not invariant. Premature ovarian failure is frequent in females, but not universal. CONCLUSIONS: Defects in the AARS2 gene are a rare cause for a variety of movement disorders, often associated with brain imaging evidence suggestive of leukoencephalopathy.

Oromandibular Dystonia: A Clinical Examination of 2,020 Cases.

Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.