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Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatme

Contains fulltext : 153652.pdf (publisher's version ) (Open Access), BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) s

Contains fulltext : 153652.pdf (publisher's version ) (Open Access), BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) s

Contains fulltext : 153652.pdf (publisher's version ) (Open Access), BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) s

We identify HS 2325+8205 as an eclipsing, frequently outbursting dwarf nova with an orbital period of 279.841731(5) min. Spectroscopic observations are used to derive the radial velocity curve of the secondary star from absorption features and also from the H-alpha emission lines, originating from the accretion disc, yielding K_secondary = K_abs = 237 +- 28 km/s and K_emn = 145 +- 9 km/s respectively. The distance to the system is calculated to be 400 (+200, -140) pc. A photometric monitoring campaign reveals an outburst recurrence time of 12-14 d, The combination of magnitude range (17-14 mag), high declination, eclipsing nature and frequency of outbursts makes HS 2325+8205 the ideal system for "real-time" studies of the accretion disc evolution and behavior in dwarf nova outbursts., Comment: 20 pages, 7 figures. Accepted for Publications of the Astronomical Society of the Pacific

We identify HS 2325+8205 as an eclipsing, frequently outbursting dwarf nova with an orbital period of 279.841731(5) min. Spectroscopic observations are used to derive the radial velocity curve of the secondary star from absorption features and also from the H-alpha emission lines, originating from the accretion disc, yielding K_secondary = K_abs = 237 +- 28 km/s and K_emn = 145 +- 9 km/s respectively. The distance to the system is calculated to be 400 (+200, -140) pc. A photometric monitoring campaign reveals an outburst recurrence time of 12-14 d, The combination of magnitude range (17-14 mag), high declination, eclipsing nature and frequency of outbursts makes HS 2325+8205 the ideal system for "real-time" studies of the accretion disc evolution and behavior in dwarf nova outbursts., Comment: 20 pages, 7 figures. Accepted for Publications of the Astronomical Society of the Pacific

We report the photometric observations of an SU UMa-type dwarf nova VW CrB during two superoutbursts in 2001 and 2003 and a normal outburst in 2003. Superhumps with a period of 0.07287(1) d were observed during the 2003 superoutburst. The change rate of the superhump period was positive. During the normal outburst, there are some hint of modulation up to a 0.2-mag amplitude. However, any periodicity was not found. The recurrence cycles of the normal outburst and the superoutburst, and the distance were estimated to be > ~50 d, 270-500 d, and 690(+230, -170) pc, respectively. These recurrence cycles are usual values for an SU UMa-type dwarf nova having this superhump period. The superhump period of VW CrB was the longest among those of the SU UMa stars with positive derivatives of the superhump period. The coverage of our observations was, however, not enough, and the variation of the Psh change rate of VW CrB is still unknown. A superhump regrowth and a brightening were seen near the end of the plateau phase. Measuring the deviation of the start timings of the brightening and the superhump regrowth (>2 days in VW CrB) will be a key to reveal the mechanism of these phenomena., Comment: 7 pages, 8 figures, to appear in PASJ

After 10 years of quiescence, HV Vir underwent a superoutburst in January 2002. We report time-series observations clearly revealing the period change of ordinary superhumps during the superoutburst. We derived a mean superhump period of 0.058260 d and a positive period derivative of $7 \times 10^{-5}$. These results are in good agreement with the value obtained from the 1992 superoutburst. We also detected early superhumps, which were not clearly recognized in the past outburst, and a possible rebrightening. Both of them are the common characteristics of WZ Sge-type stars., Comment: 9 pages, 8 figures. Accepted for publication in PASJ

We report the photometric observations of an SU UMa-type dwarf nova VW CrB during two superoutbursts in 2001 and 2003 and a normal outburst in 2003. Superhumps with a period of 0.07287(1) d were observed during the 2003 superoutburst. The change rate of the superhump period was positive. During the normal outburst, there are some hint of modulation up to a 0.2-mag amplitude. However, any periodicity was not found. The recurrence cycles of the normal outburst and the superoutburst, and the distance were estimated to be > ~50 d, 270-500 d, and 690(+230, -170) pc, respectively. These recurrence cycles are usual values for an SU UMa-type dwarf nova having this superhump period. The superhump period of VW CrB was the longest among those of the SU UMa stars with positive derivatives of the superhump period. The coverage of our observations was, however, not enough, and the variation of the Psh change rate of VW CrB is still unknown. A superhump regrowth and a brightening were seen near the end of the plateau phase. Measuring the deviation of the start timings of the brightening and the superhump regrowth (>2 days in VW CrB) will be a key to reveal the mechanism of these phenomena., Comment: 7 pages, 8 figures, to appear in PASJ

After 10 years of quiescence, HV Vir underwent a superoutburst in January 2002. We report time-series observations clearly revealing the period change of ordinary superhumps during the superoutburst. We derived a mean superhump period of 0.058260 d and a positive period derivative of $7 \times 10^{-5}$. These results are in good agreement with the value obtained from the 1992 superoutburst. We also detected early superhumps, which were not clearly recognized in the past outburst, and a possible rebrightening. Both of them are the common characteristics of WZ Sge-type stars., Comment: 9 pages, 8 figures. Accepted for publication in PASJ

We observed the 2001 November superoutburst of CC Cnc. This observation makes the first detailed coverage of a superoutburst of this object. The best-determined mean superhump period is 0.075518 +/- 0.000018 d, which is 2.7% longer than the reported orbital period. This fractional superhump excess is a quite typical value for a normal SU UMa-type dwarf nova, excluding the previously raised possibility that CC Cnc may have an anomalously large fractional superhump excess. During the superoutburst plateau, the object showed a decrease of the superhump period at dot(P)/P = -10.2(1.3) x 10^(-5), which is one of the largest negative period derivative known in all SU UMa-type dwarf novae., Comment: 5 pages, 5 figures, to appear in Publ. Astron. Soc. Japan

Our photometric monitoring revealed that DW Cnc, which was originally classified as a dwarf nova (V=15--17.5), remained at a bright state of Rc=14.68+/-0.07 for 61 days. In conjunction with optical spectra lacking a strong He II emission line, we propose that the object is not a dwarf nova, but a non-magnetic nova-like variable. Throughout our monitoring, the object showed strong quasi-periodic oscillations (QPOs) with amplitudes reaching about 0.3 mag. Our period analysis yielded a power spectrum with two peaks of QPOs, whose center periods are 37.5+/-0.1 and 73.4+/-0.4 min and, furthermore, with a significant power in frequencies lower than the QPOs. DW Cnc is a unique cataclysmic variable in which kilo-second QPOs were continuously detected for 61 days. We propose two possible interpretations of DW Cnc: (i) A permanent superhumper below the period minimum of hydrogen-rich cataclysmic variables. (ii) A nova-like variable having an orbital period over 3 hours. In this case, the QPOs may be caused by trapped disk oscillations., Comment: 6 pages, 4 figures, PASJ in press

We observed the 2001 November superoutburst of CC Cnc. This observation makes the first detailed coverage of a superoutburst of this object. The best-determined mean superhump period is 0.075518 +/- 0.000018 d, which is 2.7% longer than the reported orbital period. This fractional superhump excess is a quite typical value for a normal SU UMa-type dwarf nova, excluding the previously raised possibility that CC Cnc may have an anomalously large fractional superhump excess. During the superoutburst plateau, the object showed a decrease of the superhump period at dot(P)/P = -10.2(1.3) x 10^(-5), which is one of the largest negative period derivative known in all SU UMa-type dwarf novae., Comment: 5 pages, 5 figures, to appear in Publ. Astron. Soc. Japan

Our photometric monitoring revealed that DW Cnc, which was originally classified as a dwarf nova (V=15--17.5), remained at a bright state of Rc=14.68+/-0.07 for 61 days. In conjunction with optical spectra lacking a strong He II emission line, we propose that the object is not a dwarf nova, but a non-magnetic nova-like variable. Throughout our monitoring, the object showed strong quasi-periodic oscillations (QPOs) with amplitudes reaching about 0.3 mag. Our period analysis yielded a power spectrum with two peaks of QPOs, whose center periods are 37.5+/-0.1 and 73.4+/-0.4 min and, furthermore, with a significant power in frequencies lower than the QPOs. DW Cnc is a unique cataclysmic variable in which kilo-second QPOs were continuously detected for 61 days. We propose two possible interpretations of DW Cnc: (i) A permanent superhumper below the period minimum of hydrogen-rich cataclysmic variables. (ii) A nova-like variable having an orbital period over 3 hours. In this case, the QPOs may be caused by trapped disk oscillations., Comment: 6 pages, 4 figures, PASJ in press

We discovered a new deeply eclipsing SU UMa-type dwarf nova, IY UMa, which experienced a superoutburst in 2000 January. Our monitoring revealed two distinct outbursts, which suggest a superoutburst interval of ~800 d, or its half, and an outburst amplitude of 5.4 mag. From time-series photometry during the superoutburst, we determined a superhump and orbital period of 0.07588 d and 0.0739132 d, respectively., Comment: 5 pages, 3 figures, accepted by PASJ letter

We discovered a new deeply eclipsing SU UMa-type dwarf nova, IY UMa, which experienced a superoutburst in 2000 January. Our monitoring revealed two distinct outbursts, which suggest a superoutburst interval of ~800 d, or its half, and an outburst amplitude of 5.4 mag. From time-series photometry during the superoutburst, we determined a superhump and orbital period of 0.07588 d and 0.0739132 d, respectively., Comment: 5 pages, 3 figures, accepted by PASJ letter

We correlate the ROSAT 1/4 keV all-sky survey with the Leiden/Dwingeloo HI survey, looking for soft X-ray signatures of prominent high-velocity-cloud (HVC) complexes. We study the transfer of 1/4 keV photons through the interstellar medium in order to distinguish variations in the soft X-ray background (SXRB) intensity caused by photoelectric absorption effects from those due to excess X-ray emission. The X-ray data are modelled as a combination of emission from the Local Hot Bubble (LHB) and emission from a distant plasma in the galactic halo and extragalactic sources. The X-ray radiation intensity of the galactic halo and extragalactic X-ray background is modulated by the photoelectric absorption of the intervening galactic interstellar matter. We show that large- and small-scale intensity variations of the 1/4 keV SXRB are caused by photoelectric absorption which is predominantly traced by the total N(HI) distribution. The extensive coverage of the two surveys supports evidence for a hot, X-ray emitting corona. We show that this leads to a good representation of the SXRB observations. For four large areas on the sky, we search for regions where the modelled and observed X-ray emission differ. We find that there is excess X-ray emission towards regions near HVC complexes C, D, and GCN. We suggest that the excess X-ray emission is positionally correlated with the high-velocity clouds. Some lines of sight towards HVCs also pass through significant amounts of intermediate-velocity gas, so we cannot constrain the possible role played by IVC gas in these directions of HVC and IVC overlap, in determining the X-ray excesses., Comment: 16 pages, 8 figures, accepted for publication in Astronomy & Astrophysics main journal

We correlate the ROSAT 1/4 keV all-sky survey with the Leiden/Dwingeloo HI survey, looking for soft X-ray signatures of prominent high-velocity-cloud (HVC) complexes. We study the transfer of 1/4 keV photons through the interstellar medium in order to distinguish variations in the soft X-ray background (SXRB) intensity caused by photoelectric absorption effects from those due to excess X-ray emission. The X-ray data are modelled as a combination of emission from the Local Hot Bubble (LHB) and emission from a distant plasma in the galactic halo and extragalactic sources. The X-ray radiation intensity of the galactic halo and extragalactic X-ray background is modulated by the photoelectric absorption of the intervening galactic interstellar matter. We show that large- and small-scale intensity variations of the 1/4 keV SXRB are caused by photoelectric absorption which is predominantly traced by the total N(HI) distribution. The extensive coverage of the two surveys supports evidence for a hot, X-ray emitting corona. We show that this leads to a good representation of the SXRB observations. For four large areas on the sky, we search for regions where the modelled and observed X-ray emission differ. We find that there is excess X-ray emission towards regions near HVC complexes C, D, and GCN. We suggest that the excess X-ray emission is positionally correlated with the high-velocity clouds. Some lines of sight towards HVCs also pass through significant amounts of intermediate-velocity gas, so we cannot constrain the possible role played by IVC gas in these directions of HVC and IVC overlap, in determining the X-ray excesses., Comment: 16 pages, 8 figures, accepted for publication in Astronomy & Astrophysics main journal