Objective: Describing two mild compound heterozygote SPG5A cases.

Background: Hereditary spastic paraplegia type 5 (SPG5A) is an autosomal recessive neurodegenerative disease caused by variants in CYP7B1, an enzyme-coding gene involved in cholesterol metabolism^1–3. Clinical features are variable (gait deficits, leg spasticity, optic atrophy, and cerebellar ataxia)^4–8. We present novel genetic findings in two brothers.

Method: We retrospectively reviewed records of two brothers.

Results: Subjects A (25 years) and B (19 years) are brothers from non-consanguineous Italian-American parents. Both presented with worsening gait since childhood (A at 10 years; B at 4 years). Both had ataxic gait, mild lower extremity spasticity and hyperreflexia, with bilateral extensor plantar reflexes. Both had diminished vibration, proprioception, and touch. Neither had objective weakness. Both ambulated independently and participated in sports. Subject A had unremarkable electromyography, nerve conduction study, and brain/spine MRIs. Genetic testing revealed that both siblings were compound heterozygotes for variants in the CYP7B1 gene [c.314dupA,(p.N105KfsX3) and c.169 G>A, (p.G57R)]. These variants have been previously reported in the literature, but not together in a compound heterozygous state as reported here.

Conclusion: We present two novel cases of mild SPG5A caused by compound heterozygosity in the CYP7B1 gene. Previous reports described subjects with these variants alone or in combination with other variants with greater neurological deficits and functional impairment as compared to our subjects. The deficits associated with SPG5A are attributed to pathology in corticospinal tracts (CST), dorsal columns (DC), cerebellar pathways, and other structures ^{3,4,7,10–25}.  Our patients’ modest phenotype may reflect biallelic compensation, suggesting that the co-occurrence of these mutations preserves some level of CYP7B1 function and highlighting the sensitivity of CST and DC fibers innervating the legs to even slight disruptions in CYP7B1 activity. To develop treatments^24–26, it will be necessary to understand CYP7B1’s role in axon maintenance. An appreciation of how specific mutations alter CYP7B1 activity and thereby cause neurological dysfunction will be fundamental to these efforts­.

References: 1. Stiles, A. R., McDonald, J. G., Bauman, D. R. & Russell, D. W. CYP7B1: One Cytochrome P450, Two Human Genetic Diseases, and Multiple Physiological Functions*. J. Biol. Chem. 284, 28485–28489 (2009).
2. Tsaousidou, M. K. et al. Sequence Alterations within CYP7B1 Implicate Defective Cholesterol Homeostasis in Motor-Neuron Degeneration. Am. J. Hum. Genet. 82, 510–515 (2008).
3. Klebe, S. et al. Spastic paraplegia 5: Locus refinement, candidate gene analysis and clinical description. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 854–861 (2007).
4. Schüle, R. et al. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann. Neurol. 79, 646–658 (2016).
5. Polo, J. M., Calleja, J., Combarros, O. & Berciano, J. Hereditary ‘pure’ spastic paraplegia: a study of nine families. J. Neurol. Neurosurg. Psychiatry 56, 175–181 (1993).
6. Coutinho, P. et al. Clinical Heterogeneity of Autosomal Recessive Spastic Paraplegias: Analysis of 106 Patients in 46 Families. Arch. Neurol. 56, 943–949 (1999).
7. Arnoldi, A. et al. Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin. Genet. 81, 150–157 (2012).
8. Schüle, R. et al. The Spastic Paraplegia Rating Scale (SPRS): A reliable and valid measure of disease severity. Neurology 67, 430–434 (2006).
9. Biancheri, R. et al. White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1. Neuromuscul. Disord. 19, 62–65 (2009).
10. Schüle, R. et al. Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia. Neurogenetics 10, 97 (2008).
11. Wilkinson, P. A. et al. A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia. Neurology 61, 235–238 (2003).
12. Lan, M.-Y. et al. Clinical and genetic analysis of Taiwanese patients with hereditary spastic paraplegia type 5. Eur. J. Neurol. 22, 211–214 (2015).
13. Chou, C.-T. et al. Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5. Ann. Clin. Transl. Neurol. 7, 486–496 (2020).
14. Goizet, C. et al. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain 132, 1589–1600 (2009).
15. Roos, P., Svenstrup, K., Danielsen, E. R., Thomsen, C. & Nielsen, J. E. CYP7B1: novel mutations and magnetic resonance spectroscopy abnormalities in hereditary spastic paraplegia type 5A. Acta Neurol. Scand. 129, 330–334 (2014).
16. Manganelli, F. et al. Electrophysiological characterisation in hereditary spastic paraplegia type 5. Clin. Neurophysiol. 122, 819–822 (2011).
17. Hauser, S., Höflinger, P., Theurer, Y., Rattay, T. W. & Schöls, L. Generation of induced pluripotent stem cells (iPSCs) from a hereditary spastic paraplegia patient carrying a homozygous Y275X mutation in CYP7B1 (SPG5). Stem Cell Res. 17, 437–440 (2016).
18. Höflinger, P., Theurer, Y., Schüle, R., Schöls, L. & Hauser, S. Generation of induced pluripotent stem cells (iPSCs) from a hereditary spastic paraplegia patient carrying a homozygous R486C mutation in CYP7B1 (SPG5). Stem Cell Res. 17, 422–425 (2016).
19. Muglia, M. et al. Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus. Neurogenetics 5, 49–54 (2004).
20. Cao, L. et al. Novel mutations in the CYP7B1 gene cause hereditary spastic paraplegia. Mov. Disord. 26, 1354–1356 (2011).
21. Criscuolo, C. et al. Two novel CYP7B1 mutations in Italian families with SPG5: a clinical and genetic study. J. Neurol. 256, 1252–1257 (2009).
22. Hentati, A. et al. Linkage of ‘pure’ autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum. Mol. Genet. 3, 1263–1267 (1994).
23. Schüle, R. et al. Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. J. Lipid Res. 51, 819–823 (2010).
24. Mignarri, A. et al. Hereditary spastic paraplegia type 5: a potentially treatable disorder of cholesterol metabolism. J. Neurol. 261, 617–619 (2014).
25. Marelli, C. et al. Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain 141, 72–84 (2018).
26. Abdel-Khalik, J. et al. Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma. Biochimie 153, 86–98 (2018).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/milder-presentation-in-two-compound-heterozygote-cases-of-spastic-paraplegias-type-5/