Paroxysmal Dyskinesia in ECHS1 Defect with Globus Pallidus Lesions

Background/Purpose: Paroxysmal dyskinesias are a heterogeneous group of rare episodic movement disorders with normal interepisodic neurologic findings. We report on two patients with ECHS1 defect as a previously undescribed cause of paroxysmal dyskinesia. Methods: Paroxysmal dyskinesia has manifested in two unrelated and normally developed girls in infancy. In patient 1 at the age of 2½ years, an episodic movement disorder developed, characterized by opisthotonus continuing for 20 to 50 minutes, usually in the late afternoon, occurring at rest, especially on days with many stimuli, several times per week. At the age of 20 months, patient 2 fell acutely ill with vomiting, reduced consciousness, and dehydration and recovered within a few days. With 3 3/12 years she developed an episodic kinesigenic hemidystonia: duration of one to several hours, always in the late afternoon and immediately after increased physical strain, several times per week. Ketogenic diet interrupted the paroxysmal dyskinesia in patient 1, while patient 2 did not benefit. Results: In cMRI both patients show bilateral globus pallidus lesions. The detailed laboratory diagnostics (metabolism, endocrinology, CSF) were unremarkable. Pyruvate oxidation, PDHC- and respiratory chain complexes activities in fibroblasts were normal. Using whole exome sequencing the compound heterozygous missense variants c.394C > T (p.Ala132Thr) and c.518C > T (p.Ala173Val) were detected in ECHS1 gene. ECHS1 activity and protein expression in fibroblasts were reduced. Conclusion: ECHS1 is encoding the mitochondrial short chain enoyl CoA hydratase 1, which is involved in the degradation of valine and possibly in the fatty acid β-oxidation as well. To date ECHS1 defects were described only in neurologically severely affected patients with Leigh syndrome. ECHS1 defect should also be considered in patients with paroxysmal dyskinesia and normal neurological findings in the interval.