Objective: To present the case of a patient with a severe neurodegenerative disorder with onset in pediatric age carrying a pathogenic variant in CAPRIN1 gene confirming its role in progressive ataxic syndromes.

Background: CAPRIN1 gene encodes for Cell Cycle-Associated Protein 1, which is ubiquitously expressed in human tissues with rapid cellular turnover, highly abundant in the central nervous system and involved in transporting and translating mRNAs of synaptic proteins^1-4.

Method: Case report.

Results: This 13-year-old girl was the only child of non-consanguineous parents. Her clinical history was silent until the age of 8 years, when she presented with an insidious onset of motor clumsiness, leading to progressive gait disturbances, by the age of 10 years. At this time, she showed mild intellectual disability and speech and writing disturbances. By the age of 11 years, she developed myoclonus-ataxia, axial hypotonia, bradykinesia, sensorimotor neuropathy, and diffuse muscle atrophy. Brain MRI, performed at 10 years, showed frontal cortex and cerebellar hemispheres atrophy. Extensive metabolic workup and NGS panels for genetic ataxias, epilepsies, and mitochondrial diseases were negative. Electron microscopy of skin biopsy showed swelling of the rough Endoplasmic Reticulum (ER) and mitochondrial damage.

EEG showed diffuse epileptic abnormalities and electroneurography confirmed an axonal neuropathy. At the last follow-up, she showed further progression of neurological symptoms with loss of independent walking. Whole-exome sequencing disclosed a missense pathogenic variant in CAPRIN1 gene (c.1535C>T; p.Pro512Leu).

Conclusion: CAPRIN1 haploinsufficiency has been described so far in 14 patients with neurodevelopmental disorders⁵. Two other patients with progressive ataxia and sensorimotor axonal neuropathy carrying the same variant detected in our patient have been reported⁶. The P512L substitution is thought to cause a neurodegenerative phenotype by acting as a gain-of-function, leading to protein misfolding and aggregation⁶. Our case contributes to defining the clinical spectrum of CAPRIN1 mutations, supporting its role in the pathogenesis of this novel neurodegenerative disorder characterized by prominent childhood dementia, myoclonus-ataxia, neuropathy, ER and mitochondrial damage.

Presented at the 8th International Symposium on Paediatric Movement Disorders on February 10, 2024.

References: [1] Grill B, Wilson GM, Zhang KX et al (2004) Activation/division of lymphocytes results in increased levels of cytoplasmic
activation/proliferation-associated protein-1: prototype of a new family of proteins. J Immunol 172:2389–2400. https://doi.org/ 10.4049/jimmunol.172.4.2389
[2] Shiina N, Shinkura K, Tokunaga M (2005) A novel RNA-binding protein in neuronal RNA granules: regulatory machinery for local translation. J Neurosci 25:4420–4434. https://doi.org/10. 1523/JNEUROSCI.0382-05.2005
[3] Nakayama K, Ohashi R, Shinoda Y et al (2017) RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation. Elife. https://doi.org/10.7554/eLife.29677
[4] Shiina N, Yamaguchi K, Tokunaga M (2010) RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/
K+ ATPase subunit isoforms and leads to the degeneration of neuronal networks. J Neurosci 30:12816–12830. https://doi.org/10.1523/jneurosci.6386-09.2010
[5] Pavinato, L., Delle Vedove, A., Carli, D., Ferrero, M., Carestiato, S., Howe, J. L., Agolini, E., Coviello, D. A., van de Laar, I., Au, P. Y. B., Di Gregorio, E., Fabbiani, A., Croci, S., Mencarelli, M. A., Bruno, L. P., Renieri, A., Veltra, D., Sofocleous, C., Faivre, L., Mazel, B., Brusco, A. (2023). CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Brain: a journal of neurology, 146(2), 534–548. https://doi.org/10.1093/brain/awac278
[6] Delle Vedove, A., Natarajan, J., Zanni, G., Eckenweiler, M., Muiños-Bühl, A., Storbeck, M., Guillén Boixet, J., Barresi, S., Pizzi, S., Hölker, I., Körber, F., Franzmann, T. M., Bertini, E. S., Kirschner, J., Alberti, S., Tartaglia, M., & Wirth, B. (2022). CAPRIN1P512L causes aberrant protein aggregation and associates with early-onset ataxia. Cellular and molecular life sciences: CMLS, 79(10), 526. https://doi.org/10.1007/s00018-022-04544-3

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MDS Abstracts - https://www.mdsabstracts.org/abstract/caprin1-defect-a-new-severe-neurodegenerative-disorder-with-childhood-dementia-myoclonus-ataxia-and-sensorimotor-neuropathy/