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Keywords:

  • Genetics;
  • Eyelid myoclonia;
  • Eyelid myoclonia with absences;
  • Idiopathic generalized epilepsy;
  • Absence seizures;
  • Family studies

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

Purpose:  Eyelid myoclonia with absences (EM) is an uncommon type of absence seizure associated with a variety of epilepsy syndromes. The syndrome of epilepsy with EM (EMA) has been proposed to denote the onset of frequent EM induced by eye closure and photic stimulation beginning in childhood. The clinical genetics of EMA has not been well characterized, although a family history of seizures is not infrequent.

Methods:  Individuals with EMA were ascertained by referral and through the investigators’ clinical practices. All available family members were assessed for seizures using a validated seizure questionnaire. Electroclinical data were obtained on each proband and all affected family members; pedigrees were constructed. Families were analyzed for phenotypic patterns.

Key Findings:  Eighteen individuals with EMA were recruited. A history of seizures was found in 34 relatives in 15 (83%) of 18 families. In terms of epilepsy syndromes, 9 relatives from 7 of 15 families had febrile seizures. Two relatives had EMA. Classical genetic generalized epilepsy (GGE) syndromes were seen in five relatives: two generalized tonic–clonic seizures alone, two childhood absence epilepsy (CAE), and one juvenile myoclonic epilepsy (JME). Genetic epilepsy with febrile seizures plus (GEFS+) phenotypes occurred in 16 relatives. On review of the epilepsy syndromes within each family, seven families had a pattern consistent with GEFS+, whereas three families had classical GGE.

Significance:  The clinical genetics of EMA is suggestive of complex inheritance with shared genetic determinants overlapping with both classical GGE and GEFS+. The epilepsy syndromes in relatives of probands with EMA differ from those found in families of probands with CAE, supporting the concept that patients with EMA have a syndrome that is distinct from CAE. This presumably reflects different genetic components contributing to their genetic architecture.

Eyelid myoclonia with absences (EM) is a rare type of absence seizure (Appleton et al., 1993; Panayiotopoulos et al., 1996; Covanis, 2005). The seizures are brief lasting 1.5–6 s with repetitive, often rhythmic, fast (4–6 Hz) myoclonic jerks of the eyelids with simultaneous upward deviation of the eyeballs and extension of the head (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996a; Panayiotopoulos et al., 1996; Loiseau et al., 2002; Capovilla et al., 2009). Alteration of awareness varies markedly (Appleton et al., 1993). The ictal electroencephalography (EEG) shows high-amplitude generalized spikes and polyspikes and slow waves at a frequency of 3–6 Hz (Appleton et al., 1993; Caraballo et al., 2009). This seizure type has been reported in a variety of epilepsy syndromes including childhood absence epilepsy (CAE) and juvenile myoclonic epilepsy (JME), and in association with intellectual disability such as in Dravet syndrome and individuals with chromosomal rearrangements (Ferrie et al., 1996).

Although there has been some debate about whether a specific syndrome exists with the hallmark of EM, Jeavons and others have recognized a group of children with onset of frequent EM associated with photosensitivity and eye closure who may later develop generalized tonic–clonic seizures (Jeavons, 1977; Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996a; Panayiotopoulos et al., 1996; Loiseau et al., 2002; Capovilla et al., 2009). This syndrome of epilepsy with eyelid myoclonia with absences (EMA) occurs in children aged 2–14 years (peak 6–8 years) and is a genetic (idiopathic) generalized epilepsy (GGE) (Capovilla et al., 2009). Photosensitivity is always present, although it decreases with age and antiepileptic drug (AED) exposure. Patients usually experience generalized tonic–clonic seizures (GTCS) after EM (Giannakodimos & Panayiotopoulos, 1996b; Panayiotopoulos, 2005). Results of examination and neuroimaging are normal (Panayiotopoulos, 2005). Most individuals are in the normal cognitive range, although borderline intellectual functioning and intellectual disability may occur (Scuderi et al., 2000; Covanis, 2005; Sevgi Demirci & Saygi, 2006; Capovilla et al., 2009; Striano et al., 2009). EMA is considered a life-long condition and can be difficult to treat (Panayiotopoulos, 2005; Striano et al., 2009) .

Evidence for a genetic basis for EMA has been drawn from studies describing concordant monozygotic twins and epilepsy in relatives of patients with EMA (Giannakodimos & Panayiotopoulos, 1996a; Parker et al., 1996; Striano et al., 2002; Adachi et al., 2005; Yang et al., 2008; Caraballo et al., 2009). In general, studies have obtained the familial information from the index case rather than by explicitly studying each family member (Giannakodimos & Panayiotopoulos, 1996a; Striano et al., 2002; Capovilla et al., 2009; Caraballo et al., 2009). There is, however, one study reporting the familial phenotypes in four families selected on the basis of two family members with EMA (Parker et al., 1996).

Herein we perform detailed phenotyping of all available family members and analyze the phenotypic patterns in families of probands with EMA.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

Recruitment

Patients ascertained from the investigators’ clinical practices and following referral by colleagues were entered into our epilepsy genetics research database. The database was searched for individuals with EM recruited over a 12-year period between January 1999 and December 2010.

Probands

Probands were phenotyped by an experienced epileptologist (LGS, IES, AB) and included medical and developmental history and neurologic examination. Previous medical records, especially electroencephalography (EEG) recordings and magnetic resonance imaging (MRI) studies, were reviewed to assist with classification of the epilepsy syndrome.

Inclusion criteria:

  • 1
     Onset of daily EM in patient younger than 10 years of age induced by eye closure.
  • 2
     EM was defined as rapid jerks of the eyelids, with upward eyeball movement and head extension associated with generalized spike and wave (GSW) or polyspike and wave (PSW).
  • 3
     All patients had EM captured on EEG.
  • 4
     Every patient either had a video-EEG recording of a seizure reviewed by an epileptologist, or a seizure was witnessed by the epileptologist.
  • 5
     Photosensitivity on EEG, or the patient had a history of seizures triggered by environmental photic stimulation.

Exclusion criteria:

  • 1
     A diagnosis of classical childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME).
  • 2
     A diagnosis of another epilepsy syndrome such as Dravet syndrome or an epileptic encephalopathy.
  • 3
     Abnormal neuroimaging.
  • 4
     A chromosomal or metabolic abnormality.

Developmental delay or static intellectual disability (ID) was not exclusion criteria. These individuals were classified as EMA + ID.

Family study

Strenuous efforts were made to invite all affected relatives to participate in the study. All available affected family members underwent a clinical interview with a validated seizure questionnaire (Reutens et al., 1992). Particular emphasis was given to interviewing an eye witness of their seizures. All available previous medical records and all relevant investigations, especially EEG recordings were collected to allow classification of their epilepsy syndrome.

Classification

Seizures and syndromes were classified according to the International League Against Epilepsy (ILAE) classification of seizure types and epilepsy syndromes (Commission on Classification and Terminology of the International League Against Epilepsy, 1985, 1989; Berg et al., 2010).

Relatives with definite seizures but insufficient clinical information were categorized as unclassified epilepsy, and relatives with a history of paroxysmal events without an eyewitness account were classified as unconfirmed seizures.

Comparison of phenotypes in families

Each family was classified as genetic epilepsy with febrile seizures plus (GEFS+) if the relatives had GEFS+ phenotypes (including febrile seizures [FS], febrile seizures plus [FS+], Epilepsy with myoclonic atonic seizures [MAE], and Dravet syndrome); classical genetic generalized epilepsy (cGGE) if relatives only had CAE, JAE, JME, and GTCS alone; and genetic generalized epilepsy (GGE) if relatives had generalized epilepsies that could not be phenotyped, or only EMA was seen.

The proportion of family members with each epilepsy syndrome was compared to those of probands with cGGE including CAE, JAE, JME, and GTCS alone using Fisher exact test (Marini et al., 2004).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

Probands

Eighteen individuals (12 female [67%]) met the inclusion and exclusion criteria. The mean age of onset of seizures was 4 years (median 5 years, range 1–8 years). The clinical details of these individuals are shown in Table 1. Twelve probands had EMA and six had EMA + ID. Two patients had febrile seizures before their presentation with EMA.

Table 1.   Clinical details of probands with eyelid myoclonia with absences
FamilyAge at presentation (years)Frequency of EMAbsence seizures without eyelid myocloniaMyoclonic seizuresGTCSCognitionOther seizure typesEEGPPRSyndromeFamily history of seizures
  1. EM, eyelid myoclonia with absences; GTCS, generalized tonic–clonic seizure; EEG, electroencephalogram; PPR, photo paroxysmal response; FS, febrile seizure; EMA, Epilepsy with eyelid myoclonia with absences; ID, intellectual disability; GSW, generalized spike and wave; PS, polyspike; PSW, polyspike and wave; OIRDA, occipital intermittent rhythmic delta activity.

A3DailyNoNoYesNormalNoGSW, PSWYesEMAYes
B2DailyNoNoYesNormalNoGSW, PSWYesEMAYes
C5DailyNoNoYesNormalNoGSW, PSWYesEMAYes
D8DailyYesNoYesNormalAbsence status FSGSWYesEMAYes
E2DailyYesNoNoNormalNoGSW, PSWYesEMAYes
F1DailyYesNoNoNormalNoGSW, PSWYesEMAYes
G4VariableYesYesYesNormalNoGSW, PSWYesEMAYes
H5VariableNoNoYesNormalNoGSW, PSWYesEMAYes
I3DailyNoYesYesNormalNoGSW, PSWYesEMAYes
J6DailyNoNoYesNormalNoGSW, PSYesEMAYes
K5DailyYesNoNoMild IDNoGSW, PS, OIRDAYesEMA + IDYes
L2DailyNoYesNoMild IDNoGSW, PSWYesEMA + IDYes
M2DailyNoYesNoMild IDFSGSW, PSWYesEMA + IDYes
N4DailyYesNoNoMild IDNoGSW, PSWYesEMA + IDYes
O3DailyYesNoYesMild IDNoGSWYesEMA + IDYes
P5DailyNoNoNoMild IDNoGSW, PSWYesEMA + IDNo
Q6DailyNoYesNoNormalNoGSW, PSWYesEMANo
R6DailyNoNoNoNormalNoGSW, PSW, Occipital SWYesEMANo

Family history data

Fifteen of 18 probands had a family history of seizures, with 34 affected relatives (Fig. 1). There was a mean of 2.3 affected relatives in these families (range 1–7). Adequate data were available for phenotyping of 26 of 34 affected relatives.

image

Figure 1.  Pedigrees of 15 families of EMA probands. Specific GEFS+ and GGE phenotypes can be found in Table 3. Additional clinical information for relatives in families A, G, J, L, and N can be found in the supporting information.

Download figure to PowerPoint

Seizure types in relatives and families

Generalized seizures occurred in 25 of 26 affected relatives, whereas one individual had only focal seizures with temporal lobe semiology. Typical absence seizures occurred in 8 relatives, myoclonic seizures in 7 relatives, and GTCS in 10 relatives, with some individuals having more than one seizure type (Table 2). Six families had family members with myoclonic seizures, six had family members with typical absence seizures, and six families had family members with GTCS.

Table 2.   Seizure types seen in relatives of probands
FamilyProband syndromeNumber of affected relativesMyoclonic seizuresTypical Absence seizuresEMGTCSFSFocalUnclassified/unconfirmed
  1. EM, eyelid myoclonia with absences; EMA, epilepsy with eyelid myoclonia with absences; ID, intellectual disability; GTCS, generalized tonic–clonic seizure; FS, febrile seizure.

AEMA211
BEMA11
CEMA11
DEMA11
EEMA2111
FEMA1111
GEMA2112
HEMA11
IEMA7134
JEMA211
KEMA + ID11
LEMA + ID31233
MEMA + ID5221241
NEMA + ID4121
OEMA + ID11
Total 34783101528

Photosensitivity, defined either clinically and/or electrographically, was seen in 8 (31%) of 26 affected relatives.

Syndromes in relatives

Two relatives had EMA. cGGE syndromes were seen in five relatives: two with GTCS alone, two with CAE, and one with JME. GEFS+ phenotypes were seen in 16 relatives: nine with febrile seizures (FS), three febrile seizures plus (FS+), two Dravet syndrome, one epilepsy with myoclonic atonic seizures (MAE), and one with GEFS+ and GGE. The remaining affected family member had temporal lobe epilepsy (Table 3). Additional phenotyping information on families A, G, J, L, and N can be found in the supporting information. The heterogeneity of both seizure types and epilepsy syndrome in affected relatives did not appear to differ between the probands with EMA and EMA + ID (Tables 2 and 3).

Table 3.   Epilepsy syndromes in relatives of probands
FamilyProband syndromeFamily epilepsy syndromeNumber of affected relativesGEFS+GGEEpilepsy with focal seizuresSingle seizureUnclassified or unconfirmed
  1. EMA, epilepsy with eyelid myoclonia with absences; FS, febrile seizure; FS+, febrile seizures plus; cGGE, classical genetic generalized epilepsy; GEFS+, genetic epilepsy with febrile seizures plus; MAE, epilepsy with myoclonic atonic seizures; AS, absence seizures; MEE, myoclonic epileptic encephalopathy; CAE, childhood absence epilepsy; JME, juvenile myoclonic epilepsy; GTCSA, generalized tonic–clonic seizures alone (adult onset); TLE, temporal lobe epilepsy.

AEMAGGE21 MEE1
BEMAN/A11
CEMAN/A11
DEMAcGGE11 CAE
EEMAGEFS+21 FS1 EMA
FEMAGGE11 EMA
GEMAGEFS+21 FS 1 Dravet
HEMAcGGE11 JME
IEMAGEFS+72 FS, 1 FS+4
JEMAGEFS+21 FS1 TLE
KEMA + IDN/A11
LEMA + IDGEFS+32 FS+ and AS 1 GEFS+ and GGE
MEMA + IDGEFS+53 FS, 1 Dravet 1 MAE
NEMA + IDcGGE42 GTCSA 1 CAE1
OEMA + IDGEFS+11 FS
Total  34168118

Febrile seizures were seen in first- or second-degree relatives in 7 of the 15 families (Table 3). These were simple febrile seizures in all of the individuals, apart from the two individuals with Dravet syndrome who also had complex febrile seizures. There were seven GEFS+ families (families E, G, I, J, L, M, and O), and three families with cGGE phenotypes (families D, H, and N) (Table 3).

The epilepsy syndromes in our families of probands with EMA were compared to those observed in families of probands with cGGEs (Table 4, Marini et al., 2004). Considering probands with the three cGGE phenotypes grouped together (CAE/JAE/JME), affected relatives were more likely to have cGGE than GEFS+ phenotypes (73% vs. 23%). In contrast, probands with EMA were significantly more likely to have relatives with GEFS+ than cGGE (62% vs. 19%) (comparing data from Marini et al., 2004 with data presented here, p < 0.001; Fisher exact test).

Table 4.   Comparison of epilepsy syndromes in relatives of EMA probands to syndromes in family members of cGGE probands ( Marini et al., 2004 )
 EMA (n = 26 affected individualsa from 15 families) (%)CAE (n = 33 affected individuals from 15 families) (%)JAE (n = 37 affected individuals from 15 families) (%)JME (n = 43 affected individuals from 15 families) (%)GTCSA (n = 14 affected individuals in 10 families) (%)
  1. aUnclassified and unconfirmed seizures were excluded from this analysis.

  2. EMA, epilepsy with eyelid myoclonia with absences; FS, febrile seizure; FS+, febrile seizures plus; cGGE, classical genetic generalized epilepsy; GEFS+, genetic epilepsy with febrile seizures plus; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy; JME, juvenile myoclonic epilepsy; GTCSA, generalized tonic–clonic seizures alone (adult onset).

EMA 8
FS/FS+4615193221
Other GEFS+15
CAE/JAE8 42 46 936
JME4123 32 7
Other cGGE12303214 21
Focal Epilepsy21214
Other2

Epilepsy syndrome concordance was less prominent in EMA families than in cGGE families (Table 4). Relatives of probands with EMA were significantly less likely to have the same syndrome as the proband (2/26, 8%), compared with relatives of probands with JME (33%, p = 0.02) or CAE/JAE (44%, p < 0.001; Fisher exact test).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

GGEs fall into two major groups; the classical genetic generalized epilepsies (cGGEs), and genetic epilepsy with febrile seizures plus (GEFS+) (Scheffer & Berkovic, 1997; Singh et al., 1999; Marini et al., 2004). The cGGEs are the best recognized GGEs and include the well-defined epilepsy syndromes of CAE, JAE, JME, and GTCS alone (Marini et al., 2004). GEFS+ is characterized by phenotypic heterogeneity within families with a range of phenotypes including FS, FS+, MAE, and Dravet syndrome, as well as other epilepsies in which febrile seizures are a prominent feature (Scheffer & Berkovic, 1997; Singh et al., 1999). Family studies have suggested that these two major groups are distinct and contributed to by different susceptibility genes (Scheffer & Berkovic, 1997; Singh et al., 1999; Marini et al., 2004).

EMA is believed to have a genetic etiology (Giannakodimos & Panayiotopoulos, 1996a; Parker et al., 1996; Striano et al., 2002; Adachi et al., 2005; Yang et al., 2008; Capovilla et al., 2009; Caraballo et al., 2009). Little is known about the family history of seizures in probands with EMA. In the only previous study in which the relatives were directly interviewed, 14 of 18 probands had a family history, but the only families that were phenotyped were the four with relatives who also had EMA. Only three possibly affected relatives were studied, and further information was gleaned from the probands’ family (Parker et al., 1996). In these “EMA enriched” families, 11 affected relatives had GGE.

Here, we studied the families of 18 probands with EMA and phenotyped all available affected family members. Fifteen (83%) of 18 probands with EMA had family members with seizures, with a total of 34 affected relatives, of which 26 had adequate data for phenotyping. Our finding of 83% of probands having a positive family history is similar to previous reports that range from 40–78% (Giannakodimos & Panayiotopoulos, 1996a; Parker et al., 1996; Striano et al., 2002; Capovilla et al., 2009; Caraballo et al., 2009). In contrast to our phenotyping methods, many studies have not directly asked the relatives and have relied on reports from the probands’ families (Giannakodimos & Panayiotopoulos, 1996a; Striano et al., 2002; Capovilla et al., 2009; Caraballo et al., 2009).

Our families showed different patterns, with three having exclusively cGGE syndromes, and seven having exclusively GEFS+ phenotypes. This provides a more representative picture of the phenotypic spectrum associated with EMA than previous studies that have limited their phenotyping to families in which two individuals had EMA (Parker et al., 1996).

Syndromes in relatives

Looking at the syndromes in affected relatives, we found that the most common phenotype in relatives was FS in 9 (35%) of 26 of affected relatives; a further 6 had FS as part of a more complex phenotype. cGGE syndromes occurred in 5 (19%) of 26, and GEFS+ syndromes (excluding FS syndrome) in 7 (27%) of 26 of affected relatives. The remaining four had the following: EMA (2), myoclonic epileptic encephalopathy (1), focal epilepsy (1), and a single unprovoked seizure.

Differentiation into specific subgroups of cGGE, GEFS+, and GGE was based on the data available in each family. Where affected relatives had clearcut cGGE, the family was called cGGE, as previously EMA has been considered as part of the absence epilepsy syndrome group (family D, H). If there was no cGGE and a relative had FS, we called this GEFS+ (family E, J, O). There were larger families with clearer patterns consistent with GEFS+ (family G, I, L, M) or cGGE (family N). In families with just EMA or non-cGGE, we have called them GGE in order not to bias our analysis (family A, F). We acknowledge that the data emerging from the small families is open to debate, but the large families show a more compelling picture of the familial epilepsy syndrome. Ongoing clinical and molecular genetic studies will elucidate these relationships further.

The epilepsy syndromes in our families of probands with EMA were different from those observed in families of probands with cGGEs (Marini et al., 2004). The EMA probands were significantly more likely to have relatives with GEFS+ (62% vs. 23%) and less likely to have relatives with cGGE (19% vs. 73%). They also had less syndromic concordance (8%) compared to probands with CAE (42%), JAE (46%), or JME (32%). The reasons for this comparative lack of syndromic concordance is not clear, but may relate to GEFS+ susceptibility genes being more important in this syndrome than in the cGGE, and GEFS+ being a more heterogeneous familial epilepsy syndrome. Photosensitivity susceptibility genes may be important for EMA to occur in a GEFS+ family, and in general GEFS+ families have a low rate of photosensitivity (unpublished data Scheffer IE).

Although the syndrome of EMA has not been recognized as a distinct epilepsy syndrome in the ILAE organization of the epilepsies (Berg et al., 2010), debate continues as to whether it should be regarded as a specific epilepsy syndrome (Striano et al., 2009). Some regard individuals with EM to be part of CAE or JAE/JME depending on the age of onset (Striano et al., 2009). Here, we have looked at EMA and compared the family history with CAE. Relatives of probands with EMA are different from relatives of probands with CAE, as fewer family members have CAE (8% vs. 42%) and more have FS or FS+ (46% vs. 15%; Table 4, Marini et al., 2004). Our findings showing the absence of CAE in relatives of probands with EMA and different familial patterns in EMA compared to CAE provide support for EMA as a distinct epilepsy syndrome from CAE.

It has been suggested that EMA should be considered a myoclonic epilepsy with overlap between JME and EMA (Panayiotopoulos, 2005; Yalcin et al., 2006). Although seven family members had myoclonic seizures, only 4% of relatives had JME, compared with 32% of relatives in families with JME probands. This absence of JME in relatives of EMA probands and difference in familial patterns between JME and EMA probands provides a similar argument for JME as CAE, suggesting that EMA is a separate entity from JME.

In conclusion, relatives of EMA probands have heterogeneous epilepsy phenotypes that are almost exclusively generalized. EMA appears to have shared genetic determinants with both cGGE and GEFS+. The clinical genetics of EMA as defined in this cohort would add support to the contention that EMA is a distinct syndrome from CAE, JAE, or JME.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

We thank the patients and their families for participating in our research. We gratefully acknowledge the assistance received from the Health Research Council of New Zealand, Child Health Research Foundation, and the Australian National Health and Medical Research Council. We are grateful to Dr Saul Mullen for statistical assistance and Viger Yang for administrative assistance.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Funding

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

Health Research Council of New Zealand, Cure Kids New Zealand, National Health and Medical Research Council of Australia.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. Funding
  9. References
  10. Supporting Information

Data S1. Additional clinical information for relatives in families A, G, J, L, and N.

FilenameFormatSizeDescription
epi3692_sm_DataS1.doc26KSupporting info item

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