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Abstract
IntroductionThis study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified. MethodsIndex patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing. ResultsWe identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed. DiscussionVariants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.
Highlights
This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified
An overlap between hereditary spastic paraplegia (HSP) and other neurogenetic disorders like Charcot-Marie-Tooth disease (CMT) and genetic forms of ataxia or parkinsonism is increasingly recognized and various of these HSP overlap syndromes are caused by specific genes
This study reports a series of 25 patients with an HSP-predominant phenotype in whom variants in the NEFL gene were identified
Summary
This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified. Results: We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Discussion: Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients. Pathogenic variants in the neurofilament light chain gene NEFL are a cause of autosomal dominant Charcot-Marie-Tooth disease (CMT), first identified in 2000 [1,2]. We report a large series of patients with a clinical picture dominated by adult-onset, hereditary spastic para plegia (HSP) caused by a variant in the NEFL gene
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