PURPOSE:Protein-altering gene variants in SEPSECS disrupt the biosynthesis of selenoproteins, leading to a spectrum of neurological diseases. METHODS:We studied 27 individuals with biallelic SEPSECS variants, identifying 13 unreported gene variants. To better understand and diagnose the disorder, broad biochemical correlation of neurological symptoms, focused metabolomics, and structural and in vitro activity analyses were deployed. RESULTS:Our results suggest three general clinical courses: (i) severe early-onset with cerebellar or cerebral atrophy, (ii) milder early-onset with gradual deterioration, and (iii) late-onset, mild disease. SEPSECS variants primarily affect the brain. In only one individual out of eight, thyroid hormone measurements suggested a defect of T4 to T3 conversion. Accompanied increase in glutathione and sulfur metabolites in plasma indicates elevated oxidative stress. Variants mapping to conserved N- and C-termini and catalytic site elicit SEPSECS misfolding, aggregation, thermal instability, and loss of function, that could ultimately lead to ferroptosis of neurons and perhaps oligodendrocytes. For differential diagnosis and monitoring therapeutic attempts, we recommend measuring levels of plasma selenium, glutathione and sulfur metabolites, GPX activity, and SELENOP. Given the pontine involvement in less than half of the cases, we suggest renaming the syndrome from PCH2D to SEPSECS-related neurodevelopmental disorder. CONCLUSION:Our study expands the understanding of SEPSECS-related neurodevelopmental disorders, highlighting the need for updated diagnostic criteria and potential treatment strategies.

Short-read genome sequencing (GS) is a powerful technique for investigating the genetic etiologies of rare diseases, capturing diverse genetic variations that are challenging to approach with exome sequencing (ES). We performed GS on 260 families with intellectual disability/developmental delay. GS detected potentially disease-related variants in 55 of the 260 families, with structural resolution by long-read sequencing or optical genome mapping, and functional assessment by RNA sequencing. Excluding 31 theoretically ES-resolvable cases, GS yielded likely pathogenic variants in 17 of 229 as well as variants of unknown significance in 7 of 229, totaling 10.5%. These variants implicated several new etiological mechanisms: a microduplication syndrome involving ATP6V0C; disturbed interactions of TBL1XR1 and NR2F1 with putative cis-regulatory elements by chromosomal rearrangements; and a CCG repeat expansion near the CHD3 transcription start site. This study highlights the critical role of GS in clinical diagnostics and its potential to advance understanding of genetic disorders.

This article reviews typical congenital dysplasias of the central nervous system (CNS) in childhood. A wide variety of CNS dysplasias is known. Symptoms in infancy are often nonspecific, and include psychomotor retardation and epilepsy. Brain imaging and genetic studies are important for definitive diagnosis. Although there is no established treatment for congenital CNS dysplasia, a significant number of people with childhood-onset congenital CNS dysplasia reach adulthood. It is hoped that clinicians who treat adults will provide comprehensive support for these patients who have reached the age of adulthood.

Interferon regulatory factor 2 binding protein-like (IRF2BPL) is a single-exon gene that is ubiquitously expressed in various tissues, including the brain. IRF2BPL encodes a transcription factor with two zinc-finger domains that potentially downregulate WNT signaling in the nervous system. Pathogenic IRF2BPL variants have been reported to cause developmental delay, seizures, myoclonus epilepsies, autistic spectrum disorder, and other neurodevelopmental disorders. Exome sequencing of 10 patients with developmental delay and/or epilepsy from nine families revealed nine pathogenic IRF2BPL variants, of which eight were novel: five missense, one in-frame indel, and three truncating variants. Using reported pathogenic and benign variants, we highlight here several regions of IRF2BPL that deviate in the frequency of pathogenic and benign variants. This study of detailed clinical and genetic information shows that IRF2BPL missense and in-frame indel variants are often associated with seizures and developmental delay.

We reviewed published articles on representative inherited cerebral white matter disorders that develop in childhood. In this paper, we described demyelinating disorders (adrenoleukodystrophy, globoid cell leukodystrophy or Krabbe disease, and metachromatic leukodystrophy), astrocytic disorders (Alexander disease and vanishing white matter disease), and disorders of water homeostasis in the myelin sheath (megalencephalic leukoencephalopathy with subcortical cysts and CLCN2-related leukoencephalopathy). The causes, symptoms, diagnostic imaging, and forefront of treatment for these disorders are discussed. Each disease is rare and progressive. Although the number of analyzed cases is very small, establishing a radical treatment is still necessary. We do hope that the patients with these disorders could be treated completely in the near future.

Duchenne muscular dystrophy (DMD) is a severe muscle disorder caused by mutations in the DMD gene, leading to dystrophin deficiency. Antisense oligonucleotide (ASO)-mediated exon skipping offers potential by partially restoring dystrophin, though current therapies remain mutation specific with limited efficacy. To overcome those limitations, we developed brogidirsen, a dual-targeting ASO composed of two directly connected 12-mer sequences targeting exon 44 using phosphorodiamidate morpholino oligomers. An open-label, dose-escalation, phase 1/2 trial assessed the safety, pharmacokinetics, and efficacy of brogidirsen in six ambulant patients with DMD amenable to exon 44 skipping. Following dose escalation, extended 24-week treatment with 40 mg/kg and 80 mg/kg yielded dose-dependent increases in dystrophin (16.63% and 24.47% of normal). Functional assessments indicated motor stabilization, and plasma proteomics revealed reductions in peptidyl arginine deiminase 2 (PADI2), titin (TTN), and myomesin 2 (MYOM2), highlighting potential biomarkers. Brogidirsen’s efficacy was supported in vitro using urine-derived cells from patients with DMD. These promising results warrant a subsequent trial for DMD. This study was registered at ClinicalTrials.gov (NCT04129294).

Introduction: SATB1 encodes a protein of the same name, and its genetic alteration causes SATB1 (special AT-rich sequence-binding protein 1) dysfunction, which clinically presents as developmental delay, intellectual disability, facial features, and epilepsy. However, detailed clinical information, especially regarding respiratory disorders, has not yet been fully described.Case Presentation: We report the case of a 3-year-old Japanese girl with a de novo variant of SATB1, c.1588G > A:p.(Glu530Lys), who presented with a frequent breath-holding and hyperventilation while awake, in addition to typical phenotype. The long-term EEG showed no corresponding epileptiform changes, and breath-holding was considered non-epileptic rather than epilepsy, such as ictal central apneas. Valproic acid and acetazolamide alleviated breath-holding; however, it was intractable.Conclusion: Respiratory disorders were thought to be non-epileptic, not reported in SATB1 disorders, and were resistant to treatment. The case was considered critical and may provide new research clues to this severe and not yet fully understood phenomenon.

BACKGROUND:The identification of surgical candidates is a critical issue in patients with magnetic resonance imaging (MRI)-negative drug-resistant focal epilepsy and latent accompanying resectable lesions, such as focal cortical dysplasia (FCD). Recently, periodic seizure cycles have been associated with FCD in both patients with MRI-positive and MRI-negative epilepsy. We investigated the presurgical evaluation and postsurgical outcome of patients with MRI-negative epilepsy with FCD and a history of periodic seizure cycles. METHODS:We retrospectively reviewed the characteristics of presurgical evaluation and postsurgical seizure outcome in 14 children with MRI-negative drug-resistant focal epilepsy and a history of periodic seizure cycles. All the patients had FCD histopathologically. RESULTS:The mean age at epilepsy surgery was 7.7 ± 4.7 years (0.7-16.1 years). Favorable postsurgical seizure outcome (ILAE classes 1-3) was obtained in 10 (71 %) patients five years after surgery. The relative risk of the complete concordance between imaging findings and resected area for five-year seizure freedom was 2.25 in positron emission tomography (PET) and 2.22 in subtraction ictal single-photon emission computed tomography co-registered to MRI (SISCOM), and 1.86 in magnetoencephalography (MEG). CONCLUSION:All the children with MRI-negative focal epilepsy and a history of periodic seizure cycles were turned out to have FCD pathologically, and are good surgical candidates. Favorable seizure outcome can be expected in such patients when resective epilepsy surgery is planned based on presurgical evaluation with PET or SISCOM.

Background: Two preclinical studies using mouse models of Pelizeaus-Merzbacher disease (PMD) have revealed the potential therapeutic effects of curcumin. In this study, we examined the effects of curcumin in patients with PMD.Methods: We conducted a study administering an open-label oral bioavailable form of curcumin in nine patients genetically confirmed to have PMD (five to 20 years; mean 11 years) for 12 months (low doses for two months followed by high doses for 10 months). We evaluated changes in clinical symptoms as the primary end point using two scales, Gross Motor Function Measure (GMFM) and the PMD Functional Disability Score (PMD-FDS). The level of myelination by brain magnetic resonance imaging (MRI) and the electrophysiological state by auditory brainstem response (ABR) were evaluated as secondary end points. The safety and tolerability of oral curcumin were also examined. Results: Increase in GMFM and PMD-FDS were noted in five and three patients, respectively, but overall, no statistically significant improvement was demonstrated. We found no clear improvement in their brain MRI or ABR. No adverse events associated with oral administration of curcumin were observed.Conclusions: Although we failed to demonstrate any significant therapeutic effects of curcumin after 12 months, its tolerability and safety were confirmed. This study does not exclude the possibility of therapeutic effects of curcumin, and a trial of longer duration should be considered to compare the natural history of the disease with the effects of curcumin.(c) 2023 Elsevier Inc. All rights reserved.

OBJECTIVE AND RATIONALE:To investigate the longitudinal incidence of kidney/urinary stones in patients with severe motor and intellectual disabilities and explore health burden events in patients with stone formation. METHODS:This was a retrospective, observational study. We identified patients with severe motor and intellectual disabilities who had the following: 1) admission to our hospital wards for >10 years; 2) two or more assessments for stone formation by ultrasonography or computed tomography; and 3) absence of kidney/urinary stones in the first imaging study. The Kaplan-Meier method was used to analyze the cumulative incidence of kidney/urinary stones. Recurrent urinary tract infections, hydronephrosis, renal dysfunction, and death were identified as health burdens. RESULTS:Among the 41 patients (19 men, 22 women; median age, 28 years; range, 8-50 years), stone formation was detected in 11 (27%) patients during the observation period. The cumulative incidence rate of stone formation was 9.8% (95% confidence interval, 3.8-23.9) and 18.7% (95% confidence interval, 9.2-35.7) at five and 10 years, respectively. Death was frequently observed in patients with stone formation; six (55%) of the 11 patients with stone formation died during the follow-up period; two (15%) died among the other 30 patients without stone formation. However, only one patient with stone formation died in a renal event; the causal relationship between the stone formation and the deaths was not clarified. CONCLUSION:The longitudinal incidence of kidney/urinary stones was higher in patients with severe motor and intellectual disabilities than in the general population. Considering the difficulty of patients with severe motor and intellectual disabilities in conveying their symptoms, regular assessment of the kidney using abdominal imaging may be recommended.

OBJECTIVE:This study aimed to investigate the clinical characteristics of pediatric-onset dystonia in Japan, addressing the diagnostic challenges arising from symptom variations and etiological diversity. METHODS:From 2020 to 2022, questionnaires were distributed to 1218 board certified child neurologists (BCCNs) by Japanese Society of Child Neurology. In the primary survey, participants were asked to report the number of patients with pediatric-onset dystonia under their care. Subsequently, the follow-up secondary survey sought additional information on the clinical characteristics of these patients. RESULTS:The primary survey obtained 550 responses (response rate: 45 %) from BCCNs for their 736 patients with dystonia. The predominant etiologies included inherited cases (with DYT10 being the most prevalent, followed by DYT5 and ATP1A3-related neurologic disorders), acquired cases (with perinatal abnormalities being the most common), and idiopathic cases. The secondary survey provided clinical insights into 308 cases from 82 BCCNs. Infancy-onset dystonia presented as persistent and generalized with diverse symptoms, primarily linked to ATP1A3-related neurologic disorders and other genetic disorders resembling acquired dystonia. Conversely, childhood/adolescent-onset dystonia showed paroxysmal, fluctuating courses, predominantly affecting limbs. The most common etiologies were DYT5 and DYT10 , leading to therapeutic diagnoses. CONCLUSION:Pediatric-onset dystonia in Japan was treated by 28 % of BCCNs. The majority of cases were inherited, with high prevalence rates of DYT5 and DYT10 . Infancy-onset dystonia exhibits diverse etiologies and symptoms, emphasizing the utility of various examinations, including genetic testing. These findings significantly contribute to our understanding of pediatric-onset dystonia in Japan, although this study has the limitation of questionnaire survey.

Introduction/Aims: Merosin is a protein complex located in the basement membrane of skeletal muscles and laminin alpha 2-containing regions of the central and peripheral nervous systems. However, because of the prominence of muscle-related symptoms, peripheral neuropathy associated with merosin-deficient congenital muscular dystrophy type 1A (MDC1A) has received little clinical attention. This study aimed to present pathological changes in intramuscular nerves of three patients with MDC1A and discuss their relationship with electrophysiological findings to provide new evidence of peripheral nerve involvement in MDC1A.Methods: MDC1A was confirmed by clinical features, muscle biopsy, and genetic testing for variants in LAMA2. To clarify peripheral nerve involvement, we statistically evaluated electrophysiological and muscle pathology findings of intramuscular nerves. These findings were compared with those of age-matched boys with Duchenne muscular dystrophy (DMD) as controls with normal nerves. Nerve conduction studies (NCS) were performed before biopsy. Biopsied intramuscular nerves were examined with electron microscopy using g-ratio, which is the ratio of axon diameter to myelinated fiber diameter.Results: The myelin sheaths were significantly thinner in MDC1A patients than in age-matched DMD patients, with a mean g-ratio of 0.76 +/- 0.07 in MDC1A patients and 0.65 +/- 0.14 in DMD patients (p < .0001). No neuropathic changes were identified in muscle pathology. Low compound muscle action potential amplitudes, positive sharp waves and fibrillation potentials, and low-amplitude motor unit potentials with increased polyphasia indicated myopathic changes; no neurogenic changes were seen.Discussion: We postulate that the thin myelin associated with MDC1A reflects the role of merosin in myelin maturation.

Duchenne muscular dystrophy (DMD) is a severe muscle disorder caused by mutations in the DMD gene, resulting in dystrophin loss. Exon-skipping using antisense oligonucleotides (ASO) is a promising approach that partially restores dystrophin by correcting the frameshift during pre-mRNA splicing. However, a weakness of the current approach is that it is mutation-specific and has poor efficacy. To address these, we aim to develop brogidirsen, a new dual-targeting ASO that targets two sequences in exon 44 of the DMD using phosphorodiamidate morpholino oligomer. Here, we conducted an open-label, dose-escalation, Phase I/II trial to evaluate the safety, pharmacokinetics, and activity of brogidirsen, administered intravenously to six ambulant patients with DMD amenable to exon 44 skipping. The study consisted of a dose-escalation part to determine the optimal doses, followed by extended treatment with 40 mg/kg or 80 mg/kg weekly dose for 24 weeks. There were no serious adverse events related to brogidirsen. The results indicated a dose-dependent increase in dystrophin levels, reaching 10.27% and 15.79% of the normal level in the two cohorts. Motor functional tests suggested a trend toward maintaining or slightly improving motor function. There was a dose-dependent increase in Cmax and AUC0-t. High-throughput proteomic assays revealed that serum proteins such as PADI2, TTN, MYOM2, and MYLPF were observed to reduce, suggesting them as biomarkers for therapeutic effects. Notably, in vitro assays using urine-derived cells from patients with DMD support brogidirsen's high efficacy in the first-in-human studies. These promising results warrant a subsequent multinational trial for DMD. ### Competing Interest Statement H.K. received consulting fees from Nippon Shinyaku for work related to this study and from Biogen, Novartis, Sanofi, Sarepta, Chugai, Daiichi Sankyo, Kaneka, and Astellas for work unrelated to this study. H.K. received grant funding from Nippon Shinyaku for work related to this study and from Sanofi, Chugai, PTC Therapeutics, Taiho, and Pfizer for work unrelated to this study. E.T. received grant funding from Nippon Shinyaku for work related to this study and from Daiichi Sankyo, Taiho, and Takeda for work unrelated to this study. Y.A. received grant funding from Nippon Shinyaku for work associated with this study and from Shionogi, Takeda, and Kaneka for work unrelated to this study. K.K., T.I., Y.S-M., A.I., M.S., C.Y., S.M., and E.H. have no competing interests to declare. ### Clinical Trial NCT04129294 ### Clinical Protocols ### Funding Statement grants from the Japan Agency for Medical Research and Development (AMED), Japan awarded to Y.A. (18lm0203066h0001, 21lm0203086h0003), ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study complied with the ethical principles of the Declaration of Helsinki and all applicable Japanese local and national regulatory laws. The study protocol and related documentation were approved by the Institutional Review Board of the National Center of Neurology and Psychiatry, Tokyo, Japan (approval number II-012). The study was registered at clinicaltrials.gov ([NCT04129294][1]) and the University Hospital Medical Information Network (UMIN000038505). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04129294&atom=%2Fmedrxiv%2Fearly%2F2024%2F08%2F30%2F2024.08.28.24312624.atom

Background: ST3GAL5 encodes GM3 synthase (ST3 beta-galactoside alpha-2,3-sialyltransferase 5; ST3GAL5), which synthe-sizes GM3 by transferring sialic acid to lactosylceramide. GM3, a sialic acid-containing glycosphingolipid known as ganglioside, is a precursor to the biosynthesis of various more complex gangliosides that are active in the brain. Biallelic variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD), a rare congenital disorder of glycosylation. GM3SD was first identified in the Amish population in 2004.Case: We report two siblings diagnosed with GM3SD due to novel compound heterozygous ST3GAL5 variants. The novel ST3GAL5 variants, detected by whole-exome sequencing in the patients, were confirmed to be pathogenic by GM3 synthase assay. The clinical courses of these patients, which began in infancy with irritability and growth failure, followed by developmental delay and hearing loss, were consistent with previous case reports of GM3SD. The older sibling underwent deep brain stimulation for severe involuntary movements at the age of 9 years. The younger sibling suffered from acute encephalopathy at the age of 9 months and subsequently developed refractory epilepsy.Discussion: Reports of GM3SD outside the Amish population are rare, and whole-exome sequencing may be required to diag-nose GM3SD in non-Amish patients. Since an effective treatment for GM3SD has not yet been established, we might select deep brain stimulation as a symptomatic treatment for involuntary movements in GM3SD.(c) 2023 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. All rights reserved.

BACKGROUND AND PURPOSE:Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by ATP1A3 mutations. Using voxel-based morphometry (VBM) analysis, we compared an AHC patient cohort with controls. Additionally, with single-case VBM analysis, we assessed the associations between clinical severity and brain volume in patients with AHC.MATERIALS AND METHODS:To investigate structural brain changes in gray matter (GM) and white matter (WM) volumes between 9 patients with AHC and 20 age-matched controls, VBM analysis was performed using three-dimensional T1-weighted magnetic resonance imaging. Single-case VBM analysis was also performed on nine patients with AHC to investigate the associations between the respective volumes of GM/WM differences and the motor level, cognitive level, and status epilepticus severity in patients with AHC.RESULTS:Compared with controls, patients with AHC showed significant GM volume reductions in both hippocampi and diffuse cerebellum, and there were WM reductions in both cerebral hemispheres. In patients with AHC, cases with more motor dysfunction, the less GM/WM volume of cerebellum was shown. Three of the six cases with cognitive dysfunction showed a clear GM volume reduction in the insulae. Five of the six cases with status epilepticus showed the GM volume reduction in hippocampi. One case had severe status epilepticus without motor dysfunction and showed no cerebellar atrophy.CONCLUSION:With single-case VBM analysis, we could show the association between region-specific changes in brain volume and the severity of various clinical symptoms even in a small sample of subjects.

Background: Meningoencephalocele (ME) of the temporal lobe through a bone defect in the middle cranial fossa is a rare known cause of refractory temporal lobe epilepsy (TLE). ME-induced drug-resistant TLE has been described in adults; however, its inci-dence in children is very rare.Case report: A 7-year-old girl presented at our hospital with brief episodes of impaired consciousness and enuresis. Initial brain MRI results were interpreted as normal. Her seizures could not be controlled even with multiple anti-seizure medications. She was diagnosed with drug-resistant TLE, which presented with prolonged impaired awareness seizures for 30-60 s and secondary bilateral tonic seizures. At 9 years of age, brain MRI revealed a left temporal anteroinferior ME with a congenital bone defect in the left middle cranial fossa. She was referred for presurgical epilepsy evaluation. Long-term video electroencephalography (EEG) failed to reveal regional abnormality in the left temporal lobe; invasive evaluation using stereoelectroencephalography (SEEG) was thus indicated. Ictal onset SEEG was identified in the temporal pole near the ME which was rapidly propagated to the mesial temporal struc-tures and other cortical regions. The left temporal pole including the ME was micro-surgically disconnected while preserving the hippocampus and amygdala. The patient's seizures have been completely controlled for 1 year and 6 months post-operatively.Conclusion: SEEG revealed rapid propagation of ictal activity in this patient's case, confirming that the ME was epileptogenic. Since the majority of patients with refractory epilepsy caused by ME have favorable postoperative seizure outcomes, it is important to carefully check for ME in drug-resistant TLE patients with apparently normal MRI.(c) 2022 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.

Background: Heterozygous KCNQ2 variants cause benign familial neonatal seizures and early-onset epileptic encephalopathy in an autosomal dominant manner; the latter is called KCNQ2 encephalopathy. No case of KCNQ2 encephalopathy with arthrogry-posis multiplex congenita has been reported. Furthermore, early-onset scoliosis and opisthotonus have not been documented as characteristics of KCNQ2 encephalopathy.Case report: A male infant born with scoliosis and arthrogryposis multiplex congenita developed intractable epilepsy on the sec-ond day of life. At 4 months of age, he developed opisthotonus. The opisthotonus was refractory to medication in the beginning, and it spontaneously disappeared at 8 months of age. Whole-exome sequencing revealed a novel de novo heterozygous variant in KCNQ2, NM_172107.4:c.839A > C, p.(Tyr280Ser).Conclusions: Early-onset scoliosis, arthrogryposis multiplex congenita, and opisthotonus may be related to KCNQ2 encephalopathy.(c) 2022 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. All rights reserved.

Suppression‐burst (SB) is an electroencephalographic pattern observed in neonatal‐ and infantile‐onset developmental and epileptic encephalopathies (DEEs), which are associated with high mortality in early life. However, the relation of SB electroencephalogram (SB‐EEG) with autonomic function requires clarification. We investigated the relationship between heart rate (HR) and phasic transition during SB‐EEG in DEEs to explore the mechanism of early death. Seven patients (two with KCNT1 ‐DEE) with neonatal‐ and infantile‐onset DEE who presented with SB‐EEG were retrospectively identified. Five‐minute SB‐EEGs were analyzed with simultaneous recording of electrocardiograms. Mean HR, suppression duration, and burst period were calculated by measuring RR intervals. Two patients with KCNT1 ‐DEE exhibited synchronous HR fluctuations, with an HR decrease during suppression and an increase during burst. The HR decrease was larger (−6.1% and −7.7%) and the median duration of suppression was longer (4.0 and 8.2 s) in patients with KCNT1 ‐DEE than the other five (range: −2.9% to 0.9% and 0.7‐1.7s, respectively). A strong negative correlation was confirmed between suppression duration and HR reduction rates in one patient with KCNT1 ‐DEE. SB phases may influence HR regulation in patients with KCTN1 ‐DEE.

Background: Real-world data have shown variability in treatment responses to nusinersen in spinal muscular atrophy (SMA). We investigated whether the magnitude of muscle impairment assessed by magnetic resonance imaging (MRI) at baseline can predict the treatment response. Methods: We retrospectively assessed the clinical data in relevance to the thigh and pelvic MRI taken before the nusinersen treat-ment. A total of 16 patients with SMA types 2 and 3 (age = mean [SD]; 9.2 [4.6] year) receiving nusinersen treatment were enrolled. The T1-weighted MRI images of the pelvis and thigh were scored for muscle fatty infiltration and atrophy. The minimally clinically important difference (MCID) was considered as gaining at least 3 points of Hammersmith Functional Motor Scale-Expanded (HFMSE) from baseline. Results: Of these 16 individuals, 14 had been treated for at least 15 months with baseline data. At 15 months, seven individuals obtained MCID in HFMSE. Baseline muscle MRI score could not differentiate the two groups; however, individuals who obtained MCID had significantly less severe scoliosis. In addition, there was a significant and negative relationship between baseline MRI score and the change of score in HFMSE after 15 months of treatment. Further, baseline Cobb angle along with MRI score also indicated the correlation to the degree of change in motor function.Conclusion: The degree of muscle damage may confer the variability in response to nusinersen in SMA types 2 and 3. Muscle MRI score along with the severity of scoliosis assessed at baseline may help to predict the motor function change. (c) 2022 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

KCNB1 encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1–S6), comprising the voltage-sensing domain (S1–S4) and the pore domain (S5-P-S6). Heterozygous KCNB1 pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novo KCNB1 variant c.574G>A, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of −50 to −30 mV. Our case could expand the phenotypic spectrum of patients with KCNB1 variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.