LAUSR

Recently, two missense mutations in NPTX1 were identified as a cause of autosomal dominant cerebellar ataxia by triggering endoplasmic reticulum stress. The NPTX1encoded protein neuronal pentraxin 1 (NP1) is exclusively expressed in the nervous system with high expression levels in neurons of the cerebellum, cerebral cortex, and hippocampus (Human Protein Atlas). In this letter, we report a novel NPTX1 de novo missense variant identified in a male individual with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome. The patient first noticed signs of cerebellar ataxia and dysarthria at the age of 47 years. A first comprehensive examination at the age of 52 years showed moderate ataxia and dysarthria. On follow-up evaluation 2 years later, no subjective deterioration of cerebellar symptoms, except for progressive dysarthria and dysphagia, were reported. Clinical examination additionally demonstrated choreiform dyskinesias and oculomotor apraxia (Table 1, Supporting Information Video S1). Family history concerning movement disorders was negative. Brain magnetic resonance imaging (MRI) demonstrated cerebellar atrophy with predominantly vermian involvement (Supporting Information Fig. S1). Neuropsychological evaluation showed moderate cognitive impairment characterized by executive dysfunction and attentional deficits, including severely impaired working memory. Further intensive diagnostic workup showed no additional findings (Supporting Information Appendix S1). Trio exome sequencing, variant calling, annotation, and clinical prioritization were performed on patient’s and parental genomic DNA as previously described, confirming biological parenthood and identifying a single heterozygous missense variant in exon 1 of NPTX1 (ENST00000306773.4: c.428G>T, p.R143L), absent from gnomAD and an in-house database. There was no evidence of a putative parental mosaicism in blood (Figures S2 and S3) and carrier testing of the healthy brother showed wildtype sequences. These findings are in line with a de novo occurrence and disease-causal role of the c.428G>T, p. R143L variant in the patient. The identified c.428G>T variant affects a CG dinucleotide and alters an arginine in NP1 highly conserved across species (Supporting Information Fig. S4) and other proteins of the pentraxin family (Supporting Information Fig. S5). Accordingly, the change p.R143L is consistently predicted by several in silico tools to be probably damaging or deleterious. Unlike the variants previously identified, p.R143L is not localized in the pentraxin domain but resides within the N-terminal region of NP1. In silico prediction of protein folding via AlphaFold indicated localization of the p.R143 residue within a coiledcoil domain assumed to be responsible for multimerization. Substitution of the arginine residue likely disrupts formation of the α-helical secondary structure and tertiary coiled-coil motif, thus possibly affecting homomultimerization and heteromultimerization of NP1. Misfolding of NP1 could therefore cause aggregation of dysfunctional multimers, explaining the deleterious effect of the p.R143L variant. Together, our case provides further evidence of pathogenic NPTX1 variants and highlights the complex neurological phenotype of NPTX1-associated disease beyond ataxia. Our patient’s clinical phenotype characterized by late-onset, slowly progressive cerebellar ataxia and multiple noncerebellar symptoms resembles the ones previously described (Table 1). Localization and de novo status of the variant in our patient underline the importance of considering NPTX1