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Background and ObjectivesKCNH5encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novoKCNH5variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies forKCNH5variants using targeted or exome sequencing. Additional individuals withKCNH5variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.DiscussionWe describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establishKCNH5as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

Neurofibromatosis type 1 (NF1) is a common neurocutaneous disorder characterized by development of pigmentary skin changes, neurogenic tumors, and other manifestations involving multiple organ systems. Penetrance is complete, though expressivity is quite variable even among the family members. Given that NF1 is a common hereditary condition, existence of a second genetic disorder in NF1 patients is not unexpected. During comprehensive evaluations of individuals with NF1, we encountered 11 patients with dual diagnosis who contributed to phenotypic complexity and challenges for long-term management. Examples include Prader-Willi Syndrome, Autosomal Dominant Polycystic Kidney Disease, Down syndrome, infantile myofibromatosis, Craniosynostosis, cleft lip and palate, 47,XYY, 22q11.2 duplication, 15q13.3 deletion syndrome, and BRCA2- and ATM- related cancer predisposition syndromes. Presence of dysmorphism, developmental delay, atypical tumors, and family history of other genetic disorders including cancers appears as determinants to consider a second genetic etiology and helps to differentiate from an extreme phenotypic spectrum of NF1. Clinicians should have high index of suspicion to exclude coexisting disorders, as apart from providing comprehensive medical care. This also has potential implications in genetic counseling. Long-term effects of the synergistic mechanisms leading to phenotypic complexity and patient outcomes are yet to be characterized, with follow-up needed.

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a. ispartof: ANNALS OF NEUROLOGY vol:90 issue:6 pages:887-900 ispartof: location:United States status: published

ObjectiveKCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies (DEEs) for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included three previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including nine with a recurrent de novo missense variant p.Arg327His, four with a recurrent missense variant p.Arg333His, and four additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using American College of Medical Genetics and Genomics (ACMG) criteria. All individuals presented with epilepsy with a median seizure onset at six months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalised epilepsy and normal intellect, while the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore-domain were more severely affected, with neonatal-onset DEE, profound disability, and childhood death.ConclusionsWe report the first cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders (NDDs) and epilepsy.

Mild/juvenile Canavan disease (M/JCD) is less frequently reported in literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel ASPA(NM_000049.4):c.526G > A(p.Gly176Ser) variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, indicated to a possibility of founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event, such as a high fixation index, increased runs of homozygosity and identity-by-descent estimation in TDC in the absence of consanguinity; large haplotype with high linkage disequilibrium comprising the pathogenic variant; presence of a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.

Aicardi-Goutières syndrome type 6 (AGS6) and dyschromatosis symmetrica hereditaria (DSH) are allelic disorders caused respectively by biallelic and heterozygous pathogenic variants in ADAR1. We report three unrelated children presenting with features of both AGS6 and DSH, two of whom had compound heterozygous pathogenic variants in ADAR1. We also describe the novel genetic variants in our cases and review the literature on association of ADAR1-related AGS6 and DSH with these phenotypes.

Background and Aims: Cutaneous lesions are the defining features of several neurocutaneous syndromes like neurofibromatosis1(NF1), tuberous sclerosis complex (TSC), and Sturge Weber syndrome to name a few. With this background, we explored the possibility of identifying congenital and nevoid cutaneous markers that may help in the early recognition of autism spectrum disorders (ASD) in Indian children. The objective of this study was to measure the strength of association between congenital and nevoid cutaneous lesions and ASD among Indian children. Methods: A case-control study was conducted from January 2018 to June 2018. 132 children (18 months-16 years of age) with ASD and equal number of age and sex-matched children without autism were studied. Diagnosis of ASD was based on DSM-5 criteria. All the children were examined for cutaneous lesions with special attention to nevoid and congenital conditions. The strength of association was measured using the diagnostic odds ratio (OR). Results: The prevalence of congenital and nevoid lesions were higher in ASD group (OR = 3.12, P = 0.0001). Among them, pigmentary mosaicism of hyperpigmented type (OR = 2.76, P = 0.02) and café-au-lait macules (CALMs) (OR = 2.40, P = 0.001) were the most prevalent with hyperpigmented pigmentary mosaicism showing a higher association with autism. Atypical CALMs (OR = 2, P = 0.09) were also more prevalent in the ASD group though not statistically significant. Conclusion: The presence of hyperpigmented pigmentary mosaicism and CALMs warrant closer surveillance by the caregivers and physicians for evolving features of autism. Larger multicentric studies are required to validate these findings.

Branchio-oto-renal spectrum disorder (BORSD) is a rare autosomal dominant condition characterized by ear abnormalities with hard of hearing/deafness, second branchial arch malformations and renal anomalies. Pathogenic variations in EYA1 gene are found in the majority of clinically diagnosed individuals with BORSD. We describe an infant with BORSD related to a paternally inherited heterozygous pathogenic variation in EYA1 gene presenting with poor growth and hypoglycemia due to growth hormone deficiency. Magnetic resonance imaging revealed a diminutive pituitary gland and morphologically abnormal sella. Upon initiation of growth hormone therapy, the hypoglycemia resolved and catch up growth ensued. Pituitary abnormalities have not been reported previously in patients with BORSD. The zebrafish ortholog of eya1 is important for the development of adenohypophysis, suggesting that this patient's growth hormone deficiency and pituitary abnormality are part of BORSD. Inclusion of screening for pituitary hormone deficiency and pituitary imaging should be considered as a part of surveillance in patients with BORSD.

Prader-Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11-q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader-Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15-related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co-occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15-related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS.

Hypomyelinating Leukodystrophies (HLDs) are a genetically heterogeneous, clinically overlapping group of disorders with the unifying MR imaging appearance of myelin deficit in the brain. In fact, it is the MRI phenotype that typically raises the diagnostic suspicion in this single largest group of undiagnosed leukodystrophies and guides gene testing for confirmation. This article reviews the neurobiology of myelination, focussing on the complex interplay of molecular genetic pathways and presents a practical clinico-radiological diagnostic algorithm based on the neuroimaging patterns of the common hypomyelinating disorders. The authors also address the current controversies about the definition and use of the term 'hypomyelination'.

Ischemic stroke accounts for over 80% of all strokes and is one of the leading causes of mortality and permanent disability worldwide. Intravenous administration of recombinant tissue plasminogen activator (rt-PA) is an approved treatment strategy for acute ischemic stroke of large arteries within 4.5 h of onset, and mechanical thrombectomy can be used for large arteries occlusion up to 24 h after onset. Improving diagnostic work up for acute treatment, reducing onset-to-needle time and urgent radiological access angiographic CT images (angioCT) and Magnetic Resonance Imaging (MRI) are real problems for many healthcare systems, which limits the number of patients with good prognosis in real world compared to the results of randomized controlled trials. The applied endovascular procedures demonstrated high efficacy, but some cellular mechanisms, following reperfusion, are still unknown. Changes in the morphology and function of mitochondria associated with reperfusion and ischemia-reperfusion neuronal death are still understudied research fields. Moreover, future research is needed to elucidate the relationship between continuously refined imaging techniques and the variable structure or physical properties of the clot along with vascular permeability and the pleiotropism of ischemic reperfusion lesions in the penumbra, in order to define targeted preventive procedures promoting long-term health benefits.

Background Biallelic pathogenic variants in HTRA1 cause CARASIL. More recently, monoallelic variants have been associated with the autosomal dominant disorder CADASIL2 but not all carriers develop disease manifestations. We describe the clinicoradiologic and mutation spectrum of four new CADASIL2 individuals. Methods Medical records at Mayo Clinic between 2013 and 2020 were retrospectively reviewed to identify patients with cerebral small vessel disease related to monoallelic HTRA1 variants. Results Four patients met the study inclusion criteria for cerebral small vessel disease related to HTRA1 monoallelic variants. The mean age at onset of first clinical stroke was 51.25 years (range 41–64 years). The mean disease duration was 6.5 years (range 4–12). All individuals had recurrent strokes within the duration of follow‐up with a mean number of strokes per patient being 5.5 (range 2–12). Three individuals had leukoencephalopathy with brain stem involvement. Microhemorrhages were seen on brain MRI in three patients. HTRA1 monoallelic variants identified in our cohort were missense variants in three patients and a novel frameshift variation in one patient. Interestingly, two of these missense variants were previously reported in an autosomal recessive pattern of inheritance and here are associated with a dominant effect. Conclusions Clinicoradiologic characteristics of heterozygous HTRA1‐related CSVD may overlap with sporadic CSVD. Heterozygous HTRA1 variants can contribute to dominant or recessive disease mechanisms., Clinicoradiologic features of heterozygous HTRA1‐related CSVD may overlap with sporadic CVSD. The presence of vascular risk factors and a noncontributory family history should not exclude late‐onset CSVD of inherited etiology. HTRA1 variants can be disease‐causing in both heterozygous and biallelic states, but so far, there are no defining variant characteristics to determine the pattern of inheritance.

A 9-month-old girl presented with global developmental delay and refractory generalized seizures. Microcephaly, poor visual fixation, and intermittent dystonic posturing were observed on clinical examination. MRI brain (figure) revealed delayed myelination and restricted diffusion involving optic radiations, cerebral peduncles, red nuclei, globus pallidi, and corticospinal tract. EEG showed background slowing and multifocal epileptiform discharges. Workup revealed a homozygous, likely pathogenic variant in ITPA (c.124+1 G>A) and reduced inosine triphosphate pyrophosphohydrolase (ITPase) activity in skin fibroblasts (0.19 nmol/mg protein × h, controls 6.86 ± 2.51). Imaging pattern of delayed myelination and restricted diffusion is suggestive of ITPase deficiency in a child presenting with early infantile epileptic encephalopathy.1,2

Advances in genetics has revolutionised the way we understand, diagnose and manage neurological disorders. Notwithstanding the fact that genetic confirmation has already become standard of care in routine clinical practice, radiological and clinical phenotyping has not diminished in value; in fact it has found an enhanced role in guiding and interpreting genetic test results. Inherited neurometabolic disorders are a prominent group of disorders which are seen commonly in clinical practice and many are potentially treatable. The concept of Radiogenomics is the bridge from phenotype to genotype and the strength of association varies widely across different inherited metabolic diseases. Understanding the strengths and limitations of these correlations forms the basis of success of multidisciplinary approach to diagnose these disorders. In this article authors give a brief overview of the genetic basis of a disease, available genetic tests and the prominent role of radiology in contemplating a diagnostic suspicion and guiding further confirmatory tests.

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with around 100 types described so far. Because of the limited number of reported cases in each type except PMM2-CDG, the complete clinical picture of other types is not known. RFT1-CDG is a rare type, with ten cases reported in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate, bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment. He succumbed to the illness on day 24 of life. There was a similar history of two previous sibling deaths in the early neonatal period due to respiratory insufficiency and history of multiple neonatal and infant deaths in the extended family. Transferrin iso-electric focusing was normal. Clinical exome sequencing revealed a novel homozygous missense mutation (c.1018 G > A) in RFT1 gene [NM_052859; c.1018G > A; p.G340S; ENST00000296292] and the parents were heterozygous for the same (ClinVar SVC000778540). The pathogenic variants so far reported are all missense variants affecting the luminal loops; whereas the variant in our case is in the trans-membrane helical domain. A strong family history of neonatal deaths and similar presentations in the previous 2 siblings suggests the homogenous phenotype of this mutation. Severe respiratory insuffiency and ventilator dependence shows the lethality of the disease phenotype and incompatibility with survival beyond the neonatal period.

To determine whether preoperative non-lateralizing scalp electroencephalography (EEG) influences seizure outcome following peri-insular hemispherotomy (PIH) in pediatric hemispheric epilepsy. Retrospective data was collected on all 45 pediatric patients who underwent PIH between 2005 and 2016. All underwent a basic pre-surgical evaluation consisting of detailed history and examination, neuropsychological assessment, MRI, and EEG. SPECT/PET, fRMI, or Wada testing were done in only eight patients. Seizure outcome was assessed using the Engel classification. Among those who underwent hemispherotomy, 20 (44%) were females. Mean age at surgery was 8 ± 4.3 years and mean duration of symptoms was 5.2 ± 3.7 years. The most common etiologies of hemispheric epilepsy were hemiconvulsion-hemiplegia epilepsy syndrome, Rasmussen encephalitis, and post-encephalitic sequelae, together comprising 27 (60%) patients. Among the 44 patients with follow-up data (mean duration 48 ± 33 months), seizure freedom (Engel class I) was attained by 41 (93.2%). Anti-epileptic medications were stopped or decreased in 36 (82%). Seventeen (38.6%) patients had non-lateralizing EEG. Seizure outcome was not related to lateralization of EEG activity. PIH provides excellent long-term seizure control in patients despite the presence of non-lateralizing epileptiform activity, although occurrence of acute postoperative seizures may be higher. Routine SPECT/PET may not be required in patients with a non-lateralizing EEG if there is good clinico-radiological concordance.

Brain has been considered as an immune-privileged site for centuries owing to the presence of blood-brain barrier, absent lymphatic drainage, and antigen-presenting cells. However, the present prevailing concept is of immune surveillance where brain is continuously surveyed by immune cells. However, the presence of immune cells in central nervous system (CNS) brings the risk of inflammation and autoimmunity involving both T and B cell mediated pathways. These mechanisms form the underlying pathology in a wide spectrum of pediatric CNS diseases manifesting as acquired neurological deficits. Overlapping, heterogenous, and ambiguous clinical features often delays the diagnosis. Although not always pathognomonic, magnetic resonance imaging can be an important biomarker leading to early diagnosis, prognostication, and systematic follow-up pf these diseases. This review describes the spectrum of different pediatric inflammatory disorders and their pertinent imaging features illustrated with clinical examples.

Inborn errors of metabolism (IEM) although individually rare, together constitute a significant proportion of childhood neurological disorders. Majority of these disorders occur due to deficiency of an enzyme in a specific metabolic pathway, leading to damage by accumulation of a toxic substrate or deficiency of an essential metabolite. Early diagnosis is crucial in many of these conditions to prevent or minimise brain damage. Whilst many of the neuroimaging features are nonspecific, certain disorders demonstrate specific patterns due to selective vulnerability of different structures to different insults. Along with clinical and biochemical profile, neuroimaging thus plays a pivotal role in differentiating metabolic disorders from other causes, in providing a differential diagnosis or suggesting a metabolic pathway derangement, and on occasion also helps make a specific diagnosis. This allows initiation of targeted metabolic and genetic work up and treatment. Familiarity with the clinical features, relevant biochemical features and neuroimaging findings of common metabolic disorders to facilitate a prompt diagnosis cannot thus be overemphasized. In this article, we describe the latest classification scheme, the clinical and biochemical clues and common radiological patterns. The diagnostic algorithm followed in daily practice after clinico-radiological phenotyping is alluded to and illustrated by clinical vignettes. Focused sections on neonatal metabolic disorders and mitochondrial disorders are also provided. The purpose of this article is to provide a brief overview and serve as a practical primer to clinical and radiological phenotypes and diagnostic aspects of IEM.

Background Dual diagnoses in genetics practice are not uncommon and patients with dual diagnosis often present with complex and challenging phenotypes. A combination of meticulous phenotyping and molecular genetic techniques are essential in solving these diagnostic odysseys. Methods Clinical features and genetic workup of a patient presenting with incidental schwannomatosis. Results A 19‐year‐old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies, and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1‐related schwannomatosis and 7q11.23 duplication syndrome. Conclusion We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries., A nineteen year old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1 related schwannomatosis and 7q11.23 duplication syndrome. We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries.

Rett syndrome (RTT) is an X-linked disorder caused by mutations in MECP2 in majority of cases. It is characterized by arrested development between 6 and 18 months of age, regression of acquired hand skills and speech, stereotypic hand movements, gait abnormalities and seizures. There are a very few studies in India which illustrates mutation spectrum in RTT. None of the studies have correlated seizures with the genotype. This study describes the phenotype and genotype spectrum in children with RTT syndrome and analyses the association of epilepsy with various clinical features and molecular findings. All children with RTT in our cohort had global developmental delay. Genetic diagnosis identified mutations of the MECP2 in all 25 children where RTT was suspected. We have identified point mutations in 20 patients, one insertion and four deletions by Sanger sequencing, namely c.1164_1207 (44 bp), c.1165_1207 (43 bp), c.1157_1197 (41 bp) del and c.1157_1188 (32 bp). Clinically, none of the patients with deletion had seizures. We identified one novel insertion variant c.337_338 (p.S113Ffs*9). All the deletions were located in the C-terminal region. Majority of the mutations (22/25) were identified in exon 4 which comprised of nonsense and missense types. Screening of hotspot mutations in exon 4 should be the first line evaluation in diagnosis of RTT. Molecular testing could help in specific management of seizures in RTT.

Relapsing demyelinating syndromes (RDS) in children encompass a diverse spectrum of entities including multiple sclerosis (MS) acute disseminated encephalomyelitis (ADEM), aquaporin-4 antibody associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to these, there are “antibody-negative” demyelinating syndromes which are yet to be fully characterized and defined. The paucity of specific biomarkers and overlap in clinical presentations makes the distinction between these disease entities difficult at initial presentation and, as such, there is a heavy reliance on magnetic resonance imaging (MRI) findings to satisfy the criteria for treatment initiation and optimization. Misdiagnosis is not uncommon and is usually related to the inaccurate application of criteria or failure to identify potential clinical and radiological mimics. It is also notable that there are instances where AQP4 and MOG antibody testing may be falsely negative during initial clinical episodes, further complicating the issue. This article illustrates the typical clinico-radiological phenotypes associated with the known pediatric RDS at presentation and describes the neuroimaging mimics of these using a pattern-based approach in the brain, optic nerves, and spinal cord. Practical guidance on key distinguishing features in the form of clinical and radiological red flags are incorporated. A subsection on clinical mimics with characteristic imaging patterns that assist in establishing alternative diagnoses is also included.

Akt is one of the most important downstream effectors of phosphatidylinositol 3-kinase/mTOR pathway. Hyperactivation and expression of this pathway are seen in a variety of neurological disorders including human temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Nevertheless, the expression and activation profiles of the Akt isoforms, Akt1, Akt2, and Akt3 and their functional roles in human TLE-HS have not been studied. We examined the protein expression and activation (phosphorylation) patterns of Akt and its isoforms in human hippocampal tissue from TLE and non-TLE patients. A phosphoproteomic approach followed by interactome analysis of each Akt isoform was used to understand protein-protein interactions and their role in TLE-HS pathology. Our results demonstrated activation of the Akt/mTOR pathway as well as activation of Akt downstream substrates like GSK3β, mTOR, and S6 in TLE-HS samples. Akt1 isoform levels were significantly increased in the TLE-HS samples as compared to the non-TLE samples. Most importantly, different isoforms were activated in different TLE-HS samples, Akt2 was activated in three samples, Akt2 and Akt1 were simultaneously activated in one sample and Akt3 was activated in two samples. Our phosphoproteomic screen across six TLE-HS samples identified 183 proteins phosphorylated by Akt isoforms, 29 of these proteins belong to cytoskeletal modification. Also, we were able to identify proteins of several other classes involved in glycolysis, neuronal development, protein folding and excitatory amino acid transport functions as Akt substrates. Taken together, our data offer clues to understand the role of Akt and its isoforms in underlying the pathology of TLE-HS and further, modulation of Akt/mTOR pathway using Akt isoforms specific inhibitors may offer a new therapeutic window for treatment of human TLE-HS.

Context: Krabbe disease shows considerable heterogeneity in clinical features and disease progression. Imaging phenotypes are equally heterogeneous but show distinct age-based patterns. It is important for radiologists to be familiar with the imaging spectrum to substantially contribute toward early diagnosis, prognostication, and therapeutic decisions. Aims: The study aims to describe different magnetic resonance imaging (MRI) patterns observed in a cohort of children with Krabbe disease and to assess correlation with age-based clinical phenotypes. Materials and Methods: This is a retrospective descriptive study done at the Departments of Radiodiagnosis and Neurological Sciences of our institution, a tertiary care hospital in Southern India. Imaging features of children diagnosed with Krabbe disease over a 10-year period (2009–2018) were collected and analyzed. Results: A total of 38 MRI brain studies from 27 patients were analyzed. Four distinct MRI patterns were recognizable among the different clinical subtypes. All patients from the early and late infantile group showed deep cerebral and cerebellar white matter and dentate hilum involvement. Optic nerve thickening was, however, more common in the former group. Adult-onset subtype showed isolated involvement of corticospinal tract, posterior periventricular white matter, and callosal splenium with the absence of other supra- and infra-tentorial findings. Juvenile subgroup showed heterogeneous mixed pattern with 78% showing adult subtype pattern and 22% showing patchy involvement of deep cerebral white matter with dentate hilum signal changes. Conclusion: Krabbe disease shows distinct imaging features which correspond to different clinical age-based subtypes. This article reemphasizes these distinct imaging phenotypes, highlights a novel imaging appearance in juvenile Krabbe, and also alludes to the rare variant of saposin deficiency. Awareness of these patterns is essential in suggesting the appropriate diagnosis and guiding conclusive diagnostic workup. Large multicenter longitudinal studies are needed to further define the role of imaging in predicting the clinical course and thus to guide therapeutic options.

Introduction: There is scarce literature regarding the clinical course, comorbidities and long-term outcomes after myasthenic crisis (MC). The natural history of myasthenia gravis (MG) in this subset remains uncertain. Methods: The study included a cohort admitted with MC (2007–2017) in a tertiary care hospital. The comorbidities, outcomes after discharge, and prognostic factors were analyzed. Results: Sixty-two patients (89 episodes of MC) were included. Demographic data was comparable between the early- (

Imaging plays an important role in diagnosis, management, prognostication and follow up of pediatric demyelinating and inflammatory diseases of brain and forms an integral part of the diagnostic criteria. This article reviews the spectrum of aquaporinopathies with an in-depth discussion on present criteria and differentiation from other demyelinating diseases with clinical vignettes for illustration; the latter part of article deals with the spectrum of CNS vasculitis.