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The G93C Mutation in Superoxide Dismutase 1 Clinicopathologic Phenotype and Prognosis

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The G93C Mutation in Superoxide Dismutase 1 Clinicopathologic Phenotype and Prognosis ORIGINAL CONTRIBUTION The G93C Mutation in Superoxide Dismutase 1 Clinicopathologic Phenotype and Prognosis Luc Re´gal, MD; Ludo Vanopdenbosch, MD; Petra Tilkin, RN; Ludo Van Den Bosch, PhD; Vincent Thijs, MD, PhD; Rafael Sciot, MD, PhD; Wim Robberecht, MD, PhD Background: Twenty percent of familial amyotrophic Results: The G93C mutation was associated with a purely lateral sclerosis (ALS) is caused by mutations in the su- lower motor neuron phenotype without bulbar involve- peroxide dismutase 1 gene (SOD1). Few data exist on their ment. Presence of the mutation independently pre- clinicopathologic phenotypes. dicted longer survival compared with other ALS sub- groups. Pathologic examination showed degeneration of Objectives: To determine the clinical and pathologic the anterior horn, spinocerebellar tracts, and posterior phenotype associated with the G93C mutation in SOD1 funiculi, with minimal involvement of corticospinal tracts and to compare survival in familial ALS related to this and no degeneration of brainstem motor nuclei. Sur- mutation with survival in other ALS subgroups. vival motor neuron gene copy number had no signifi- cant influence on age at onset or survival in patients with Design: Retrospective study. the G93C mutation. Setting: Tertiary referral center for neuromuscular dis- Conclusions: These findings add to the knowledge of orders. SOD1-related familial ALS and demonstrate further clini- copathologic variability between different SOD1 muta- Patients:TwentypatientswiththeG93Cmutationforwhom clinicaldatawereavailableand1patientwithpathologicdata. tions. Finally, they demonstrate the independent prog- nostic value of the G93C mutation. Main Outcome Measures: Characteristics and sur- vival compared with other ALS subgroups, adjusting for known prognostic factors. Arch Neurol. 2006;63:262-267 MYOTROPHIC LATERAL SCLE- METHODS rosis (ALS) is a fatal de- generative disease of mo- PATIENTS tor neurons. In most patients, it is sporadic Clinical records of patients with ALS A(SALS) and its cause unknown. In 10% of examined in our institution were reviewed, patients ALS is familial (FALS), and 20% and patients with definite or probable ALS6 of FALS is caused by mutations in the su- were included. A diagnosis of FALS was peroxide dismutase 1 gene (SOD1).1 Some made when a first-degree relative was of these mutations are associated with a affected. Our ALS database (January 1, 2 1993, to December 31, 2002) contained 20 Author Affiliations: faster or slower clinical course or with patients with FALS from 4 families with Departments of Neurology and predominant lower motor neuron involve- SOD1(G93C), 10 patients with SOD1(L38V) 3 Experimental Neurology ment. However, for most of these muta- FALS, 5 patients with SOD1(D90A) FALS, (Drs Re´gal, Vanopdenbosch, tions little is known about their clinico- 18 patients with FALS without SOD1 muta- Van Den Bosch, Thijs, and pathologic correlates. tions, and 359 patients with SALS. Onset Robberecht and Ms Tilkin) and In this article, we report the clinical was defined as onset of weakness, dysar- Pathology (Dr Sciot), University and pathologic phenotype associated thria, or dysphagia, because onset of fascicu- Hospital Gasthuisberg, with the G93C mutation in SOD1 lations or cramps was found to be unreli- University of Leuven, Leuven, able. Diagnostic delay was defined as the Belgium. Dr Vanopdenbosch is [SOD1(G93C)]. Also, we compared sur- interval between onset and diagnosis. Sur- now with the Department of vival in SOD1(G93C)–related FALS with vival was defined as the interval between Neurology, AZ Sint-Jan, Brugge, survival in other ALS subgroups, adjust- onset and death or initiation of artificial ven- Belgium. ing for established prognostic factors.4,5 tilation. We determined percentage of pre- (REPRINTED) ARCH NEUROL / VOL 63, FEB 2006 WWW.ARCHNEUROL.COM 262 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 dicted forced vital capacity (FVC) soon after diagnosis. No patients received artificial ventilation. A NEUROPATHOLOGIC EXAMINATION The brain and spinal cord of a 57-year-old man with SOD1(G93C) and a 67-month survival were examined by rou- tine techniques. Briefly, representative tissue blocks from for- malin-fixed brain and spinal cord were processed with paraf- fin, and 5-µm-thick sections (through motor and other neocortexes, basal ganglia, hippocampus, brainstem, and cer- vical, thoracic, and lumbar spinal cord) were stained with he- matoxylin-eosin and with the Klu¨ ver-Barrera stain. Indirect im- munoperoxidase stains were performed with the use of polyclonal antiubiquitin antibodies (DAKO, Glostrup, Den- mark) and polyclonal antineurofilament antibodies (Sigma Chemical Co, St Louis, Mo). GENETIC ANALYSIS B The SOD1 genotyping of patients with FALS with screening of all 5 exons was performed as described previously,7 after informed consent was obtained. The copy number of the survival motor neuron 1 (SMN1) and SMN2 genes in 15 of the patients with SOD1(G93C) was determined by means of the multiplex ligation-dependent probe amplification tech- nology,8 with a diagnostic kit for spinal muscular atrophy (Salsa P021; MRC Holland BV, Amsterdam, the Nether- lands). STATISTICAL ANALYSIS Age at onset and diagnostic delay in patients with FALS (SOD1 related [G93C, L38V, D90A] and non–SOD1 related) and SALS were compared by analysis of variance. Pairwise comparisons were performed by unpaired, 2-tailed t tests. Kaplan-Meier curves C of survival in SOD1(G93C)–related FALS, SOD1(L38V)– related FALS, non–SOD1-related FALS, and SALS were gener- ated and compared by the log-rank test. Because only 5 pa- tients with SOD1(D90A) were available, their data were not included. A Cox proportional hazards regression was per- formed with SOD1(G93C), age at onset, diagnostic delay, bul- bar vs spinal onset, and percentage of predicted FVC as covar- iates. Hazard ratios were calculated for presence of SOD1(G93C), per year of greater age at onset, per month of increased diag- nostic delay, for spinal onset, and per 10% increase in percent- age of predicted FVC. Age at onset and survival were compared in patients with SOD1(G93C) with 1 vs 2 copies of the SMN1 or SMN2 gene with an unpaired, 2-tailed t test. The Bonferroni method was used to correct for multiple com- parisons. A 2-sided significance level of .05 was used. Values are represented as mean ± SD, unless indicated otherwise. All Figure 1. Spinal cord examination in the G93C mutation of the superoxide statistical analyses were performed with SPSS 10.0 (SPSS Inc, dismutase 1 gene. Klu¨ver-Barrera stain of the spinal cord (A) shows prominent myelin loss of posterior funiculus and spinocerebellar tracts, but Chicago, Ill). less involvement of lateral corticospinal tracts. Hyaline inclusion (B) and paranuclear ubiquitin-positive inclusion (C) are seen in spinal motor neurons. (B, Hematoxylin-eosin; C, indirect immunohistochemistry. COMPARATIVE DATA A, Bar indicates 2 mm; B and C, 80 µm.) We reviewed the English-language literature to compare data for patients with SOD1 mutations for which at least 1 detailed RESULTS illustrated neuropathologic description and detailed clinical in- formation on at least 10 patients with FALS were available. Care was taken not to include the same patients repeatedly. When- CLINICAL CHARACTERISTICS OF SOD1(G93C) ever possible, the same criteria for age at onset, survival, and upper motor neuron involvement as in our study population All 20 patients with SOD1(G93C) FALS had slowly pro- were used. gressive weakness and atrophy, starting distally in the (REPRINTED) ARCH NEUROL / VOL 63, FEB 2006 WWW.ARCHNEUROL.COM 263 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Demographic Characteristics of ALS Subgroups G93C D90A L38V Non-SOD1 FALS SALS P Value Age at onset, mean ± SD, y 45.9 ± 10.6* 52.8 ± 17.4 38.0 ± 6.6† 54.7 ± 10.8 58.4 ± 12.0 Ͻ.001 (n = 20) (n=5) (n = 10) (n = 18) (n = 359) Diagnostic delay, mean ± SD, mo 15.3 ± 16.1 38.0 ± 47.6‡ NA 7.2 ± 4.3 12.0 ± 11.3 Ͻ.001 (n = 12) (n=5) (n = 16) (n = 269) Survival, median ± SE, mo (95% CI)§ 153.0 ± 46.1࿣ NA 24.0 ± 6.0 (12-36) 43.0 ± 12.4 30.0 ± 1.6 Ͻ.001 (62.7-243.3) (n = 10) (18.8-67.2) (26.9-33.1) (n = 20) (n = 16) (n = 269) Abbreviations: ALS, amyotrophic lateral sclerosis; CI, confidence interval; NA, not applicable; non-SOD1 FALS, familial ALS not related to the superoxide dismutase 1 gene; SALS, sporadic ALS. *G93C FALS vs SALS, PϽ.001. †L38V FALS vs SALS, PϽ.001; and vs non-SOD1 FALS, P = .004. ‡D90A vs G93C, non-SOD1 FALS, and SALS, PϽ.01. §Estimated by Kaplan-Meier curves. ࿣PϽ.001 for difference vs SALS and for difference vs mutant SOD1(L38V) FALS; P = .001 for difference vs non-SOD1 FALS. nocerebellar tracts, but only mild in the lateral corticospi- 1.0 nal tracts (Figure 1A). Severe loss of anterior horn cells was SALS G93C present, and many of the remaining neurons were atrophic L38V 0.8 and showed hyaline inclusions similar to the previously de- FALS scribed Lewy body–like hyaline inclusions9 (Figure 1B) or ubiquitin-positive inclusions (Figure 1C). Most remaining 0.6 neurons contained lipofuscin. The Clarke column was also degenerated. Neurofilament stains were unremarkable. 0.4 Bunina bodies were absent. Probability of Survival DEMOGRAPHIC CHARACTERISTICS 0.2 Age at onset in SOD1(G93C)–related FALS was 45.9±10.6 years, significantly younger than in SALS (58.4±12.0 years; 0 100 200 300 PϽ.001). The onset was earlier in SOD1(L38V)–related Disease Duration, mo FALS than non–SOD1-related FALS (P=.004) and SALS (PϽ.001) (Table 1). Bulbar onset was noted in 105 (30.2%) Figure 2. Kaplan-Meier survival curves of different subgroups of of 348 patients with SALS but in none of the patients with amyotrophic lateral sclerosis (ALS).
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