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Original Contribution
May 2007

Hereditary Spastic Paraplegia 3A Associated With Axonal Neuropathy

Author Affiliations

Author Affiliations: Laboratory of Molecular Pathology (Ms Ivanova and Drs Jordanova and Kremensky), Department of Chemistry and Biochemistry (Ms Ivanova and Dr Mitev), and Department of Pediatrics (Dr Litvinenko), Sofia Medical University, Sofia, Bulgaria; Neurogenetics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB) University of Antwerp (Drs Claeys, Nelis, and De Jonghe and Mss Deconinck, Löfgren, and Smeyers); Department of Neurology, University Hospital Antwerp, Antwerpen, Belgium (Drs Claeys, Mercelis, Ceulemans, and De Jonghe); Institute of Medical Biology and Human Genetics and Department of Internal Medicine, Diabetes and Metabolism (Dr Auer-Grumbach), and Department of Pediatrics (Dr Plecko), Medical University Graz, Graz, Austria; DNA Laboratory, Department of Child Neurology, Second School of Medicine (Drs Haberlova and Seeman) and Department of Pathology and Molecular Medicine, Second Medical Faculty and Faculty Hospital Motol (Dr Zámečník), Charles University Prague, Prague, Czech Republic; Department of Neurology and Department of Psychiatry, Charité-Universitätsmedizin Berlin, Germany (Dr Priller); Department of Neurology, Ulleval University Hospital, Oslo, Norway (Dr Erichsen); Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (Dr Björck); Northcott Neuroscience Laboratory, University of Sydney, ANZAC Research Institute, Sydney, Australia (Dr Nicholson); Molecular Medicine Laboratory, Concord Hospital, Concord, Australia (Dr Nicholson); and Department of Neurogenetics, Max-Planck Institute of Experimental Medicine, and Center of Neurology, University of Goettingen, Goettingen, Germany (Dr Sereda).

Arch Neurol. 2007;64(5):706-713. doi:10.1001/archneur.64.5.706

Objective  To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia.

Design  We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4.

Results  In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy.

Conclusions  We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.