Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia.

BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia. METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. FINDINGS: Variants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

Cabello impeinable, un diagnóstico clínico fácil / Uncombable hair, an easy diagnosis

El cabello impeinable o indomable es una entidad benigna con unas características clínicas muy peculiares y fácilmente reconocibles. La sospecha diagnóstica es clínica y la confirmación se realiza mediante estudio por microscopía óptica de una muestra de cabello del paciente. Requiere evaluación dermatológica y oftalmológica. Su pronóstico es favorable y en ocasiones se consiguen buenos resultados con champú de piritiona de zinc (AU)

Uncombable hair is a benign entity with very peculiar and easily recognizable characteristics. The diagnostic suspicion is clinical and confirmation is made by an optical microscopy study of a sample of the patient's hair. A dermatological and ophthalmological evaluation are required. Its prognosis is favorable and good results are sometimes achieved with pyrithione zinc shampoo. (AU)