Wednesday, December 28, 2022

Erenumab versus topiramate for the prevention of migraine

Reuter U, Ehrlich M, Gendolla A, et al. Erenumab versus topiramate for the prevention of migraine—a randomized, double-blind, active-controlled phase 4 trial. Cephalagia. 2022;42(2):108-118. doi:10.1177/03331024211053571



We compared the tolerability and efficacy of erenumab, a monoclonal antibody binding to the calcitonin gene-related peptide receptor, to topiramate for migraine prophylaxis in adults.


HER-MES was a 24-week, randomised, double-blind, double-dummy, controlled trial conducted in 82 sites in Germany. Patients with ≥4 migraine days per month and naïve to study drugs were randomly assigned (1:1) to either subcutaneous erenumab (70 or 140 mg/month) plus topiramate placebo (erenumab group) or oral topiramate at the individual dose with optimal efficacy (50–100 mg/day) plus erenumab placebo (topiramate group).
The primary endpoint was medication discontinuation due to an adverse event during the double-blind phase. The proportion of patients that achieved ≥50% reduction from baseline in monthly migraine days during the last 3 months of the double-blind phase was a secondary endpoint.


Seven hundred and seventy-seven patients were randomised (from 22 February 2019 to 29 July, 2020) and 95.1% completed the study. In the erenumab group, 10.6% discontinued medication due to adverse events compared to 38.9% in the topiramate group (odds ratio, 0.19; 95% confidence interval 0.13–0.27; p < 0.001). Significantly more patients achieved a ≥50% reduction in monthly migraine days from baseline with erenumab (55.4% vs. 31.2%; odds ratio 2.76; 95% confidence interval 2.06–3.71; p < 0.001). No new safety signals occurred.


Erenumab demonstrated a favourable tolerability and efficacy profile compared to topiramate.


For the treatment and prevention of migraine episodes, erenumab was found to have a higher tolerability versus topiramte among patients. The results from the HER-MES trial, funded by Novartis, were published in Cephalagia, a journal published monthly on behalf of the International Headache Society.

The HER-MES trial was a 24-week, randomized, double-blind, double-dummy, controlled trial conducted across 82 sites in Germany. Whereas previous studies have confirmed the efficacy of both erenumab and topiramate for the treatment of migraine against placebo, the primary endpoint of the HER-MES trial was the rate of medication discontinuation due to adverse events experienced during treatment. The secondary endpoint was the number of patients who achieved a 50% or higher reduction in monthly migraine days from baseline.

“Tolerability is a prerequisite for an effective migraine drug to achieve meaningful improvement in a broad migraine population,” the authors observed. “Thus, our primary objective was to compare the tolerability of topiramate and erenumab measured as the rate of medication discontinuation due to [adverse effects].”

A total of 777 patients with a history of migraine with or without aura who had never received treatment with either topiramate or a monoclonal antibody like erenumab were enrolled. Patients were randomly assigned in a 1:1 ratio to receive either topiramate verum plus an erenumab placebo or erenumab verum plus a topiramate placebo.

Patients tracked and recorded information about migraine and nonmigraine headaches experienced during the trial and completed several questionnaires to track outcomes including:

  • Medical outcome short form health survey version 2 (SF-36v2);
  • Headache impact test (HIT-6);
  • Treatment satisfaction questionnaire for medication (TSQM);
  • Beck Depression Inventory (BDI-II).

Adverse effects were assessed during regular visits.

Of the study participants, 95.1% completed the study. For the erenumab group, 10.6% of participants discontinued the medication due to adverse effects compared to 38.9% in the topiramate group (odds ratio, 0.19; 95% confidence interval 0.13-0.27; p<0.001). The most common adverse effects that led to discontinuation for the topiramate group were paranesthesia, attention disturbance, fatigue, and nausea. For the erenumab group, these were fatigue, nausea, attention disturbance, and dizziness.

In the erenumab group, 55.4% of patients achieved a 50% or greater reduction in monthly migraine days versus 31.2% for the topiramate group (odds ratio 2.76; 95% confidence interval 2.06-3.71; p<0.001).

“Compared to topiramate, treatment with erenumab has a superior tolerability profile and a significantly higher efficacy. HER-MES supports the potential of erenumab in overcoming issues of low adherence in clinical practice observed with topiramate, lessening migraine burden and improving quality of life in a broad migraine population,” the researchers concluded.

IQSEC2 mutation

Inspired by a patient

Baladron B, Mielu LM, López-Martín E, Barrero MJ, Lopez L, Alvarado JI, Monzón S, Varona S, Cuesta I, Cazorla R, Lara J, Iglesias G, Román E, Ros P, Gomez-Mariano G, Cubillo I, Miguel EH, Rivera D, Alonso J, Bermejo-Sánchez E, Posada M, Martínez-Delgado B. Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder. Int J Mol Sci. 2022 Aug 22;23(16):9480. doi: 10.3390/ijms23169480. PMID: 36012761; PMCID: PMC9409358.


Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C&gt;T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.

Brant B, Stern T, Shekhidem HA, Mizrahi L, Rosh I, Stern Y, Ofer P, Asleh A, Umanah GKE, Jada R, Levy NS, Levy AP, Stern S. IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission. Mol Psychiatry. 2021 Dec;26(12):7498-7508. doi: 10.1038/s41380-021-01281-0. Epub 2021 Sep 17. PMID: 34535765; PMCID: PMC8873005.


Mutations in the IQSEC2 gene are associated with drug-resistant, multifocal infantile and childhood epilepsy; autism; and severe intellectual disability (ID). We used induced pluripotent stem cell (iPSC) technology to obtain hippocampal neurons to investigate the neuropathology of IQSEC2-mediated disease. The neurons were characterized at three-time points during differentiation to assess developmental progression. We showed that immature IQSEC2 mutant dentate gyrus (DG) granule neurons were extremely hyperexcitable, exhibiting increased sodium and potassium currents compared to those of CRISPR-Cas9-corrected isogenic controls, and displayed dysregulation of genes involved in differentiation and development. Immature IQSEC2 mutant cultured neurons exhibited a marked reduction in the number of inhibitory neurons, which contributed further to hyperexcitability. As the mutant neurons aged, they became hypoexcitable, exhibiting reduced sodium and potassium currents and a reduction in the rate of synaptic and network activity, and showed dysregulation of genes involved in synaptic transmission and neuronal differentiation. Mature IQSEC2 mutant neurons were less viable than wild-type mature neurons and had reduced expression of surface AMPA receptors. Our studies provide mechanistic insights into severe infantile epilepsy and neurodevelopmental delay associated with this mutation and present a human model for studying IQSEC2 mutations in vitro.

Levy AP, Levy NS, Heyman E, Schertz M, Genizi J. Reduction in seizure burden in a child with a A350V IQSEC2 mutation using heat therapy with a Jacuzzi. Clin Case Rep. 2021 Aug 30;9(9):e04734. doi: 10.1002/ccr3.4734. PMID: 34484768; PMCID: PMC8405536.


A child with a A350V IQSEC2 missense mutation resulting in drug-resistant epilepsy stops having seizures when he has a fever. We demonstrate that raising the body temperature of the child using a commercial Jacuzzi dramatically reduces his seizures and appears to improve his social behavioral interactions.

Liu X, Zhang S, Wan L, Zhang X, Wang H, Zhang H, Zhu G, Liang Y, Yan H, Zhang B, Yang G. IQSEC2-related encephalopathy in male children: Novel mutations and phenotypes. Front Mol Neurosci. 2022 Oct 3;15:984776. doi: 10.3389/fnmol.2022.984776. PMID: 36267700; PMCID: PMC9577604.


The isoleucine-glutamine (IQ) motif and Sec7 domain-containing protein 2 (IQSEC2) gene, located at Xp11. 2, are associated with nervous system diseases, such as epilepsy, autism, and intellectual disabilities. Gender-related differences in the severity of phenotype severity have been described previously. Here, we report the details of seven male children with IQSEC2 mutations from different families. During this investigation, we explored the relationship between the genotype and phenotype of IQSEC2 mutations; to do so, we recruited seven children with pathogenic/likely pathogenic IQSEC2 mutations who were diagnosed with global developmental delay and/or epilepsy. Their clinical features were assessed, and Trio-based whole-exome sequencing (trio WES) was conducted in seven pedigrees. A variety of algorithms and computational tools were used to calculate the pathogenicity, protein stability, conservation, side chain properties, and protein-protein interactions of mutated proteins. The seven patients ranged in age from 18 months to 5 years. Among them, six children were found to have both developmental delay and epilepsy, and one child only exhibited developmental delay. Four novel mutations (c.316C > T, c.443_4 44dup, c.3235T > C, and c.1417G > T) were newly reported. Two patients did not have truncated aberrant proteins caused by missense mutations. Still, they did have severe phenotypes, such as early-onset epilepsy in infancy, because the mutations were located in domains like the pleckstrin homology and IQ calmodulin-binding motif domains. The bioinformatics analysis also proved that missense mutations may be located in the functional region, which affects protein stability and is harmful. In summary, severe phenotypes, such as early-onset epilepsy in infancy, occur in male patients with a missense mutation in specific domains (e.g., pleckstrin homology and IQ calmodulin-binding motif domains). Some female individuals with IQSEC2 mutations may be asymptomatic because of the skewed inactivation of the X chromosome.

Tuesday, December 27, 2022

Seizure semiology in antibody-associated autoimmune encephalitis

Kaaden T, Madlener M, Angstwurm K, Bien CG, Bogarin Y, Doppler K, Finke A, Gerner ST, Reimann G, Häusler M, Handreka R, Hellwig K, Kaufmann M, Kellinghaus C, Koertvelyessy P, Kraft A, Lewerenz J, Menge T, Paliantonis A, von Podewils F, Prüss H, Rauer S, Ringelstein M, Rostásy K, Schirotzek I, Schwabe J, Sokolowski P, Suesse M, Sühs KW, Surges R, Tauber SC, Thaler F, Bergh FT, Urbanek C, Wandinger KP, Wildemann B, Mues S, Zettl U, Leypoldt F, Melzer N, Geis C, Malter M, Kunze A; and the Generate study group. Seizure Semiology in Antibody-Associated Autoimmune Encephalitis. Neurol Neuroimmunol Neuroinflamm. 2022 Oct 20;9(6):e200034. doi: 10.1212/NXI.0000000000200034. PMID: 36266054; PMCID: PMC9621609.


Background and objectives: To assess seizure characteristics in antibody (ab)-associated autoimmune encephalitis (ab + AE) with the 3 most prevalent abs against N-methyl-d-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), and glutamic acid decarboxylase (GAD).

Methods: Multicenter nationwide prospective cohort study of the German Network for Research in Autoimmune Encephalitis.

Results: Three hundred twenty patients with ab + AE were eligible for analysis: 190 NMDAR+, 89 LGI1+, and 41 GAD+. Seizures were present in 113 (60%) NMDAR+, 69 (78%) LGI1+, and 26 (65%) GAD+ patients and as leading symptoms for diagnosis in 53 (28%) NMDAR+, 47 (53%) LGI+, and 20 (49%) GAD+ patients. Bilateral tonic-clonic seizures occurred with almost equal frequency in NMDAR+ (38/51, 75%) and GAD+ (14/20, 70%) patients, while being less common in LGI1+ patients (27/59, 46%). Focal seizures occurred less frequently in NMDAR+ (67/113; 59%) than in LGI1+ (54/69, 78%) or in GAD+ patients (23/26; 88%). An aura with déjà-vu phenomenon was nearly specific in GAD+ patients (16/20, 80%). Faciobrachial dystonic seizures (FBDS) were uniquely observed in LGI1+ patients (17/59, 29%). Status epilepticus was reported in one-third of NMDAR+ patients, but only rarely in the 2 other groups. The occurrence of seizures was associated with higher disease severity only in NMDAR+ patients.

Discussion: Seizures are a frequent and diagnostically relevant symptom of ab + AE. Whereas NMDAR+ patients had few localizing semiological features, semiology in LGI1+ and GAD+ patients pointed toward a predominant temporal seizure onset. FBDS are pathognomonic for LGI1 + AE. Status epilepticus seems to be more frequent in NMDAR + AE.

Thursday, December 22, 2022

Caregiver response to genetic diagnosis of developmental and epileptic encephalopathy

Caregivers of children with developmental and epileptic encephalopathies (DEEs) often face uncertainty regarding their child’s medical condition. DEEs are defined as a group of rare neurologic conditions that occur during early childhood. Children with DEEs often experience severe epilepsy and require aggressive treatments. Technologic advances in next-generation sequencing (NGS), commonly used for gene panel testing and whole exome sequencing (WES), have significantly improved the diagnostic yield to ~30% for those with DEEs. At the same time, NGS can find variants of unknown significance (VUS), for which the impact of an identified genetic variation is uncertain; these results can complicate the clinical picture without offering a clear answer. In this scenario, further interpretation of whether a VUS may be causative of an individual child’s phenotype may not be possible given insufficient knowledge of a gene or disease to date, limiting the understanding of an illness. In this manner, NGS can provide information with uncertain interpretation that can add to the diagnostic odyssey for both caregivers and those with a DEE with an unknown cause.

Other burdens for caregivers of children with DEEs include coping with their child’s condition and accessing medical insurance coverage, which increase the emotional burden of an unknown genetic diagnosis. Caregivers have reported depression, anxiety, and stress in response to caring for a child with early-onset epilepsy. The quest for an accurate diagnosis can increase this burden, considering that obtaining coverage or funding for WES can be challenging because it is not covered by all insurance companies and caregivers of children with epilepsy already spend on average $7522 annually on direct medical costs.

Emerging studies are beginning to address the complex experiences of caregivers for people with DEEs and many emphasize the importance of qualitative and quantitative methodologies. Considering the uncertainty and challenges associated with caring for a child with DEEs, a broader analysis of caregiver experiences is needed to inform pediatricians, neurologists, and genetic counselors on how to provide further support for affected families. In this article, we discuss our use of medical anthropologic methodologies to analyze caregiver illness accounts; based on this analysis, we make concrete suggestions for how health care professionals can enhance their support for caregivers of children with DEEs. (continued at link)

Wednesday, December 21, 2022

Intrathecal baclofen for management of spasticity in hereditary spastic paraparesis

Pointon R, Whelan H, Raza R, Peacock S, Wilsmore C, Mulkeen A, Goodden J, Lodh R. The use of intrathecal baclofen for management of spasticity in hereditary spastic paraparesis: A case series. Eur J Paediatr Neurol. 2022 Jan;36:14-18. doi: 10.1016/j.ejpn.2021.11.003. Epub 2021 Nov 11. PMID: 34794088.


Hereditary Spastic Paraparesis (HSP) causes lower limb spasticity, pain and limits ambulation resulting in a negative impact on an individual's quality of life. This case series evaluates the use of Intra-thecal Baclofen (ITB) on 5 ambulant children with HSP. Our results suggest ITB is associated with a reduction in spasticity and a trend towards improvement in patient-reported quality of life and achievement of personalised goals. This was evidenced with lower Modified Ashworth Scale (MAS) scores and increasing values using the Cerebral Palsy Quality of Life (CPQoL) tool and Goal Attainment Scale (GAS). ITB was not associated with any major immediate or longer-term adverse effects. Overall, our study supports the role of ITB, used in a goal-directed manner, in the management of children and young people with HSP where other standard treatment options have been unsuccessful.

Treatment practices and outcomes in continuous spike and wave during slow wave sleep

Baumer FM, McNamara NA, Fine AL, Pestana-Knight E, Shellhaas RA, He Z, Arndt DH, Gaillard WD, Kelley SA, Nagan M, Ostendorf AP, Singhal NS, Speltz L, Chapman KE. Treatment Practices and Outcomes in Continuous Spike and Wave during Slow Wave Sleep: A Multicenter Collaboration. J Pediatr. 2021 May;232:220-228.e3. doi: 10.1016/j.jpeds.2021.01.032. Epub 2021 Jan 20. PMID: 33484700; PMCID: PMC8934740.


Objectives: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US.

Study design: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables.

Results: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs.

Conclusions: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.

Tuesday, December 20, 2022

NPRL3 mutations

Inspired by a patient

Korenke GC, Eggert M, Thiele H, Nürnberg P, Sander T, Steinlein OK. Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3. Epilepsia. 2016 Mar;57(3):e60-3. doi: 10.1111/epi.13307. Epub 2016 Jan 20. PMID: 26786403.


Mutations in NPRL3, one of three genes that encode proteins of the mTORC1-regulating GATOR1 complex, have recently been reported to cause cortical dysplasia with focal epilepsy. We have now analyzed a multiplex epilepsy family by whole exome sequencing and identified a frameshift mutation (NM_001077350.2; c.1522delG; p.E508Rfs*46) within exon 13 of NPRL3. This truncating mutation causes an epilepsy phenotype characterized by early childhood onset of mainly nocturnal frontal lobe epilepsy. The penetrance in our family was low (three affected out of six mutation carriers), compared to families with either ion channel- or DEPDC5-associated familial nocturnal frontal lobe epilepsy. The absence of apparent structural brain abnormalities suggests that mutations in NPRL3 are not necessarily associated with focal cortical dysplasia but might be able to cause epilepsy by different, yet unknown pathomechanisms.

Weckhuysen S, Marsan E, Lambrecq V, Marchal C, Morin-Brureau M, An-Gourfinkel I, Baulac M, Fohlen M, Kallay Zetchi C, Seeck M, de la Grange P, Dermaut B, Meurs A, Thomas P, Chassoux F, Leguern E, Picard F, Baulac S. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia. 2016 Jun;57(6):994-1003. doi: 10.1111/epi.13391. Epub 2016 May 13. PMID: 27173016.


Objective: The discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum.

Methods: We performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho-S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants.

Results: We identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1-related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP).

Significance: GATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.

Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, de Saint Martin A, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez-Hernandez L, Krithika S, Oegema R, Hagebeuk E, Gunning B, Deckers C, Berghuis B, Wegner I, Niks E, Jansen FE, Braun K, de Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, Nordli DR Jr, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, de Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, Baulac S. The landscape of epilepsy-related GATOR1 variants. Genet Med. 2019 Feb;21(2):398-408. doi: 10.1038/s41436-018-0060-2. Epub 2018 Aug 10. Erratum in: Genet Med. 2018 Aug 29;: Erratum in: Genet Med. 2018 Sep 27;: PMID: 30093711; PMCID: PMC6292495.


Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.

Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.

Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

ZMYND11-related syndromic intellectual disability and epilepsy

Inspired by a colleague's patient

Oates S, Absoud M, Goyal S, Bayley S, Baulcomb J, Sims A, Riddett A, Allis K, Brasch-Andersen C, Balasubramanian M, Bai R, Callewaert B, Hüffmeier U, Le Duc D, Radtke M, Korff C, Kennedy J, Low K, Møller RS, Nielsen JEK, Popp B, Quteineh L, Rønde G, Schönewolf-Greulich B, Shillington A, Taylor MR, Todd E, Torring PM, Tümer Z, Vasileiou G, Yates TM, Zweier C, Rosch R, Basson MA, Pal DK. ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder. Clin Genet. 2021 Oct;100(4):412-429. doi: 10.1111/cge.14023. Epub 2021 Jul 16. PMID: 34216016.


ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

Huynh MT, Tran CT, Joubert M, Bénéteau C. Intragenic Deletion of the ZMYND11 Gene in 10p15.3 is Associated with Developmental Delay Phenotype: A Case Report. Cytogenet Genome Res. 2021;161(8-9):445-448. doi: 10.1159/000518689. Epub 2021 Oct 15. PMID: 34818214.


Submicroscopic 10p15.3 microdeletions were previously reported to be associated with developmental delay, and the smallest region of overlap of 10p15.3 deletion including DIP2C and ZMYND11 was defined. Moreover, pathogenic ZMYND11 truncating variants were subsequently identified in a cohort of patients with developmental delay. Of interest, patients harboring 10p15.3 microdeletions or pathogenic ZMYND11 truncating variants share similar clinical features including hypotonia, intellectual disability, facial dysmorphisms, speech and motor delays, seizures, and significant behavioral problems. Only 1 patient with whole ZMYND11 gene deletion was recorded, and no intragenic ZMYND11 deletion was reported up to date. Here, we describe a 7-year-old boy with developmental delay, carrying the smallest de novo 10p15.3 microdeletion, harboring the 5'UTR and the first 2 exons of ZMYND11. Taken together, our report contributes to expand the clinical and mutational spectrum of ZMYND11 and confirms haploinsufficiency as the underlying disease mechanism.

Yates TM, Drucker M, Barnicoat A, Low K, Gerkes EH, Fry AE, Parker MJ, O'Driscoll M, Charles P, Cox H, Marey I, Keren B, Rinne T, McEntagart M, Ramachandran V, Drury S, Vansenne F, Sival DA, Herkert JC, Callewaert B, Tan WH, Balasubramanian M. ZMYND11-related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum. Hum Mutat. 2020 May;41(5):1042-1050. doi: 10.1002/humu.24001. Epub 2020 Mar 5. PMID: 32097528.


Pathogenic variants in ZMYND11, which acts as a transcriptional repressor, have been associated with intellectual disability, behavioral abnormalities, and seizures. Only 11 affected individuals have been reported to date, and the phenotype associated with pathogenic variants in this gene have not been fully defined. Here, we present 16 additional patients with predicted pathogenic heterozygous variants in including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11-related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild-moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense-mediated decay. Two ZMYND11 variants located in the final exon-p.(Gln586*) (likely escaping nonsense-mediated decay) and p.(Cys574Arg)-are predicted to disrupt the MYND-type zinc-finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss-of-function.

Monday, December 19, 2022

Canadian life alert just euthanizes you when you push the button

 OTTAWA — The Canadian Medical System has officially rolled out its own "Life Alert" which provides immediate, medically-assisted death to geriatric patients who push the button.

"If you fall and can't get up, now you can comfortably die right there!" said Dorian Michel, director of Canada's Euthanasia Initiative. "This will save so much hassle with trying to help old people back up to their feet. I don't know if you have ever tried to help an eighty-year-old off a bathroom floor, but it is a HUGE pain."

According to sources, the Canadian team got the idea when an old man called for an ambulance and said he was hurting so badly, he wished he were dead. "That's when we partnered with Life Alert systems – so a fallen geriatric in maximum pain could finish the job right then and there!" said Mr. Michel, loading cyanide into one of the systems. "Old people don't want us to make such a fuss over them when they break their hips. Now, they can go straight from undignified fall to dignified death!"

At publishing time, investigators revealed that Roomba had agreed to start directing their units to trip old people in exchange for kickbacks from Life Alert.

Thursday, December 8, 2022

Stiff person syndrome

Muranova A, Shanina E. Stiff Person Syndrome. 2022 Jul 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 34424651.


Stiff person syndrome (SPS) is a rare disorder of the central nervous system characterized by rigidity and stimulus triggered painful muscle spasms of predominantly axial and proximal limb muscles. It was first described in 1956 by Frederick Moersch and Henry Woltman based on a case series of 14 patients with progressive fluctuating tightness of the spinal, abdominal, and thigh muscles. This condition was formerly named stiff-man syndrome and is also known as Moersch-Woltman Syndrome.

The current clinical classification of SPS includes:

  1. Classic SPS

  2. Partial SPS variants

  3. Progressive encephalomyelitis with rigidity and myoclonus (PERM).

Classic SPS is the most common clinical form, present in 70 to 80% of SPS patients. It is associated with anti-glutamic acid decarboxylase (anti-GAD) antibodies. The condition has an insidious onset with gradual worsening over time and often leads to permanent disability and, in some cases, mortality. SPS may coexist with other autoimmune disorders, including Diabetes Mellitus Type 1 (DM-1), autoimmune thyroid disease, pernicious anemia, celiac disease, vitiligo.

Several clinical variants of SPS have been described and include stiff limb syndrome, jerky SPS, cerebellar variant, SPS with epilepsy, and dystonia. The paraneoplastic variant is associated with breast, colon, thyroid, lung malignancies, Hodgkin and non-Hodgkin lymphomas and tends to clinically manifest before cancer itself.

PERM, first described in 1956, is known as SPS-plus syndrome. Patients have the rigidity of axial and limb muscles, diffuse myoclonus in addition to prominent autonomic instability.

There is increasing evidence for immune-mediated etiology of this disorder. Identification of associated antibodies and common comorbidities with other autoimmune diseases and malignancies has been important for a better understanding of disease mechanisms and approaches to treatment.

Yi J, Dalakas MC. Long-term Effectiveness of IVIg Maintenance Therapy in 36 Patients With GAD Antibody-Positive Stiff-Person Syndrome. Neurol Neuroimmunol Neuroinflamm. 2022 Jul 7;9(5):e200011. doi: 10.1212/NXI.0000000000200011. PMID: 35798561; PMCID: PMC9262284.


Background and objectives: IVIg has been the preferred immunotherapy in stiff-person syndrome (SPS) based on a 3-month controlled trial, but whether it is also effective in inducing long-term benefits or arresting disease progression is unknown. The information is needed because SPS is a progressively disabling disease and IVIg is liberally used as chronic therapy without efficacy data. The present study explores the long-term effects of IVIg in the largest cohort of well-characterized patients with SPS followed by the same clinicians over 10 years.

Methods: Data of 36 patients (32 glutamic acid decarboxylase [GAD] positive), diagnosed and treated with monthly maintenance IVIg by the same neurologists, were analyzed. Response was assessed by physician-observed changes, patients' reports of symptom improvement, modified Rankin Scale (mRS) scores, and dependency trials evaluating symptom recurrence after stopping IVIg, prolonging infusion frequency, decreasing monthly dose, or wearing-off effects in between doses. Clinically meaningful long-term response was defined by improved mRS scores, improvement in physician-assessed stiffness, balance and gait, and functional decline with dependency trials.

Results: Twenty-four of 36 (67%) patients had clinically meaningful response over a median 40-month period. Patients with improved mRS scores by 1-2 points manifested improved gait, posture, balance and decreased stiffness, spasms, and startle response; some patients using a wheelchair and those ambulating with devices walked unassisted. In 25% of responders, treatment benefit was sustained for a 40-month median period, but in 29.1%, it declined over a 39-month period; 12.5% exhibited a conditioning effect. Three of 5 patients with cerebellar GAD-SPS variant also improved over time. The 12 patients who did not respond the first 3 months remained unresponsive even if IVIg continued for several months.

Discussion: This is a large study in 36 patients with SPS demonstrating that monthly maintenance IVIg therapy offers long-term benefits in 67% of patients for a median 3.3-year period. Because 29.1% experienced diminishing benefit over time due to disease progression, the study highlights the need for more effective therapies.

Yeshokumar AK, Sun LR, Newsome SD. Defining the Expanding Clinical Spectrum of Pediatric-Onset Stiff Person Syndrome. Pediatr Neurol. 2021 Jan;114:11-15. doi: 10.1016/j.pediatrneurol.2020.09.007. Epub 2020 Sep 23. PMID: 33189024.


Background: We aimed to characterize the spectrum of clinical features and examination findings in pediatric-onset stiff person syndrome.

Methods: Medical records were reviewed for all patients treated for stiff person syndrome with symptom onset in childhood at a tertiary medical center between March 2001 and February 2019.

Results: Of the 15 individuals who met inclusion criteria, 11 (73%) were female and 13 (87%) were Caucasian. Median age at symptom onset was 14.8 years (range 8.4 to 16.9), and median latency from symptom onset to diagnosis was 6.2 years (range 0.4 to 15.0). Nine individuals (60%) were not diagnosed until adulthood. The most common presenting features were painful spasms (n = 12, 80%), hyper-reflexia (n = 11, 73%), axial rigidity (n = =9, 60%), lower extremity rigidity or spasticity (n = 8, 53%), gait abnormalities (n = 6, 40%), and hyperlordosis (n = 6, 40%). Other noted features included anxiety (n = 5, 33%), dysautonomia (n = 3, 20%), and cranial neuropathies (n = 3, 20%). Personal (n = 9, 60%) and family history (n = 9, 60%) of autoimmune conditions was common. Serum antiglutamate decarboxylase 65 antibodies were found in 13 individuals (87%). Nearly all individuals received immunotherapy (n = 14, 93%), symptomatic medications (n = 15, 100%), and nonpharmacologic therapies (n = 14, 93%). However, most had persistent physical limitations, particularly impaired walking (n = 7, 47%) and inability to carry out previous activities (n = 14, 93%).

Conclusions: There is a wide spectrum of typical and less common features seen in individuals with pediatric-onset stiff person syndrome. Despite symptom onset in childhood, diagnosis is often delayed until adulthood, at which point disability accrual is frequently seen. Early recognition is vital to address symptoms and may potentially limit future disability.

Newsome SD, Johnson T. Stiff person syndrome spectrum disorders; more than meets the eye. J Neuroimmunol. 2022 Aug 15;369:577915. doi: 10.1016/j.jneuroim.2022.577915. Epub 2022 Jun 12. PMID: 35717735; PMCID: PMC9274902.


Stiff person syndrome spectrum disorders (SPSD) are a group of rare neuroimmunological disorders that often include painful spasms and rigidity. However, patients have highly heterogeneous signs and symptoms which may reflect different mechanistic disease processes. Understanding subsets of patients based on clinical phenotype may be important for prognosis and guiding treatment. The goal of this review is to provide updates on SPSD and its expanding clinical spectrum, prognostic markers, and treatment considerations. Further, we describe the current understanding in immunopathogenesis and highlight gaps in our knowledge appropriate for future research directions. Examples of revised diagnostic criteria for SPSD based on phenotype are also presented.

Monday, December 5, 2022


A review of the clinical records of 44 patients who died under the care of the disgraced former neurologist Michael Watt has found a misdiagnosis rate of 45%.

In 2018, more than 2,500 of Watt’s neurology patients in Northern Ireland, including children, were recalled for a case review.

An independent inquiry launched in 2018 found there were numerous failures, that opportunities were missed by the Belfast Health Trust to identify problems with the neurologist’s practice and that earlier intervention by the trust would have “made a difference”.

In October last year, Watt was removed from the medical register after he made a voluntary application – meaning allegations about his work could not be heard in a tribunal of the Medical Practitioners Tribunal Service, the disciplinary arm of the General Medical Council.

Now, a review of 44 deceased cases, conducted by the Royal College of Physicians at the request of the regulator, the Regulation and Quality Improvement Authority (RQIA), has highlighted concerns over clinical decision-making, prescribing and diagnostics, the BBC reported.

It reveals a misdiagnosis rate of 45% among the group of 44 patients.

In several cases, a review of death certification, or referral to a medical examiner or coroner, was recommended, meaning coroners could be asked to reopen inquests.

That could mean the reopening of some cases by the coroner if he is approached by families to do so.

In a preface to the latest review, the RQIA’s chair, Christine Collins, said: “Family accounts starkly illustrate how failings by the individual practitioner, and by the system, led to deep human impacts and resulting harm, both to the deceased patients and to their bereaved families.”

In the wake of the 2018 recall, the Belfast health and social care trust set up special clinics so that the patients concerned – some as young as 14 – could have their condition reassessed as soon as possible.

The patients were being treated by Watt for conditions such as epilepsy, multiple sclerosis and motor neurone disease.

The trust apologised for the “significant anxiety” felt by the affected patients but said the move was necessary to ascertain if they were receiving the right treatment.

About one in five patients had to have their diagnoses changed.

The recall followed separate reviews into the notes detailing the care he provided to some people, which were undertaken by the trust and the Royal College of Physicians.

Watt ceased medical practice – through the trust or privately – in June 2017.

A review of the clinical records of 44 patients who died under the care of former neurologist Michael Watt has found "significant failures in their treatment" and "poor communication with families".

While this review looked at a sample of cases in which people died, potentially thousands more could be affected.

The review arises from a 2018 recall of 2,500 outpatients who were in Dr Watt's care at the Belfast Health Trust.

He worked there until 2017.

About one in five patients had to have their diagnoses changed.

This separate review into 44 deaths was conducted by the Royal College of Physicians (RCP) at the request of the regulator, the Regulation and Quality Improvement Authority (RQIA).

It highlighted concerns over clinical decision-making, prescribing and diagnostics.

It reveals a misdiagnosis rate of 45% among this group of patients, twice that for living patients.

Speaking to BBC News NI, the RQIA's chair, Christine Collins, said the outcome of the review was "shocking and gut-wrenching as so many had experienced unpleasant deaths which they ought not to have done".

In a litany of complaints, the panel said Michael Watt was often a poor record keeper, that he did not refer to patient notes which were often kept on scraps of paper and that cases were not taken seriously.

He was also found to be "rude and unhelpful".

The review into deaths was limited and has been likened to a pilot project.

Its terms of reference was also limited which meant the panel was confined to how much they could investigate.

It is also unprecedented as no other review on this scale has been carried out on patients in Northern Ireland who died under the care of one doctor.

In almost half the cases reviewed the panel did not consider the diagnosis to have been secure; also they noted in several cases the review of death certification, or referral to a medical examiner or coroner, was recommended.

Potentially that could mean the reopening of some cases by the coroner if he is approached by families to do so.

Briege Donaghy, the chief executive of the RQIA, said it was a "powerful report" which had "vindicated" the concerns of patients and relatives about some of the drugs that were incorrectly prescribed.

"They were boxed in, if you like, into a diagnosis that may not have been their actual condition and that led them down a pathway of treatments that were inappropriate, medications that were inappropriate - for some with devastating consequences," she told the BBC's Good Morning Ulster programme.

Ms Donaghy said the report "demands change" and people were now asking the RQIA to take action.

"Our questions in future must be more probing. They must get into the culture of an organisation and say to people who work there: 'Are you afraid to speak up? Are you supported to speak up? Are you working with colleagues that worry you - that you're concerned about their practice?'"

Colin Armstrong's late mother Ruth was misdiagnosed by Michael Watt in 2001 and prescribed medication for epilepsy.

"While I'm glad that the RCP have admitted that my mother did not have epilepsy... they have failed to investigate the potential impact on her health of the drugs she was prescribed," he said.

Mr Armstrong said the report was "limited in its scope" and was "just the beginning" of the work that needed to be done.

An independent inquiry and a separate review of those people who had died while in Michael Watt's care was launched in 2018.

Earlier this year, the inquiry found there were numerous failures, that opportunities were missed by the Belfast Trust to identify problems with the neurologist's practice and that earlier intervention by the trust would have "made a difference".

This latest review into deaths also identified concerns or omissions and their potential to lead to harm in almost half of the cases examined, including that some treatments were unnecessary and invasive.

Also in several cases, the review team believed patients had been "denied holistic supportive care that may have made their condition and ultimately end of life care, easier to manage".

In October last year, Dr Watt was removed from the medical register after he made a voluntary application - meaning allegations about his work could not be heard in a tribunal by the General Medical Council (GMC).

Since the launch of the inquiry in 2018, the focus has been on the experience of both patients and families.

Both the independent inquiry and the review of deceased patients found communication between Michael Watt was poor, as was communication with other consultants.

The panel found that the overriding theme of Dr Watt's clinical records tended to be "brief".

However, correspondence with private patients held in his private clinics was found to be a lot more "detailed".

A number of recommendations were made including:

  • That the RQIA will need to consider the implication of the finding that 14 of the 29 cases were found to be unsatisfactory for its wider consideration of the cases included in the recall of patients who died.
  • That the RQIA should consider the potential for harm arising from the concerns identified by the review team with respect to 13 patients' cases.

The PSNI said police were currently considering the findings of the various reviews and investigations, namely: the General Medical Council, The Royal College of Physicians, the RQIA and the Independent Neurology Inquiry.

"We will continue to liaise with the RQIA, Department of Health and Public Prosecution Service and will consider all relevant material before determining whether or not it will be necessary to conduct a formal investigation," a spokesperson said.

The Department of Health said the review's findings were "deeply concerning" and it apologised to the families affected "for the significant healthcare failings that have been identified".

It said that along with the RQIA, it would assess the findings to inform "next steps in the review of deceased patients' records".

At a glance - the Michael Watt controversy:

  • Michael Watt is a former neurology consultant who worked for more than 20 years at the Belfast Health and Social Care Trust
  • In May 2018, the trust recalled more than 2,500 of his patients for checks due to concerns about misdiagnosis
  • Three reviews were commissioned - one into the medical records of deceased patients; two examining governance arrangements within in the Belfast Trust and in private hospitals
  • In October 2018, the recall was extended to a further 1,044 patients
  • In December 2020, an independent inquiry into Dr Watt's work was converted into a statutory public inquiry
  • In April 2021, a review of 927 of Dr Watt's "high-risk" patients found almost 20% of them were given a wrong diagnosis.
  • In October 2021, Michael Watt succeeded in his request to be removed from the medical register