Novel lissencephaly-associated DCX variants in the C-terminal DCX domain affect microtubule binding and dynamics.

OBJECTIVE: Pathogenic variants in DCX on the X chromosome lead to lissencephaly and subcortical band heterotopia (SBH), brain malformations caused by neuronal migration defects. Its product doublecortin (DCX) binds to microtubules to modulate microtubule polymerization. How pathogenic DCX variants affect these activities remains not fully investigated. METHODS: DCX variants were identified using whole exome and Sanger sequencing from six families with lissencephaly/SBH. We examined how these variants affect DCX functions using microtubule binding, regrowth, and colocalization assays. RESULTS: We found novel DCX variants p.Val177AlafsTer31 and p.Gly188Trp, as well as reported variants p.Arg196His, p.Lys202Met, and p.Thr203Ala. Incidentally, all of the missense variants were clustered on the C-terminal DCX domain. The microtubule binding ability was significantly decreased in p.Val177AlafsTer31, p.Gly188Trp, p.Lys202Met, and previously reported p.Asp262Gly variants. Furthermore, expression of p.Val177AlafsTer31, p.Gly188Trp, p.Arg196His, p.Lys202Met, and p.Asp262Gly variants hindered microtubule growth in cells. There were also decreases in the colocalization of p.Val177AlafsTer31, p.Thr203Ala, and p.Asp262Gly variants to microtubules. SIGNIFICANCE: Our results indicate that these variants in the C-terminal DCX domain altered microtubule binding and dynamics, which may underlie neuronal migration defects during brain development.

Prognostic factors for functional recovery in children with moderate to severe acute disseminated encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an immune-mediated encephalopathy with heterogeneous disease courses. However, clinical characteristics for a prognostication of functional recovery from acute episodes of ADEM remain limited. The study aims to characterize the clinical presentations and neuroimaging findings of children with poor functional recoveries from acute episodes of moderate to severe ADEM. METHODS: The multicenter retrospective cohort study included children under 18 years of age who presented with moderate to severe ADEM (modified Rankin Scale [mRS] ≥ 3 at nadir) from 2002 to 2019. Children were assigned to a good recovery group (mRS ≤ 2) and a poor recovery group (mRS ≥ 3) after mean 4.3 months of follow-up. The clinical presentations and the distribution of brain lesions on magnetic resonance imaging were compared between the two groups by the t-test for numerical variables and Fisher's exact test for categorical variables. Analyses of logistic regression were conducted and significant variables in the multivariate model were examined by the receiver operating characteristic curve for the prediction of functional recovery. RESULTS: Among the 73 children with moderate to severe ADEM, 56 (77%) had good functional recoveries and 17 (23%) showed poor functional recoveries. Children with poor recoveries had a lower rate of prodromal headache (12% vs. 39%, p = 0.04), and presented with higher proportions of dystonia (29% vs. 9%, p = 0.046), myoclonus (24% vs. 2%, p = 0.009), and cerebellar lesions on neuroimages (59% vs. 23%, p = 0.01). The multivariate analyses identified that a lack of prodromal headache (OR 0.1, 95% CI 0.005 - 0.7, p = 0.06) and the presentations of myoclonus (OR 21.6, 95% CI 1.7 - 874, p = 0.04) and cerebellar lesions (OR 4.8, 95% CI 1.3 - 19.9, p = 0.02) were associated with poor functional recoveries. These three factors could prognosticate poor outcomes in children with moderate to severe ADEM (area under the receiver operating characteristic curve 0.80, 95% CI 0.68 - 0.93, p = 0.0002). CONCLUSION: Nearly one-fourth of children with moderate to severe ADEM had a poor functional recovery from acute episodes, who were characterized by a lack of prodromal headache, the presentation of myoclonus, and the neuroimaging finding of cerebellar lesions. The clinical variables associated with poor functional recoveries could assist in the planning of immunotherapies during hospitalization for a better outcome in moderate to severe ADEM.