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.
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.
Authors: Xin Bian; Robin W Klemm; Tina Y Liu; Miao Zhang; Sha Sun; Xuewu Sui; Xinqi Liu; Tom A Rapoport; Junjie Hu Journal: Proc Natl Acad Sci U S A Date: 2011-02-22 Impact factor: 11.205
Authors: Tina Y Liu; Xin Bian; Sha Sun; Xiaoyu Hu; Robin W Klemm; William A Prinz; Tom A Rapoport; Junjie Hu Journal: Proc Natl Acad Sci U S A Date: 2012-07-16 Impact factor: 11.205
Authors: Christian Guelly; Peng-Peng Zhu; Lea Leonardis; Lea Papić; Janez Zidar; Maria Schabhüttl; Heimo Strohmaier; Joachim Weis; Tim M Strom; Jonathan Baets; Jan Willems; Peter De Jonghe; Mary M Reilly; Eleonore Fröhlich; Martina Hatz; Slave Trajanoski; Thomas R Pieber; Andreas R Janecke; Craig Blackstone; Michaela Auer-Grumbach Journal: Am J Hum Genet Date: 2010-12-30 Impact factor: 11.025
Authors: Tyler J Moss; Camilla Andreazza; Avani Verma; Andrea Daga; James A McNew Journal: Proc Natl Acad Sci U S A Date: 2011-06-20 Impact factor: 11.205
Authors: Christian Beetz; Adam Johnson; Amber L Schuh; Seema Thakur; Rita-Eva Varga; Thomas Fothergill; Nicole Hertel; Ewa Bomba-Warczak; Holger Thiele; Gudrun Nürnberg; Janine Altmüller; Renu Saxena; Edwin R Chapman; Erik W Dent; Peter Nürnberg; Anjon Audhya Journal: Proc Natl Acad Sci U S A Date: 2013-03-11 Impact factor: 11.205