Paroxysmal Dyskinesia in ECHS1 Defect with Globus Pallidus Lesions

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene

“…53 White matter demyelination and brain atrophy, dilated ventricles, and thinning of the corpus callosum was commonly observed in our SCEH patients, as in other causes of LS. 47 Stroke-like events were observed in one patient from our cohort and one previously reported patient 36 Finally, dentate T2-WI hyperintensity and cerebellar atrophy was observed in 4/6 patients with HIBCH, similar to LS patients with MT-ATP6 and SURF1 genetic defects. 43,47,48 Biochemical features in our 19 patients suggested mitochondrial energy dysfunction, with elevated plasma lactate and alanine levels, respiratory chain complex and PDHc deficiencies, as described for other patients.…”

“…To date, 63 SCEH patients are described, all presenting between 0 and 18 years of age. 2,4,[26][27][28][29][30][31][32][33][34][35]8,36,[10][11][12][13]22,24,25,59 Three distinct clinical phenotypes are reported: LS (79%), paroxysmal dystonia (10%), and fatal neonatal lactic acidosis (11%) ( Table S1). Kaplan-Meier survival curves showed that half of the patients died before 10 years of age.…”

“…This metabolite was found in 75% of HIBCH cases in our study and in previous series. 4,9,26,27,40,41,45,54 Forty-three different ECHS1 mutations in 63 SCEH patients from 54 families have been described 2,4,[26][27][28][29][30][31][32][33][34][35]8,36,[10][11][12][13]22,24,25,59 ( Figure S2). Overall, 73% of the variants were present exclusively in one or two alleles, confirming the wide genetic heterogeneity of ECHS1.…”

“…On the opposite side of the severity spectrum, the SCEH‐related paroxysmal dystonia phenotype was identified in two patients from our cohort and in four previous cases. All six patients were normally developing children who presented with paroxysmal dystonia at 3.4 (1.7‐8) years 11,32,36 . Two clinical scenarios were identified: (a) paroxysmal and asymmetric dystonic episodes in the lower limbs lasting a few minutes, and normal neurological examination in between episodes (P1, 11,32 ); and (b) stroke‐like events with acute hemydystonia and residual pyramidal and extra‐pyramidal signs (P2, 32 ).…”

Unravelling of the paroxysmal dyskinesias

“…S15 Thus, ECHS1 mutations have been associated with intermittent episodes of long-duration (30–50 min) opisthotonus with no identifiable trigger, S15 but also with episodes of dystonia clearly induced by sustained exercise 29 30. Although a previous report has labelled the latter episodes as ‘kinesigenic’,28 a careful analysis of the original case description reveals that the attacks were actually triggered by ‘physical strain’ 28. Two more recent reports have confirmed that PxD due to ECHS1 mutations are more likely to be in the form of PED, with or without normal interictal neurological examination 29 30…”