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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder and the most debilitating condition of heterotopic ossification in humans. Misdiagnosis is common and they suffer from complications of incorrect diagnosis and subsequent inappropriate treatment hence, to create awareness, we are reporting a genetically confirmed case of FOP. A 10-year-old boy, born to a non-consanguineously married couple, presented with progressive stiffness of the neck, back, and limbs with restriction of movements. Examination showed two firm non-tender immobile swellings over the back with scoliosis towards the left side. A bilateral hallux valgus deformity with restricted movements of the great toe was noted. Outside treated as mixed connective tissue disorder without any improvement. The X-ray showed calcifications in the swellings. Genetic testing showed the pathogenic variant in the activin A receptor type 1 gene. The FOP should be considered in children presenting with progressive stiffness, deformity of the feet, and ectopic ossifications to avoid misdiagnosis and inappropriate treatment.

Objectives: Movement disorders are common neurological problems. There is a considerable delay in the diagnosis of movement disorders which indirectly indicates their under-recognition. The studies regarding relative frequencies and their underlying etiology are limited. Describing and classifying them with a diagnosis helps in treating the condition. To study the clinical pattern of various movement disorders in children and to establish their etiology and outcome. Materials and Methods: This observational study was conducted in tertiary care hospital from January 2018 to June 2019. Children from 2 mo. to 18 years of age presenting with involuntary movements on the first Monday of every week were included in the study. History and clinical examination were carried out with a pre-designed proforma. A diagnostic workup was done, results were analyzed to find the common movement disorders and their etiology, and follow-up was analyzed for 3 years. Results: A total of 100 cases out of 158 with known etiology were included in the study of which 52% were females and 48% were males. The mean age at presentation was 3.15 years. The various movement disorders are dystonia-39(39%), choreoathetosis-29(29%), tremors-22(22%), gratification reaction-7(7%), and shuddering attacks-4(4%). Ballismus and myoclonus were found in 3(3%) children each. Tics, stereotypes, and hypokinesia were found in 2(2%) children each. A total of 113 movement disorders were found in 100 children. Etiologically, perinatal insult was the most common cause 27(27%), followed by metabolic/genetic/hereditary causes 25(25%). Infantile tremor syndrome due to Vitamin B12 deficiency-16/22(73%), was a major contributor in children with tremors. Rheumatic chorea was less in our study 5(5%). Out of the 100 study subjects, 72 cases were followed up. Out of which 26 children have completely recovered. Based on the modified Rankins score(MRS), 7 children belong to category I, 2 children belong to category II, 1 child to category III, 6 children to category IV, and 14 children to category V of MRS. A total of 16 children have died (MRS VI). Conclusion: Perinatal insult and Infantile tremor syndrome are more important and preventable causes. Rheumatic chorea is found to be less common. A significant number of children had more than one type of movement disorder, which warrants the need to look for varied types of movement disorders in the same child. Long-term follow-up shows complete recovery in one-fourth of children and the remaining surviving with disability.

Galactosaemia is a group of autosomal recessive metabolic disorders characterised by increased blood levels of galactose. It is characterised by cataracts, organomegaly, sepsis and developmental delay. We are reporting a case of galactosaemia presenting as a neurodegenerative disease with a leukodystrophy-like presentation. An 11-month-old boy born to a second-degree consanguineously married couple presented with developmental delay, vomiting, lethargy and refusal of feeds. Examination showed normocephaly, cataract, hepatomegaly and spasticity in all limbs with exaggerated deep tendon reflexes. Magnetic resonance imaging (MRI) of the brain was suggestive of diffuse hyperintensities in periventricular, subcortical and deep white matter on T2WI. Plasma galactose levels were high (3784.0 u M/L) and the RBC Galactose 1-Phosphate uridylyltransferase (GALT) enzyme was low (T (p.Ser143Leu) in exon 5 of the GALT gene. For any child who presents with cataracts, hepatomegaly, developmental delay and leukodystrophy picture on an MRI of the brain, a treatable cause of galactosaemia should be considered.

Background Nearly 30% of patients with epilepsy are refractory to currently available antiseizure drugs (ASDs). Although the U.S. Food and Drug Administration approved perampanel (PER) for patients as young as 4 years, there are limited data on using PER in children. Objective The aim of this study was to determine the efficacy and tolerability of adjunctive PER treatment in children with refractory epilepsy (RE). Methodology This prospective intervention study was conducted in the tertiary care center, in Bengaluru, India from December 2020 to May 2022. PER was added after the failure of a minimum of two ASDs and patients with 6 months follow-up. Treatment response was classified as complete, partial, or none with ≥90, ≥50, and Results Our cohort consisted of 100 cases, a mean age of 9.3 ± 3.8 years and male:female ratio of 3:1. The predominant seizure type was generalized seizures (74%), and concomitant enzyme-inducing ASD use was noted in 27%. Structural etiology was noted in 57%. A total of 76% of participants responded to PER therapy (46% complete response and 30% partial response), while 23% showed no response and 1% discontinued the treatment. Adverse events were observed in 25% of participants (11/25 [44%] drowsiness/sedation, 10/25 [40%] behavioral problems, and 4 [16%] other side effects). Early PER add-on provided a statistically significant benefit over late PER add-on (p = 0.01). Response to PER did not differ significantly with the type of seizure and ASD used (p > 0.05). Conclusion Adjunctive PER therapy is safe and effective for treating children with RE. An early add-on of PER is more beneficial in controlling seizures than a late add-on.

Acute necrotizing encephalitis of childhood (ANEC) is characterized by respiratory or gastrointestinal infection and high-grade fever accompanied by rapid alteration of consciousness and seizures. Diagnosis is based on clinical presentation and characteristic neuroimaging features. The aim of this study was to report the etiological, clinical, and radiological findings and therapeutic outcomes of ANEC. This is a retrospective chart review of children aged 1 month to 18 years diagnosed with ANEC, from January 2017 to May 2022 at a tertiary care center in Bangalore, India. Of 36 patients, 17 were males, with age ranging from 10 months to 15 years. Major presenting complaints were altered sensorium in 36 (100%), fever in 33 (91.6%), and seizures in 27 (75%). The etiologies included dengue and chikungunya in 2 (5.5%) cases, Japanese encephalitis, influenza, and RAN binding protein 2 (RANBP2) in 1 (2.7%) case each, and unknown in 29 (80.5%) cases. Common findings of the magnetic resonance imaging (MRI) of the brain were abnormal signals in thalami in 20/20 (100%) and in brainstem in 11/20 (55%). Computed tomography (CT) of the brain done in all 16 cases showed thalamic hypodensities. All patients received empiric antibiotics, antivirals, and intravenous methylprednisolone. The modified Rankin scale showed excellent outcomes in 19/25 (76%), 3 were bedridden (8.3%), and 3 died (8.3%). ANEC is common in children under 5 years of age (76.7%). Altered sensorium, fever, and seizures were the main presenting symptoms. Genetic testing must be done in case of family history and recurrence. CT brain is also very useful in an emergency setup; MRI brain can be useful to suspect and prognosticate.

Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents during the neonatal or early infantile period with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay and dysarthria. We present a 7-year-old female born to a nonconsanguineous marriage with developmental delay. On examination, she had 22 teeth, and nystagmus with pseudophakia. Neurological examination showed spasticity with increased deep tendon reflexes. On investigation, MRI of the brain done at 3 years showed hypomyelination. Targeted exome sequencing revealed a homozygous non-synonymous variation c.138C>G in exon 2 of the GJC2 gene. Sanger sequencing was done which showed the presence of a variant in the heterozygous state in both parents. PMLD1 should be suspected in any child presenting with diffuse hypomyelination with abnormal eye movements, especially in a girl child with PelizaeusMerzbacher disease phenotype with hypomyelination in the pons.

Data de publicació electrònica: 04-04-2022 Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Funding: most families were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This study was also supported by JSPS/MEXT KAKENHI (Grants 19H03331, 19K22439 and 21K19390 to Y.F., Grant 19K16269 to Y.M., and Grants 20H00459 and 20H04915 to M.F.) and Japan Agency for Medical Research and Development (21wm0525022h0001 to Y.F.); intramural funding (fortüne) from the University of Tübingen (Grant 2545-1-0) and the Ministry of Science, Research and Art Baden-Württemberg to B.V. P.S. contributed to this work within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). T.B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 418081722, 433158657. I.S.P., V.Y.V. are supported by the Government Assignment of the Russian Ministry of Health (#121061500066-2). HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). S.H. is funded by TUBITAK (Turkish Scientific and Technological Research Council) Project number 216S771. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who received support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)

Purpose: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype–phenotype correlations in individuals with biallelic SLC18A2 variants. Methods: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype–phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. Results: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. Conclusion: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders. © 2022 American College of Medical Genetics and Genomics, National Institutes of Health, NIH: T32 GM007526-42; National Heart, Lung, and Blood Institute, NHLBI; National Human Genome Research Institute, NHGRI: K08 HG008986; National Institute of Neurological Disorders and Stroke, NINDS: R35NS105078; International Rett Syndrome Foundation, IRSF: 3701-1; Muscular Dystrophy Association, MDA: 512848; American Brain Foundation, ABF; American Academy of Neurology, AAN; Takeda Science Foundation, TSF; Japan Agency for Medical Research and Development, AMED: JP22ek0109486, JP22ek0109493, JP22ek0109549; Horizon 2020 Framework Programme, H2020; Muscular Dystrophy UK, MDUK; Multiple System Atrophy Trust, MSAT; Brain Research UK, BRUK; Baylor-Hopkins Center for Mendelian Genomics, BHCMG: UM1 HG006542; Medical Research Council, MRC: G0601943, MR/S005021/1, MR/S01165X/1; Ataxia UK; European Research Council, ERC; Rosetrees Trust; Great Ormond Street Hospital Charity, GOSH; Japan Society for the Promotion of Science, KAKEN: JP19H03621, JP20K07907, JP20K08164, JP20K16932, JP20K17936, JP21k15907; Horizon 2020: 714853, MC-A658-5TY30; University College London Hospitals Biomedical Research Centre, UCLH BRC; King Salman Center for Disability Research, KSCDR: RG-2022-010, We thank the participants and their families for their involvement in this study. This work was supported by the Japan Agency for Medical Research and Development ( AMED ) under grant numbers JP22ek0109486, JP22ek0109549, and JP22ek0109493 (N.Ma.); Japan Society for the Promotion of Science ( JSPS) KAKENHI under grant numbers JP19H03621 (N.Mi.), JP20K07907 (S.M.), JP20K08164 (T.Miz.), JP20K17936 (A.F.), JP20K16932 (K.H.), and JP21k15907 (Y.U.); and the Takeda Science Foundation (T.Miz., N.Mi., and N.Ma.). This study was partially supported by the US National Human Genome Research Institute and National Heart Lung and Blood Institute to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542 to J.R.L.), US National Institute of Neurological Disorders and Stroke (R35NS105078 to J.R.L.), and Muscular Dystrophy Association (512848 to J.R.L.). D.Ma. was supported by a Medical Genetics Research Fellowship Program through the National Institutes of Health (T32 GM007526-42). D.P. was supported by a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology , American Brain Foundation , and Muscle Study Group and by the International Rett Syndrome Foundation (grant number #3701-1). J.E.P. was supported by the National Human Genome Research Institute (K08 HG008986). H.H. was funded by the Medical Research Council ( MRC) (MR/S01165X/1, MR/S005021/1, and G0601943), NIHR University College London Hospitals Biomedical Research Centre , Rosetree Trust, Ataxia UK , Multiple System Atrophy Trust , Brain Research UK , Sparks Great Ormond Street Hospital Charity , Muscular Dystrophy UK , and Muscular Dystrophy Association . N.D. was supported by an MRC strategic award to establish International Centre for Genomic Medicine in Neuromuscular Diseases (MR/S005021/1). This project also received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement number 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. We acknowledge the support of King Salman Center for Disability Research through Research Group no RG-2022-010 (F.S.A.). Figure 1A, 2A, and Graphical Abstract were created with BioRender.com ., We thank the participants and their families for their involvement in this study. This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP22ek0109486, JP22ek0109549, and JP22ek0109493 (N.Ma.); Japan Society for the Promotion of Science (JSPS) KAKENHI under grant numbers JP19H03621 (N.Mi.), JP20K07907 (S.M.), JP20K08164 (T.Miz.), JP20K17936 (A.F.), JP20K16932 (K.H.), and JP21k15907 (Y.U.); and the Takeda Science Foundation (T.Miz., N.Mi., and N.Ma.). This study was partially supported by the US National Human Genome Research Institute and National Heart Lung and Blood Institute to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542 to J.R.L.), US National Institute of Neurological Disorders and Stroke (R35NS105078 to J.R.L.), and Muscular Dystrophy Association (512848 to J.R.L.). D.Ma. was supported by a Medical Genetics Research Fellowship Program through the National Institutes of Health (T32 GM007526-42). D.P. was supported by a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology, American Brain Foundation, and Muscle Study Group and by the International Rett Syndrome Foundation (grant number #3701-1). J.E.P. was supported by the National Human Genome Research Institute (K08 HG008986). H.H. was funded by the Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1, and G0601943), NIHR University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, Multiple System Atrophy Trust, Brain Research UK, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy UK, and Muscular Dystrophy Association. N.D. was supported by an MRC strategic award to establish International Centre for Genomic Medicine in Neuromuscular Diseases (MR/S005021/1). This project also received funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Program (grant agreement number 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. We acknowledge the support of King Salman Center for Disability Research through Research Group no RG-2022-010 (F.S.A.). Figure 1A, 2A, and Graphical Abstract were created with BioRender.com.

Gama aminobutyric acid (GABA) transaminase deficiency is an autosomal recessive disorder caused by mutations in the 4-aminobutyrate aminotransferase (ABAT) gene. The disorder is characterised by epileptic encephalopathy, hypersomnoloscnec, movement disorders, and tone changes. Here, we report a 4-year-6-month-old boy child born to non-consanguineous marriage with a normal birth history presented with global developmental delay, refractory seizures, and increased sleep. On examination showed normal anthropometry with mild dysmorphism. Neurological examination showed autistic features and spasticity with brisk deep tendon reflexes. On investigation, electroencephalography showed multifocal epileptiform discharges with secondary generalisation, and magnetic resonance imaging of the brain showed mild hyperintensity of the superior cerebellum. Exome sequencing identified compound heterozygous variants in the ABAT gene and segregates with the condition in the family. The child was treated with antiseizure medications and responded partially. For any child with excessive sleep on the background of epileptic encephalopathy with a movement disorder, a diagnosis of GABA transaminase deficiency has to be considered.

On behalf of Queen Square Genomics On behalf of Genomics England Research Consortium; International audience; Purpose: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.Methods: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.Results: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.Conclusion: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.

Malate dehydrogenases (MDH) serve a critical role in maintaining equilibrium of the NAD+/NADH ratio between the mitochondria and cytosol through the catalysis of the oxidation of L-malate to oxaloacetate in a reversible, NADH-dependent manner.

Mutations in ALDH3A2 cause Sjogren-Larsson Syndrome (SLS), a neuro-ichthyotic condition that is caused by deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro; and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of non-classical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed 5 novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5&6-NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupts the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde oxidizing activity was observed with cases-2&3. Cases-2 & 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-milia like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder. This article is protected by copyright. All rights reserved.

Objectives: West syndrome (WS) is a triad of epileptic spasms, developmental delay/regression, and hypsarrhythmia. SCN related epileptic encephalopathy is a rare epilepsy syndrome characterized by an early-onset, severe, and epileptic encephalopathy. The causes of WS are multiple and diverse ranging from genetic to structural, metabolic, and unknown causes. The objectives of the study were to report SCN related epileptic encephalopathies with epileptic spasms. Materials and Methods: This is retrospective chart review of children presenting with epileptic spasms secondary to SCN gene variants from January 2015 to March 2020 in a tertiary care referral center. Results: Out of 15 children, ten were boys. The mean age of presentation was 5 months. Thirteen children had preceded seizures before epileptic spasms in the 1st year of life, two children presented initially with epileptic spasms. No neuro-deficits were noted in all the children. In all the cases electroencephalogram was suggestive of hypsarrhythmia. Routine testing, neuroimaging, and metabolic tests were normal in all the cases. Various pathogenic variants seen in next-generation sequencing were SCN1A in 11, SCN1B and SCN2A in two children each. Three children responded for vigabatrin and five children responded for steroids but all of them had relapse and were refractory to other antiepileptic drugs. Conclusion: SCN related epileptic encephalopathy should be considered in the differential diagnosis of epileptic spasms. These infants present earlier compare to classical Dravet syndrome children.

PURPOSE Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy (DEE) with early-onset seizures and severe intellectual disability. METHODS By international collaboration we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders (NDDs). By western blotting we investigated the consequences of missense variants in vitro. RESULTS In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe DEE in 16 individuals. We now identified also de novo missense variants in the GTPase domain in six individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences.Furthermore, we observed bi-allelic splice-site and truncating variants in nine families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION By identifying phenotype-genotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying bi-allelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2 related disorders including both autosomal dominant and recessive NDDs.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

The study attempts to characterize the clinical, demographic, risk factors, electroencephalographical, and neuroimaging features of hot-water epilepsy (HWE) in children. This is a hospital-based observational study in the pediatric neurology clinic and who met the clinical definition of hot-water epilepsy were studied from January 2017 to October 2018. Clinical history, demographic data, and examination findings were recorded in a pre-structured proforma. Electroencephalography (EEG) and neuroimaging were carried out. A total of 68 children with male to female ratio of 2.4:1 were studied. The most common age of onset of seizures was between 1 and 5 y. Focal seizures with impaired awareness were the most common semiology (48.5%). Abnormal EEG was detected in 13.2% and abnormal neuroimaging in 4.4% which consisted of incidental abnormalities. Nonreflex seizures occurred in 35.3% of the children with HWE and the risk factors associated with this were not statistically significant. Clobazam before taking bath helped to achieve seizure control in 85.7% of the children. Hot-water epilepsy should be suspected in children who develop seizures following a hot-water bath. The most common age of onset is 1–5 y. EEG and neuroimaging are normal in the majority of cases. Nonreflex seizures occurred in 35.3% of the children.

Biotinidase deficiency is a treatable neurometabolic disorder. It usually presents during the first year of life with seizures, ataxia, hypotonia, vision and hearing disturbance, alopecia, and skin rashes. It can have various neuroimaging findings but demyelinating leukoencephalopathy is an unusual finding in children with biotinidase deficiency that can cause diagnostic challenge as it can radiologically mimic perinatal hypoxic–ischemic encephalopathy or other leukodystrophies. It reverses with early diagnosis and treatment with biotin supplementation and the outcome is rewarding.

The words unpreventable, incurable, and untreatable are still synonymous with cerebral palsy (CP). However, research and evidence coming from the fields of neuroplasticity, neuroregeneration, and neuroprotection provide considerable cause for optimism for children with CP. There are now at least 64 different interventions for CP seeking 131 outcomes. A search of the Cochrane Library, PubMed, and Google Scholar was made using the keywords: CP, static encephalopathy, birth asphyxia, perinatal insult, hypoxic-ischemic encephalopathy, and neonatal encephalopathy. We found evidence to suggest that following interventions: Anticonvulsant drugs, ankle casting, botulinum toxin for focal spasticity, bisphosphonates, diazepam, hip surveillance, and dorsal rhizotomy are effective. The following interventions improve function: Bimanual training, constraint-induced movement therapy, context focused therapy, goal-directed/functional training, home programs, and occupational therapy. These interventions are effective if started early in life. Therapies such as hyperbaric oxygen, hip bracing, and neurodevelopmental therapy when child contractures are already developed are ineffective. In the last decade, the evidence on CP has rapidly expanded, providing clinicians and families with the possibility of newer, safer, and more effective interventions. In this update, the author reviews the current evidence of the management of CP and provides a comprehensive evaluation and multidisciplinary management.

Alternating hemiplegia of childhood (AHC) is a rare autosomal dominant neurodevelopmental disorder with mutation on ATP1A3 gene. Delay in diagnosis and inappropriate diagnosis are common. In this article, we described four genetically confirmed AHC patients to provide an improved understanding of the disorder. First symptom in two patients was seizures and in other two patients was abnormal eye deviation. All had onset of plegic attacks within the first 18 months of their life. Tone abnormalities and movement disorders were present in all patients. Electroencephalogram was abnormal in two patients and all had normal magnetic resonance imaging of the brain. Response to treatment of plegic attacks was poor and also epilepsy was drug resistant. All cases had significant development delay and disability as of last follow-up. Although there is no effective treatment so far, early diagnosis is required to avoid unnecessary treatment.

Neuronal ceroid Lipofuscinosis (NCL), inherited disorders of lysosomal storage disorders, constitute the most common progressive encephalopathies with an incidence of 1.3 to 7 in 100,000 live births. We reported clinical, electrophysiological, radiological, ultrastructural, and molecular genetic features of NCL. This is a retrospective review, in a tertiary care center from January 2016 to December 2019. All children with clinical features of NCL and confirmed by pathogenic mutation and/or enzyme assay were included. A total of 60 children (male:female = 3:1) were studied. The commonest type was CLN 2 (41.7%). Neuroregression, seizures, and ataxia were present in all cases. Retinal arterial attenuation was seen in 38.33% cases. Magnetic resonance imaging (MRI) brain was abnormal in all patients, thalamic and caudate nucleus atrophy common in CLN1 (62%). Electroencephalography was abnormal in all children, but photoparoxysmal response at low intermittent photic stimulation frequencies was seen in four children of CLN2. Electron microscopy done in 43 children revealed abnormal inclusions in 20 (46.52%) children. Enzyme study showed low levels in 36 (78%) out of 46 cases. Of these, 21 had low tripeptidyl peptidase and 15 had low palmitoyl protein thioesterase levels. Molecular testing done in 26 cases showed pathogenic variant in 23 (88%) cases. Infantile onset with thalamic atrophy on MRI is common in CLN1 and refractory epilepsy, visual impairment and specific EEG changes are common in CLN2. These features are helpful in selecting enzyme assay for CLN1 versus CLN2. Electron microscopy helped in the diagnosis and genetic testing in subtyping. Thus, a multimode approach played a role in the diagnosis of NCL.

Background Childhood ataxia with central nervous system hypomyelination (CACH) is a recently described childhood inherited white matter disease, caused by mutations in any of the five genes encoding eukaryotic translation initiation factor (eIF2B). Methods Retrospective review of the charts of children with CACH was performed from January 2014 to March 2020 at tertiary care center from Southern India. Diagnosis was based on magnetic resonance imaging (MRI) criteria or genetic testing. Results Total number of children with CACH enrolled were 18. Male/female ratio was 10:8. Mean age of presentation was 37.11 months (range = 6–144 months). Affected siblings were seen in five (28%) cases. All children had spasticity, ataxia, and diffuse white matter changes with similar signal as cerebrospinal fluid on all pulse sequences on MRI brain. Of the 18 children, only nine are alive. Duration of illness among deceased children was 9.6667 months (range = 2–16 months). Waxing and waning of symptoms were seen in seven cases. Genetic analysis of EIF2B gene was performed in five cases, among which three mutations were novel. Conclusion A diagnosis of childhood ataxia with central nervous system hypomyelination should be considered in patients presenting with acute onset neuroregression following infection or trauma with associated neuroimaging showing classical white matter findings.

Objective Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants. Methods A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics. Results Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy. Significance Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.

Hyperphosphatemic familial tumoral calcinosis (HFTC) presents with varied neurological manifestations that have been reported in the literature like facial palsy, vision and hearing impairment, stroke, and headache. In this article, we reported a 12-year-old girl child patient with recurrent facial weakness with bilateral hearing impairment and multiple ulcerative lesions on lower limbs and elbows. On examination, she had lower motor neuron (LMN) facial palsy with conductive hearing loss. The investigations showed hyperphosphatemia (9.3 mg/dL) with normal serum calcium (10.4 mg/dL), alkaline phosphatase (147.9 U/L), parathyroid hormone (23.12 pg/mL), and renal function tests. Elevated serum calcium and phosphorus product (96.72 mg2/mL2) and elevated renal tubular reabsorption of phosphate (TMPxGFR) value (9.16) were noted. Skeletal survey showed hyperostosis in the long bone diaphysis, vertebrae, ribs, pelvic bone, skull, and facial bones with narrowing of cranial ostium, characteristically without any peri-articular soft tissue calcifications. An angiogram showed multiple intravascular calcifications. She was managed with a low-phosphate diet, sevelamer, niacinamide, acetazolamide, sucroferric oxyhydroxide to lower serum phosphate level, and topical sodium thiosulfate ectopic cutaneous calcification. Exome sequencing showed novel homozygous inframe deletion of ACG in FGF23 gene exon 3 at c.374_376 delins position (p. Asp125del) in the proband and a mutation in the heterozygous state in the mother and elder sibling, thus confirming a molecular diagnosis of HFTC. Our case had a unique neurological presentation of recurrent bilateral lower motor nerve facial palsy, hearing loss, multiple ectopic cutaneous calcifications without peri-articular deposits, multiple intravascular, intracranial, and vertebral endplate calcification, which has not been reported earlier. The proband showed a novel pathogenic variant suggesting an expanding phenotype of HFTC.

Transient receptor potential vanilloid 4 channel (TRPV4) gene mutations have been described in skeletal system and peripheral nervous system pathology. The case described here is a 9-year-old male child patient, born to a nonconsanguineous marriage with normal birth history who had difficulty in walking and stiffness of joints for the last 7 years, and progressive weakness of all four limbs and urine incontinence for 1 year following falls. Physical examination showed below-average weight and height and short trunk. Musculoskeletal examination revealed bony prominence bilaterally in the knee joints and contractures in knee and elbow joints with brachydactyly; muscle tone was increased, with brisk deep tendon reflexes. Skeletal survey showed platyspondyly with anterior beaking with metaphyseal dysplasia. Magnetic resonance imaging of the spine revealed atlantoaxial instability with hyperintense signal changes at a cervicomedullary junction and upper cervical cord with thinning and spinal canal stenosis suggestive of compressive myelopathy with platyspondyly and anterior beaking of the spine at cervical, thoracic and lumbar vertebrae. Exome sequencing revealed a heterozygous de novo variant c.2389G > A in exon 15 of TRPV4, which results in the amino acid substitution p.Glu797Lys in the encoded protein. The characteristics observed indicated spondylometaphyseal dysplasia, Kozlowski type (SMD-K). The child underwent surgical intervention for compressive myelopathy by reduction of atlantoaxial dislocation with C1 lateral mass and C2 pars fusion using rib graft and fixation using screws and rods. To conclude, for any child presenting with progressive kyphoscoliosis, short stature, platyspondyly, and metaphyseal changes, a diagnosis of SMD-K should be considered and the patient and family should be advised to avoid spinal injuries.

Background Hypermanganesemia with dystonia 1 and 2 (HMNDYT1 and 2) are rare, inherited disorders of manganese transport. Objectives We aimed to describe clinical, laboratory features, and outcomes among children with HMNDYT. Methods We conducted a retrospective multicenter study involving tertiary centers across India. We enrolled children between 1 month to 18 years of age with genetically confirmed/clinically probable HMNDYT. Clinical, laboratory profile, genetic testing, treatment details, and outcomes scored by treating physicians on a Likert scale were recorded. Results We enrolled 27 children (19 girls). Fourteen harbored SLC30A10 mutations; nine had SLC39A14 mutations. The SLC39A14 cohort had lower median age at onset (1.3 [interquartile range (IQR), 0.7-5.5] years) versus SLC30A10 cohort (2.0 [IQR, 1.5-5.1] years). The most frequent neurological features were dystonia (100%; n = 27), gait abnormality (77.7%; n = 21), falls (66.7%; n = 18), and parkinsonism (59.3%; n = 16). Median serum manganese (Mn) levels among SLC39A14 (44.9 [IQR, 27.3-147.7] mcg/L) cohort were higher than SLC30A10 (29.4 [17.1-42.0] mcg/L); median hemoglobin was higher in SLC30A10 (16.3 [IQR, 15.2-17.5] g/dL) versus SLC39A14 cohort (12.5 [8.8-13.2] g/dL). Hepatic involvement and polycythaemia were observed exclusively in SLC30A10 variants. A total of 26/27 children underwent chelation with disodium calcium edetate. Nine demonstrated some improvement, three stabilized, two had marked improvement, and one had normalization. Children with SLC39A14 mutations had poorer response. Two children died and nine were lost to follow-up. Conclusions We found female predominance. Children with SLC39A14 mutations presented at younger age and responded less favorably to chelation compared to SLC30A10 mutations. There is emerging need to better define management strategies, especially in low resource settings.