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					1.      Appendices
E-Methods
Categorising disease families
      Until date, mutations in SCN1A have been found in patients with GEFS+,2,5,8,11,14,18,28,E1-
E10
    SMEI and SMEB,4-14,E11-E17 intractable childhood epilepsies with frequent generalized
tonic-clonic seizures (ICEGTC),8,E8 cryptogenic generalized epilepsy (CGE), cryptogenic
focal epilepsy (CFE),E18 myoclonic–astaticepilepsy (MAE), severe infantile multifocal
epilepsy (SIMFE), Lennox–Gastaut syndrome (LGS), Panayiotopoulos syndrome (PS),E9
Rasmussen encephalitisE19 and infantile spasm.5,E11 Previous investigations showed that SMEI
and these epileptic syndromes were part of the SRIEE spectrum.5,6,15
      Because information about intellectual disability of three GEFS+ families2,E2 was
described in other reports,3,E20,E21 we investigated such information in the previous reports.
      Because information about ataxia of the patients was described in another report,E22 we
investigated the information in the report. As our previous investigation of SMEI/SMEB6 did
not examine the presence/absence of ataxia, we re-investigated the clinical symptoms of the
reported patients. Their clinical data (ataxia) are shown in E-Table 1.

E-Table 1. Summary of clinical information of our previous report. The presence/absence of
ataxia in previously reported SMEI patients.

       E-Table 1. Presence/absence of ataxia in previously reported SMEI patients
       patient mutation gender ataxia       phenotype          segment

       2        R101Q    M        +        SMEB     N-terminal
       6        W190R    F        -        SMEI     S3
       38       L1355P   F        -        SMEB     S5
       51       F1692S   F        -        SMEI     S5
       52       Y1694C   F        +        SMEI     S5
       20       M934I    F        +        SMEI     S5-S6linker
       21       M934I    F        +        SMEB     S5-S6linker
       23       V944A    F        +        SMEB     S5-S6linker
       24       R946C    F        +        SMEI     S5-S6linker
       25       R946C    M        +        SMEB     S5-S6linker
       26       R946H    F        +        SMEB     S5-S6linker
       56       Y1781C   M        -        SMEI     S6
Physico-chemical properties of amino acid residues
       P, PR and HP are the indices of hydrophobicity of the residue. C is defined as the atomic
weight ratio of non-carbon elements in end groups or rings to carbons in the side chain, and
MV is the value of Å of side chain.21
       The values of C, P and MV are taken from Table 1 of Ref. 21. The values of PR, HP and
IE are taken from Table 2 of Ref. 24, Table 2 of Ref. 25 and Table 2 of Ref. 23, respectively.
Inclusion and exclusion criteria
      As described in Methods, we have categorized all reported missense mutations according
to the ratio of the severe phenotypes that were included in SRIEE.
      Most of the previously reported GEFS+ families were included in the GEFS+ group.
Although learning disability and behaviour disturbance were sometime seen in families with
GEFS+, we did not consider them as intellectual disability in this analysis. However, some
families previously described as GEFS+, where there were significant numbers of patients
with intellectual disturbance whose phenotype was considered to be included in the SRIEE
spectrum, were categorized into the intermediate phenotype group.
      Several SCN1A missense mutations have been reported in patients with idiopathic
generalized epilepsy. We included such patients with normal intellect into GEFS+ and those
with intellectual disturbance into SRIEE. In the report by Escayg et al.,E1 information about
intellectual ability was not available; however, we categorized four JME/JAE patients with
SCN1A mutations into GEFS+ except those with V699I and T1174S, because JME/JAE
patients usually show normal intellectual ability. We excluded the two mutations from this
analysis because V699I was found in none of the other affected family members and T1174S
was found in normal controls.
      Almost all sporadic patients with SMEI and the above mentioned epileptic syndromes
with SCN1A mutation except GEFS+ were categorized into SRIEE in this study.
      It has been reported that some patients with familial hemiplegic migraineE23 and with
autismE24 had SCN1A missence mutations. However we excluded them from this study,
because precise information about epilepsy in those families was not available.
      We included Rasmussen encephalitis patient with SCN1A missense mutation into SRIEE,
because several studies showed that focal and asymmetrical cerebral atrophy was often
observed in SMEI patients4,E25 and relationship between Rasmussen encephalitis and anti-
GluR3 antibody has still remained to be controversial. E26,E27
      In the investigation of the presence/absence of ataxia, only those cases whose histories of
the presence/absence of ataxia were clearly described were included in this study. In regard to
the cases reported by Fujiwara et al.,8 the absence of the description of ataxia was considered
as the absence of ataxia.
Functional analysis of mutant SCN1A channels
      We also reviewed previous functional studies of epilepsy-associated mutant SCN1A
channels. We investigated the mutation positions, phenotype of wild-type sodium channels
(rat/human, scn1a or scn4a), co-expressed proteins and their expression patterns
(homogeneously/heterogeneously expressed with wild-type channel), and types of changes in
channel functions.
Confirmation of the validity of the definition of S1–S4 region
      In S1–S4 region, both transmembrane segments, lying within the lipid bilayer, and inter-
transmembrane segment linkers, spanning cytoplasmic or extracellular space, are involved.
Any distinction between mutations in those two distinct regions remains unclear. To confirm
the issue, we analyzed differences in changes of the physico-chemical properties between
mutations in transmembrane segments and inter-transmembrane segment linkers.
Statistical Analysis
       Statistical analyses of value changes in the physico-chemical properties for missense
mutations in SCN1A in SRIEE, intermediate phenotypes, and GEFS+ patient groups were
compared by nonparametric multiple comparison tests (Dwass, Steel, Chitchlow–Fligner
tests) to determine which pairs differed significantly. Differences in value changes of the
physico-chemical properties in the patients with and without ataxia also were compared by
nonparametric Mann–Whitney’s U-tests. The relationships between disease onset and value
changes in the physico-chemical properties were analyzed using Spearman’s rank correlation
coefficient. Fisher’s exact test was used for statistical analyses of different distribution pattern
in physico-chemical property changes with missense mutations between GEFS+ and SRIEE
groups. The chi-square test was used for the distribution pattern analysis of the missense
mutations in SCN1A among the three groups. All the statistical tests used were two-sided.

E-Results
Reported SCN1A missense mutations and their phenotypes
       Data on disease onset of 122 SRIEE patients4-9,12-14,E2,E4,E8,E15,E17-E19 and
presence/absence of ataxia of 52 patients4-6,8,9,13, E12,E13,E15,E17,E18,E22 were available (Table 1).
In terms of disease onset, we excluded data described in the form of years.
Relationship between clinical symptoms in SCN1A-related epileptic encephalopathies and
value changes in the physico-chemical properties of amino acid residue substitutions
       In the analysis of the association between the change in physico-chemical properties and
clinical symptoms, the disease onset of SRIEE patients showed a tendency to correlate
negatively with IE value changes of missense mutations in the whole regions (n = 122, p =
0.06) (Figure 3A) but not in the pore region of SCN1A (n = 73). With respect to missense
mutations in the pore region of SCN1A, the mean IE absolute value changes of SRIEE
patients with ataxia (n = 28, 2.72 ± 0.43; mean ± SEM) were significantly larger than those of
patients without ataxia (n = 8, 0.90 ± 0.56; mean ± SEM) (Figure 3B; p < 0.05).
Confirmation of the validity of the definition of S1–S4 region
      In S1–S4 region, the mean value differences of the hydrophobicity indices (HP, P and
PR) in the GEFS+ group were significantly different from those in SRIEE. Compared to the
SRIEE group, the difference in HP value of the GEFS+ group was significantly smaller, both
in transmembrane segments [GEFS+ (n = 6) −2.63 ± 1.65 vs. SRIEE (n = 25) 1.78 ± 0.70
(mean ± SEM); p < 0.05] and inter-transmembrane segment linkers of S1–S4 region [GEFS+
(n = 4) −5.65 ± 0.99 vs. SRIEE (n = 9) 0.49 ± 1.12 (mean ± SEM); p < 0.05]. With regard to
P, the difference in P value of the GEFS+ group tended to be larger than that of the SRIEE
group, both in transmembrane segments [GEFS+ (n = 6) 2.23 ± 1.22 vs. SRIEE (n = 25)
−0.79 ± 0.59 (mean ± SEM); p < 0.10] and inter-transmembrane segment linkers of S1-S4
region [GEFS+ (n = 4) 3.45 ± 1.56 vs. SRIEE (n = 9) −0.54 ± 0.88 (mean ± SEM); p < 0.10].
These changes showed that decreasing hydrophobicity with amino acid replacements were
associated with a more severe phenotype both in transmembrane segments and inter-
transmembrane segment linkers of S1–S4 region.

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 E-Table 2. SCN1A mutations whoes functional abnormalities were studied by patch-
clamp method.
E-Table 2. SCN1A mutations whoes functional abnormalities were studied by patch-clamp method.


              type          expression                                region        Phenotypes      persistent Na current   current density              activation      inactivation recovery from innactivation   frequency dependence   Ref.


W1204R        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   II-III linker   GEFS+           ↑                    →               hyperpolarize                                                          E28
W1204R        rat scn1a     homo          alpha:beta=10:1                           II-III linker   GEFS+           →                                    hyperpolarize hyperpolarize                            →               E29
D1866Y        rat scn1a     homo          alpha1:beta1=10:1           C-terminal    GEFS+           ↑                                    hyperpolarize                                             ↓                E5
M145T         human SCN1A                 homo          beta1(+)                    S1              GEFS+                                ↓               depolarize, rise time↑                                                 E7
D188V         human SCN1A                 homo          beta1(+)                    S2-S3 linker GEFS+                                   →                                                                      ↓               E30
V1611F        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S3              GEFS+           ↑                    →               hyperpolarize hyperpolarize                            ↓               E31
T875M         rat scn1a     homo          alpha:beta=10:1                           S4              GEFS+                                →               →                                                      ↓               E32
T875M*        rat scn4a     homo          (-)                         S4            GEFS+                                                rise time↑      hyperpolarize                                              E33
T875M         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S4              GEFS+           ↑                    →               depolarize                                                             E28
R859C         rat scn1a     homo/hetero alpha1:beta1=10:1             S4            GEFS+                                   ↓            depolarize                      ↓                                          18
R1657C        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5              GEFS+           →                    ↓                               depolarize      ↑                                      28
V1353L        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5              GEFS+                                ND                                                                                     28
A1685V        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5              GEFS+                                ND                                                                                     28
R1657C        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5              GEFS+                                ↓                                                                                      17
M1841T        human SCN1A                 homo          beta1,beta2,beta3,beta4,CaM C-terminal      Interemediate                        ↓                                                                                      27
R1575C        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S2              Interemediate ↑                      →               →               →               →                                      E19
R1648H**      rat scn4a     homo          beta(-)       S4            Interemediate →                                                    rise time↑      hyperpolarize ↑                                            E34
R1648H        rat scn1a     homo          alpha1:beta1=10:1           S4            Interemediate                                        →               →               ↑                         ↓                E32
R1648H        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S4              Interemediate ↑                      →                                                                                      E28
R1648H        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S4              Interemediate ↑                                                                                                             17
I1656M        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5              Interemediate →                                      depolarize                                                             28
T1709I        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5-S6 linker Interemediate                           ND                                                                                     E31
Y426N         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   I-II linker     SRIEE                                ↓                               hyperpolarize                                          E35
N1011I        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   II-III linker   SRIEE                                ↓                                                                      ↓               E31
F1808L        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   C-terminal      SRIEE           ↑                    ↓               hyperpolarize hyperpolarize                            ↓               E31
T1909I        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   C-terminal      SRIEE           ↑                    ↓                                                                                      E35
T808S         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S2              SRIEE                                ↑                                                                      ↓               E31
G177E         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S2-S3 linker SRIEE                                   ND                                                                                     E35
P1632S        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S3-S4 linker SRIEE              ↑                    →               hyperpolarize hyperpolarize                            ↓               E31
R1648C        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S4              SRIEE           ↑                                    depolarize      hyperpolarize                                          E36
I227S         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S4              SRIEE                                ND                                                                                     E35
F1661S        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S4-S5 linker SRIEE              ↑                    ↓                               depolarize                                             E36
F902C         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5              SRIEE                                ND                                                                                     E36
G1674R        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5              SRIEE                                ND                                                                                     E36
G1749E        human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5-S6 linker SRIEE                                   ↓                                                                                      E36
R393H         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5-S6 linker SRIEE                                   ND                                                                                     E35
H939Q         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5-S6 linker SRIEE                                   ND                                                                                     E35
C959R         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S5-S6 linker SRIEE                                   ND                                                                                     E35
G979R         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S6              SRIEE                                ND                                                                                     E31
L986F         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S6              SRIEE                                ND                                                                                     28
V983A         human SCN1A                 homo          alpha1:beta1:beta2=10:1:1   S6              SRIEE                                ↓               depolarize      hyperpolarize                          ↓               E31
*Analyzed in scn4a T685M
** Analyzed in scn4a R1460H
↑: increase
↓: decrease
→: no significant change
ND: not detected
homo: mutant channel is expressed homologously.
hetero: mutant channel was expressed with wild type channel heterogeneously
activation: voltage dependency of activation
innactivation: voltage dependency of innactivation

				
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