Objective: To describe a novel truncating variant in UBAP1 gene in a first Malay population, and expand the genotype and phenotype.

Background: Hereditary Spastic paraplegia (HSP) type 80 is an autosomal dominant juvenile-onset neurologic condition caused by the heterogenous mutation in the ubiquitin-associated protein 1

(UBAP1) gene that was established recently. This SPG80 is characterized by the onset of development of spasticity and hyperreflexia predominantly involving the lower limbs which can lead to difficulties for walking or loss of independent ambulation, often as early as the second decade. The majority of individuals have a pure form of the illness, while some may have cerebellar symptoms and minor cognitive impairment.

Method: A case report and Comprehensive literature review search using the PubMed search engine.

Results: Here, we report a Malay HSP family presenting a frameshift mutation in the UBAP1 gene leading to complex HSP. Their clinical features encompassed lower limb spastic paraparetic gait, in addition to painful leg cramps, proximal myopathy and elevated creatine kinase. Additionally, the proband experienced significant incontinence due to terminal neurogenic detrusor overactivity, which is uncommon in HSP patients. A novel heterozygous mutation for UBAP1 (c.226G>T (p.Glu76Ter) was identified following whole-exome sequencing, that segregated with the family’s phenotype and resulted in truncating UBAP1 protein (p.Glu76Ter). Together with the presented case, 93 cases were available for analysis. We discovered that there were demographic disparities in the age of onset, however majority of the patients presented at young age with median age at the

diagnosis was 9.5 years. Gait unsteadiness secondary to lower extremities spasticity and weakness were the most common presenting feature. Subsequently, more than half of the patients requiring walking assistant. It is clinically imperative to suspect this disease in children with early-onset spastic paraparesis, especially in cases accompanied by painful leg cramps, proximal myopathy and urinary incontinence.Taken together, our findings expand the genotype and phenotype spectrum of UBAP1 variants in HSP.

Conclusion: In conclusion, we described a new Malay Malaysian family affected by SPG80 caused by the unique frameshift mutation c.226G>T (p.Glu76Ter) in UBAP1. Our understanding of the genotype and phenotype of SPG80 has indeed been fostered by this work.

References: References

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truncating variants in UBAP1 are responsible for hereditary spastic paraplegia. PLoS ONE,
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Vandrovcova, J., Houlden, H., & Tucci, A. (2020). Identification of UBAP1 mutations in
juvenile hereditary spastic paraplegia in the 100,000 genomes project. European Journal of
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3. Farazi Fard, M. A., Rebelo, A. P., Buglo, E., Nemati, H., Dastsooz, H., Gehweiler, I., Reich, S.,
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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-truncating-variant-in-ubap1-gene-causing-hereditary-spastic-paraplegia-type-80/