Abstract
SPG3A-linked hereditary spastic paraplegia (HSP) is a rare autosomal dominant motor disorder caused by a mutation in the SPG3A gene, and is characterized by progressive motor weakness and spasticity in the lower limbs, without any other neurological abnormalities. SPG3A-linked HSP caused by a R239C mutation has been reported to present a pure phenotype confined to impairment of the corticospinal tract. However, there is still a debate about the etiology of this motor deficit with regard to whether it is peripheral or central. We herein report two patients who were heterozygous for a R239C mutation in the SPG3A gene. Two middle-aged Japanese sisters had been suffering from a pure phenotype of HSP since their childhood. Both patients had a significant decrease in glucose metabolism in the frontal cortex medially and dorsolaterally in a [18F]-fluorodeoxyglucose (FDG) positron emission photography (PET) study and low scores on the Frontal Assessment Battery. A real-time PCR analysis in normal subjects showed the frontal cortex to be the major location where SPG3A mRNA is expressed. The present finding that the frontal glucose hypometabolism was associated with frontal cognitive impairment indicates that widespread neuropathology associated with mutations in the SPG3A gene may be present more centrally than previously assumed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Fink JK. Advances in hereditary spastic paraplegia. Curr Opin Neurol. 1997;10:313–8.
Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 2008;7:1127–38.
Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet. 2001;29:326–31.
Depienne C, Stevanin G, Brice A, Durr A. Hereditary spastic paraplegias: an update. Curr Opin Neurol. 2007;20:674–80.
Hedera P, Fenichel GM, Blair M, Haines JL. Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia. Arch Neurol. 2004;61:1600–3.
Abel A, Fonknechten N, Hofer A, Durr A, Cruaud C, Voit T, et al. Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A. Neurogenetics. 2004;5:239–43.
Wilkinson PA, Hart PE, Patel H, Warner TT, Crosby AH. SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia. J Neurol Sci. 2003;216:43–5.
Zhu PP, Patterson A, Lavoie B, Stadler J, Shoeb M, Patel R, et al. Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. J Biol Chem. 2003;278:49063–71.
Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med. 1995;36:1238–48.
Scarano V, Mancini P, Criscuolo C, De Michele G, Rinaldi C, Tucci T, et al. The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy. J Neurol. 2005;252:901–3.
Ivanova N, Claeys KG, Deconinck T, Litvinenko I, Jordanova A, Auer-Grumbach M, et al. Hereditary spastic paraplegia 3A associated with axonal neuropathy. Arch Neurol. 2007;64:706–13.
Fusco C, Frattini D, Farnetti E, Nicoli D, Casali B, Fiorentino F, et al. Hereditary spastic paraplegia and axonal motor neuropathy caused by a novel SPG3A de novo mutation. Brain Dev. 2010;32:592–4.
Namekawa M, Muriel MP, Janer A, Latouche M, Dauphin A, Debeir T, et al. Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. Mol Cell Neurosci. 2007;35:1–13.
Rismanchi N, Soderblom C, Stadler J, Zhu PP, Blackstone C. Atlastin GTPases are required for Golgi apparatus and er morphogenesis. Hum Mol Genet. 2008;17:1591–604.
Muriel MP, Dauphin A, Namekawa M, Gervais A, Brice A, Ruberg M. Atlastin-1, the dynamin-like GTPase responsible for spastic paraplegia SPG3A, remodels lipid membranes and may form tubules and vesicles in the endoplasmic reticulum. J Neurochem. 2009;110:1607–16.
Orso G, Pendin D, Liu S, Tosetto J, Moss TJ, Faust JE, et al. Homotypic fusion of er membranes requires the dynamin-like GTPase atlastin. Nature. 2009;460:978–83.
Evans K, Keller C, Pavur K, Glasgow K, Conn B, Lauring B. Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proc Natl Acad Sci USA. 2006;103:10666–71.
Sanderson CM, Connell JW, Edwards TL, Bright NA, Duley S, Thompson A, et al. Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. Hum Mol Genet. 2006;15:307–18.
McMonagle P, Byrne P, Hutchinson M. Further evidence of dementia in SPG4-linked autosomal dominant hereditary spastic paraplegia. Neurology. 2004;62:407–10.
Murphy S, Gorman G, Beetz C, Byrne P, Dytko M, McMonagle P, et al. Dementia in SPG4 hereditary spastic paraplegia: clinical, genetic, and neuropathologic evidence. Neurology. 2009;73:378–84.
Scheuer KH, Nielsen JE, Krabbe K, Simonsen C, Koefoed P, Sorensen SA, et al. Reduced regional cerebral blood flow in SPG4-linked hereditary spastic paraplegia. J Neurol Sci. 2005;235:23–32.
Charvin D, Cifuentes-Diaz C, Fonknechten N, Joshi V, Hazan J, Melki J, et al. Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Hum Mol Genet. 2003;12:71–8.
Wharton SB, McDermott CJ, Grierson AJ, Wood JD, Gelsthorpe C, Ince PG, et al. The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. J Neuropathol Exp Neurol. 2003;62:1166–77.
Abrahams S, Goldstein LH, Kew JJ, Brooks DJ, Lloyd CM, Frith CD, et al. Frontal lobe dysfunction in amyotrophic lateral sclerosis. A pet study. Brain. 1996;119(Pt 6):2105–20.
van der Graaff MM, de Jong JM, Baas F, de Visser M. Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: a clinical and brain imaging review. Neuromuscul Disord. 2009;19:53–8.
Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology. 2003;60:1094–7.
Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, et al. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol. 2009;66:180–9.
Acknowledgments
The authors express their gratitude to Mr. Etsuji Yoshikawa (Hamamatsu Photonics KK) and Mr. Toshihiko Kanno (Hamamatsu Medical Center) for their valuable technical assistance with this project.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Terada, T., Kono, S., Ouchi, Y. et al. SPG3A-linked hereditary spastic paraplegia associated with cerebral glucose hypometabolism. Ann Nucl Med 27, 303–308 (2013). https://doi.org/10.1007/s12149-012-0673-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12149-012-0673-5