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 subgroups. 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 significant 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 clinicopathologic variability between different SOD1 muta- Patients:TwentypatientswiththeG93Cmutationforwhom clinicaldatawereavailableand1patientwithpathologicdata. tions. Finally, they demonstrate the independent prognostic value of the G93C mutation. Main Outcome Measures: Characteristics and survival 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 (SALS)A 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-

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©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 hematoxylin-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 patients with SOD1(D90A) were available, their data were not included. A Cox proportional hazards regression was performed with SOD1(G93C), age at onset, diagnostic delay, bulbar 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 diagnostic delay, for spinal onset, and per 10% increase in percentage 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 comparisons. 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 information 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

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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). FALS indicates familial ALS (not related SOD1-related FALS (P=.001). to the superoxide dismutase 1 gene); SALS, sporadic ALS. Median disease durations were estimated by Kaplan- Meier curves (Table 1, Figure 2). Log-rank analysis showed a statistically significant difference among the lower extremities. Symptoms gradually spread proxi- Ͻ mally and to the upper extremities. Throughout the groups (P .001). Pairwise analysis showed that me- course, distal involvement predominated and bulbar func- dian disease duration in patients with SOD1(G93C) (153.0 tion was preserved. Death resulted from respiratory fail- months) was significantly longer than that of patients with ure in all 11 patients who had died. Deep tendon re- SALS (30.0 months), SOD1(L38V) (24.0 months), and flexes were initially present but gradually disappeared. non–SOD1 FALS (43.0 months). There was no differ- There were no brisk reflexes, spasticity, Babinski signs, ence in survival between patients with SALS, non– jaw jerk, or other upper motor neuron signs. Several pa- SOD1 FALS, and SOD1(L38V). tients (not the patient who underwent autopsy) had mild In a multivariate analysis, the hazard ratios (and cor- sensory symptoms, and in 1 patient with advanced dis- responding 95% confidence intervals) for age at onset, ease, mild distal loss of pinpoint sensation was found. diagnostic delay, spinal site of onset, and percentage of predicted FVC were 1.03 (1.02-1.05; PϽ.001), 0.94 (0.91- Ͻ NEUROPATHOLOGIC FINDINGS 0.96; P .001), 0.64 (0.44-0.93; P=.02), and 0.84 (0.78- 0.91; PϽ.001), respectively, all statistically significant. Brain and spinal cord of a 57-year-old man with In addition, the presence of the G93C mutation was found SOD1(G93C) were obtained at autopsy, after a 67-month- to represent an independent, statistically significant, posi- long disease course. tive prognostic factor for survival (hazard ratio, 0.2; 95% The motor cortex appeared normal. No loss of brainstem confidence interval, 0.05-0.81; P=.02). motor neurons was observed, but in most brainstem motor nuclei, lipofuscin-loaded motor neurons were prominent. SMN GENE ANALYSIS Lipofuscin was most prominent in hypoglossal motor neurons, which also showed hyaline inclusions. Loss of myelin- Two patients had 1 SMN1 gene copy but 3 SMN2 cop- ated fibers was pronounced in the posterior column and spi- ies, and 9 patients had 1 SMN2 gene copy. There was no

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SOD1 Mutation*

A4V H46R I113T† G93C D101N* A4T No. of patients‡ 167 62 29 20 15 15 With clinical neurologic details 19 56 10 20 14 14 With pathologic details 9 3 6 1 2 1 Age at onset, y Mean±SD 47±14 45±10 57±13 46±11 41±10 44±11 Range 21-78 25-68 26-84 33-71 26-57 21-60 Survival, y Mean ± SD 1.2 ± 0.9 17 ± 7§ 4.2 ± 4.2 13 ± 4 2.4 ± 0.9 1.2 Range 0.5-4.0 6-47 0.6-21 5-20 1.1-4.0 NA Clinical information ࿣ Onset site Spinal/bulbar Lower limb Upper limb/ Lower limb Lower limb/ Lower limb/ lower limb upper limb upper limb UMN signs − (ϩ)−/ϩ −/ϩ/ϩϩ −−/ϩ (ϩϩ)−(ϩ) Atypical signs − (Sens) (EO)¶ −/Sens − − (Sens) − − (Sens) Pathologic findings BS motor nuclei# ϩϩ XII/X −/ϩ XII ϩϩ XII/VII/X − ϩ XII ϩ XII, VII, V Motor cortex −/ϩϩ−/ϩ −− − CST degeneration ϩ/ϩϩ ϩ ϩϩ/ϩϩ − ϩ PC degeneration ϩϩ/ϩϩ/− ϩϩ/− ϩϩ − ϩϩ SCT-Cl degeneration ϩϩ/ϩϩ/ϩϩ** ϩϩ/− ϩϩ − ϩϩ Other neurodegeneration −/SN/dorsal vagal nucleus, − OI/SN, LC, GP − − Posterior horn, substantia gracile nucleus intermedia, accessory cuneate nucleus LBHI ϩ −/ϩ −†† ϩϩ ϩ References 2, 3, 10-14 13, 15-18 2, 13, 14, 19-26 Current study 27-29 30-32

Abbreviations: BS, brainstem; CST, corticospinal tract; EO, external ophthalmoparesis; GP, globus pallidus; LBHI, Lewy body–like hyaline inclusions; LC, locus ceruleus; NA, not available; OI, oliva inferior; PC, posterior column; SCT-Cl, spinocerebellar tract and Clarke nucleus; Sens, sensory signs; SN, substantia nigra; SOD1, superoxide dismutase 1 gene; UMN, upper motor neuron; −, absent; ϩ, mild; ϩϩ, moderate to severe. *Clinical signs and neuropathological findings of anterior horn degeneration were moderate to severe in all of the mutations. †Reduced penetrance and apparently sporadic cases.23,29 ‡Number of patients included in weighted means of age at onset. §Two reports16,18 did not specifically include the number of patients included in analysis of duration; therefore, these patients were not included in the corresponding weighted means. ࿣Signs shown in parentheses were rarely reported (typically only once). Scorings separated by virgules (/) occurred in comparable numbers, in order of frequency. ¶Prolonged artificial ventilation. #Roman numerals indicate the corresponding somatic motor nuclei of the cranial nerves. **Discordance between degeneration in Clarke nucleus and SCT. ††There were neurofibrillary tangles associated with the degeneration of SN, LC, and GP; in other cases, hyaline conglomerates and argyrophilic inclusions were observed.

statistically significant difference in age at onset or sur- tic factor in SALS,33,34 did not explain this variability in vival between patients with 1 or 2 SMN1 gene copies, nor our patients. This suggests that other modifiers exist.19 between patients with 1 or 2 SMN2 gene copies, al- Predominant lower motor neuron involvement, as found though onset was earlier in the population with 2 SMN2 in our patients with SOD1(G93C) FALS, is also a frequent copies than in that with 1 SMN2 copy (42.7±3.4 vs finding in other SOD1 mutations, especially in SOD1(A4V) 50.3±3.4 years; P=.17) and SOD1(A4T) (Table 2). Although pathologic data on SOD1-related ALS are limited, findings similar to those in COMMENT our patient, such as mild corticospinal tract involvement, prominent myelin loss in posterior columns and spinocer- We present clinical data on the largest group of patients ebellar tracts, and degeneration of Clarke column, seem to with SOD1(G93C)–related FALS yet reported, and the define the pathologic picture in SOD1(A4V),3 SOD1(A4T),30 first pathologic data of a patient with this mutation, to and SOD1(E100G).35 However, in these reports, brain- our knowledge. stem involvement was more pronounced than in our pa- In our population, SOD1(G93C) was associated with tient, who showed only hyaline inclusions in the hypo- a purely lower motor neuron clinical phenotype and ab- glossal nucleus, without neuronal loss. Absence of Bunina sence of bulbar involvement. Aside from variability in age bodies has been a consistent finding in SOD1-related ALS, at onset and survival, this phenotype was quite constant except for 1 patient with a de novo H80A mutation36 and in comparison with some other SOD1 mutations, espe- a patient with an insertion at codon 127.37 cially SOD1(I113T) (Table 2). The SMN gene copy num- The earlier onset of SOD1(G93C)–related FALS com- ber, previously proposed as a susceptibility or prognos- pared with SALS is a shared feature of most SOD1 mu-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 tations and FALS in general. Among SOD1 mutations, lished abstract appears in Neurology. 2001;56(8, suppl SOD1(L38V) and SOD1(G37R) have been shown to pre- 3):A445. sent earlier than other mutations,2 reflected in a mean Acknowledgment: We thank Gert Matthijs, PhD, for the age at onset of 38 years in our patients with SOD1(L38V). molecular analysis of the patients’ samples. In our population, the comparison with patients with FALS carrying other mutations in SOD1 did not reach statistical significance, probably because of small num- REFERENCES bers. Indications of a better prognosis associated with SOD1(G93C) (median survival, 153 months) were re- 1. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dis- ported before, but these analyses were done only on pa- mutase gene are associated with familial amyotrophic lateral sclerosis. 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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 the effects of rituximab in neuromyelitis optica. Neurology. 2005;64:1270-1272. 10. Weinshenker BG, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG pre- 7. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple dicts relapse after longitudinally extensive transverse myelitis. Ann Neurol. 2006; sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 59:566-569. 2002;360:2018-2025. 11. Weinstock-Guttman B, Jacobs LD, Brownscheidle CM, et al. Multiple sclerosis 8. Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined characteristics in African American patients in the New York State Multiple Scle- with methylprednisolone in multiple sclerosis: a randomised multicentre study rosis Consortium. Mult Scler. 2003;9:293-298. of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 12. Weinshenker B. Western vs optic-spinal MS: two diseases, one treatment? 1997;62:112-118. Neurology. 2005;64:594-595. 9. Fidler JM, DeJoy SQ, Smith FR III, Gibbons JJ Jr. Selective immunomodulation by 13. Saida T, Tashiro K, Itoyama Y, Sato T, Ohashi Y, Zhao Z. Interferon beta-1b is the antineoplastic agent mitoxantrone, II: nonspecific adherent suppressor cells de- effective in Japanese RRMS patients: a randomized, multicenter study. Neurology. rived from mitoxantrone-treated mice. J Immunol. 1986;136:2747-2754. 2005;64:621-630.

Correction

Errors in Table. In the Original Contribution by Re´gal et al titled “The G93C Mutation in Superoxide Dismutase 1: Clini- copathologic Phenotype and Prognosis,” published in the February issue of the ARCHIVES (2006;63:262-267), several errors occurred on page 265 in Table 2. In that table, the asterisk next to the column heading “D101N” should have been a dagger to refer to “Reduced penetrance and apparently sporadic cases.” In addition, the sideheadings “Other neurodegeneration” and “LBHI” should have been indented to indicate that these are also pathologic findings, and the following definitions should have appeared at the end of the Abbreviations footnote: “(for UMN signs: −, absent; ϩ, hyperreflexia; ϩϩ, Babinski sign or spasticity).” The corrected table is reprinted here with its footnotes.

Table 2. Clinicopathologic Comparison With Other SOD1 Mutations

SOD1 Mutation*

A4V H46R I113T† G93C D101N† A4T No. of patients‡ 167 62 29 20 15 15 With clinical neurologic details 19 56 10 20 14 14 With pathologic details 9 3 6 1 2 1 Age at onset, y Mean±SD 47±14 45±10 57±13 46±11 41±10 44±11 Range 21-78 25-68 26-84 33-71 26-57 21-60 Survival, y Mean ± SD 1.2 ± 0.9 17 ± 7§ 4.2 ± 4.2 13 ± 4 2.4 ± 0.9 1.2 Range 0.5-4.0 6-47 0.6-21 5-20 1.1-4.0 NA Clinical information࿣ Onset site Spinal/bulbar Lower limb Upper limb/ Lower limb Lower limb/ Lower limb/upper lower limb upper limb limb UMN signs − (ϩ)−/ϩ −/ϩ/ϩϩ −−/ϩ (ϩϩ)−(ϩ) Atypical signs − (Sens) (EO)¶ −/Sens − − (Sens) − − (Sens) Pathologic findings BS motor nuclei# ϩϩ XII/X −/ϩ XII ϩϩ XII/VII/X − ϩ XII ϩ XII, VII, V Motor cortex −/ϩϩ−/ϩ −− − CST degeneration ϩ/ϩϩ ϩ ϩϩ/ϩϩ − ϩ PC degeneration ϩϩ/ϩϩ/− ϩϩ/− ϩϩ − ϩϩ SCT-Cl degeneration ϩϩ/ϩϩ/ϩϩ** ϩϩ/− ϩϩ − ϩϩ Other neurodegeneration −/SN/dorsal vagal − OI/SN, LC, GP − − Posterior horn, nucleus, gracile substantia nucleus intermedia, accessory cuneate nucleus LBHI ϩ −/ϩ −†† ϩϩ ϩ References 2, 3, 10-14 13, 15-18 2, 13, 14, 19-26 Current study 27-29 30-32

Abbreviations: BS, brainstem; CST, corticospinal tract; EO, external ophthalmoparesis; GP, globus pallidus; LBHI, Lewy body–like hyaline inclusions; LC, locus ceruleus; NA, not available; OI, oliva inferior; PC, posterior column; SCT-Cl, spinocerebellar tract and Clarke nucleus; Sens, sensory signs; SN, substantia nigra; SOD1, superoxide dismutase 1 gene; UMN, upper motor neuron; −, absent; ϩ, mild; ϩϩ, moderate to severe (for UMN signs: −, absent; ϩ, hyperreflexia; ϩϩ, Babinski sign or spasticity). *Clinical signs and neuropathological findings of anterior horn degeneration were moderate to severe in all of the mutations. †Reduced penetrance and apparently sporadic cases.23,29 ‡Number of patients included in weighted means of age at onset. §Two reports16,18 did not specifically include the number of patients included in analysis of duration; therefore, these patients were not included in the corresponding weighted means. ࿣Signs shown in parentheses were rarely reported (typically only once). Scorings separated by virgules (/) occurred in comparable numbers, in order of frequency. ¶Prolonged artificial ventilation. #Roman numerals indicate the corresponding somatic motor nuclei of the cranial nerves. **Discordance between degeneration in Clarke nucleus and SCT. ††There were neurofibrillary tangles associated with the degeneration of SN, LC, and GP; in other cases, hyaline conglomerates and argyrophilic inclusions were observed.

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