Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia
Abstract
We describe two pairs of siblings from a consanguineous family manifesting autosomal recessive hereditary spastic paraplegia caused by a novel mutation in the EXOSC3 gene, previously reported in pontocerebellar hypoplasia type 1. Clinical findings included delayed motor milestones, early-onset spastic paraplegia, variable cognitive disability, and cerebellar signs. Cerebral imaging demonstrated enlarged cisterna magna and mild hypoplasia and atrophy of the lower vermis with a normal pons. Genetic analysis using homozygosity mapping followed by whole exome sequencing identified homozygous c.571G>T; p.G191C mutation in the EXOSC3 gene. We suggest that EXOSC3 mutations may present not only as pontocerebellar hypoplasia type 1, but also as a complicated form of hereditary spastic paraplegia without pontine hypoplasia or atrophy.
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Pathogenic variants in EXOSC3 cause pontocerebellar hypoplasia type 1B (PCH1B).
“Pathogenic variants in EXOSC3, a noncatalytic subunit of the RNA exosome, cause pontocerebellar hypoplasia type 1B (PCH1B)”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [23]
PCH1B is characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction.
“PCH1B is a subtype characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction and caused by variants in the EXOSC3 gene15,18,21–23,25.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [23]
Variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F).
“variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F)15–25.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [23]
PCH1B patients who are carriers of compound heterozygous EXOSC3 D132A/G191D variants present with milder disease, without involving the pons, and show intrafamilial variability.
“PCH1B patients who are carriers of compound heterozygous EXOSC3 D132A/G191D variants present with milder disease, without involving the pons, and show intrafamilial variability23,53,54.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [23]
The lesser thermodynamic severity of the G191C variant compared to G191D correlates well with less severe clinical outcomes observed in G191C homozygous patients compared to G191D homozygous patients.
“Notably, the lesser thermodynamic severity of the G191C variant compared to G191D correlates well with less severe clinical outcomes observed in G191C homozygous patients (previously classified with complicated hereditary spastic paraplegia) compared to G191D homozygous patients (classified with moderate PCH1b) 23,53,54.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [23]
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The RNA exosome maintains cellular RNA homeostasis by controlling transcript abundance in the brain
Higginson, L. A., Wang, X., He, K., Torstrick, M., Kim, M., Wijeratne, H. R. S., Runnebohm, A. M., Benayoun, B. A., MacLean, A., Chanfreau, G. F., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116729 · Cited by 7 · see citing works
EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery
Wijeratne, H. R. S., Runnebohm, A. M., Barron, M. P., Hampton, A. J., Li, R., Peck Justice, S. A., Lenceski, S. H., Rooney, J. D., Smith-Kinnaman, W. R., Chang, G. S., et al. (2026) · doi:10.64898/2026.01.26.701775 · Cited by 1 · see citing works
“Within the PCH spectrum, PCH1B is a subtype characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction and caused by variants in the EXOSC3 gene 15,18,21-23 , 25 .”
Influential
- Authors
- Halevy, A., Lerer, I., Cohen, R., Kornreich, L., Shuper, A., Gamliel, M., Zimerman, B.-E., Korabi, I., Meiner, V., Straussberg, R., & Lossos, A.
- Affiliations
- Schneider Children's Medical Center (IL)
- Hebrew University of Jerusalem (IL)
- Tel Aviv University (IL)
- Hadassah Medical Center (IL)
- Corresponding author
- Halevy, Ayelet
- Venue
- Journal of Neurology
- Published
- 2014-08-23
- Volume
- 261
- Issue
- 11
- Pages
- 2165-2169
- ISSN
- 0012-1037 (ISSN-L)
- 0340-5354
- 1432-1459
- OpenAlex
- W2022372816
- Cited by
- 46
- References
- 0
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 2 · 2015: 2
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- EXOSC3, hereditary spastic paraplegia, novel mutations, autosomal recessive inheritance, consanguinity, cerebellar vermis hypoplasia, cisterna magna enlargement, cognitive disability, spastic paraplegia, homozygosity mapping
- MeSH terms
- Amino Acid Sequence, Child, Female, Humans, Male, Molecular Sequence Data, Mutation, Pedigree, Spastic Paraplegia, Hereditary, RNA-Binding Proteins, Young Adult, Exosome Multienzyme Ribonuclease Complex
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