LAUSR

With great interest we read the study of Schob et al in Annals of Neurology identifying 6 dominantly inherited or de novo KPNA3 mutations, in 8 patients from 5 families. In doing so, they implicate dysfunctional nucleocytoplasmic shuttling as a new pathomechanism for Hereditary Spastic Paraplegia (HSP). As such, they put nuclear metabolism back on stage for future therapy development among other key protagonists, such as autophagy, dysfunctional axonal trafficking, and many more. Here, we report an additional family with an autosomal dominant pure HSP caused by a recurrent missense variant in KPNA3. The family under study (the Fig) is of Belgian origin and provided written informed consent for genetic studies. Routine clinical evaluations were performed as part of standard care. Whole exome sequencing (WES) was performed using Illumina Nextera Rapid Capture Expanded exome kit for exome enrichment and Illumina HiSeq2000 platform for sequencing. WES data was uploaded to and analyzed in the Genesis platform, a next-generation sequencing (NGS) data-sharing and analysis platform (tgp-foundation.org). We identified a segregating KPNA3 missense variant c.944C>T (p.Thr315Ile) in both the affected father and daughter (see the Fig), the mutation is absent in the unaffected mother. The currently 45-year-old father and 16-year-old daughter both showed gait abnormalities at 2 years of age. The father showed a slow disease progression and is currently full ambulatory. In contrast, his daughter is wheelchair dependent since the age of 5 years. Clinical examination in both patients is in line with a pure spastic paraplegia. The daughter showed a marked lower limb distal paresis without arguments of peripheral nervous system involvement on nerve conduction and electromyography (EMG) studies. Brain magnetic resonance imaging (MRI) showed no callosal or cerebellar structural abnormalities in both patients. Nucleocytoplasmic transport is an emerging research area in neurodegenerative diseases (eg, amyotrophic lateral sclerosis [ALS] and Huntington’s disease) although the connection with HSP was not very well established prior to the recent report of Schob et al. Although the authors show a diminished expression of several KPNA3 variants in HEK293T cells, this is not the case for the p.Thr315Ile mutation. Furthermore, impaired endogenous cargo binding is only shown for 2 of the 4 tested partners, whereas other mutations affect all 4 partners. By describing this Belgian family presenting with HSP and bearing the now recurrent p.Thr315Ile variant, we provide an independent observation in favor of pathogenicity even for variants that do not complete abolish KPNA3 cargo binding, thereby implicating the critical role of nucleocytoplasmic traffic in the pathogenesis of HSP.