Abstract
Hereditary spastic paraparesis (HSP) is a progressive neurodegenerative disorder, characterized by progressive lower limb weakness and spasticity. Multiple genes are associated with both the pure and complicated HSP types. Our study is aimed at seeking for novel genetic basis of HSP in a family with two affected siblings. Genetic analysis using whole exome sequencing was conducted in a family quartet with two female siblings, who presented with complicated HSP featuring slowly progressive paraparesis, mild-moderate intellectual disability, normal head circumference (HC), and normal magnetic resonance imaging (MRI). A homozygous pathogenic variant was identified in both siblings in the VPS53 gene (c.2084A>G: c.2084A>G, p.Gln695Arg). This gene acts as a component of the Golgi-associated retrograde protein (GARP) complex that is involved, among others, in intracellular cholesterol transport and sphingolipid homeostasis in lysosomes and was previously associated with progressive cerebello-cerebral atrophy (PCCA) type 2. This is the first description of the VPS53 gene as a cause of autosomal recessive complicated HSP. Lysosomal dysfunction as a result of impaired cholesterol trafficking can explain the neurodegenerative processes responsible for the HSP. Our finding expands the phenotype of VPS53-related disease and warrants the addition of VPS53 analysis to the genetic investigation in patients with autosomal recessive HSP. The exact role of GARP complex in neurodegenerative processes should be further elucidated.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- HSP:
-
Hereditary spastic paraparesis
- PCCA:
-
Progressive cerebello-cerebral atrophy
- GARP:
-
Golgi-associated retrograde protein
- HC:
-
Head circumference
- MRI:
-
Magnetic resonance imaging
- MRS:
-
Magnetic resonance spectroscopy
- ID:
-
Intellectual disability
- ADHD:
-
Attention deficit hyperactivity disorder
- CMA:
-
Chromosomal microarray analysis
- WES:
-
Whole exome sequencing
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Acknowledgments
Irina Opincariu is thanked for editorial assistance. We would like to express our sincere gratitude to the patients and their family.
Funding
The study received the Bircher-Benner Grant for Preventative Medicine from the Sackler Faculty of Medicine, Tel Aviv University.
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All study protocols were reviewed and approved by the Institutional Review Board at the Tel Aviv Sourasky Medical Center.
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Hausman-Kedem, M., Ben-Shachar, S., Menascu, S. et al. VPS53 gene is associated with a new phenotype of complicated hereditary spastic paraparesis. Neurogenetics 20, 187–195 (2019). https://doi.org/10.1007/s10048-019-00586-1
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DOI: https://doi.org/10.1007/s10048-019-00586-1