First reported cases with Xia-Gibbs syndrome from India harboring novel variants in AHDC1.

We report here two girls from different Indian families identified with novel variants in the AT Hook DNA Binding Motif Containing 1 gene (AHDC1) causing Xia-Gibbs syndrome. The diagnosis was made by clinical exome in both cases. Inconsistent dysmorphic features such as dolichocephaly in the first patient and brachycephaly in the second were observed. Prominent jaw and gelastic seizures were other features of patient 1. Thus, this syndrome, with developmental delay, poor expressive language and overlapping clinical phenotype requires the utility of next generation sequencing for diagnostic confirmation.

Utility of Chromosomal Microarray in Children with Unexplained Developmental Delay/Intellectual Disability.

ObjectiveTo evaluate the chromosomal microarray (CMA) yield among children who presented with global developmental delay/intellectual disability (GDD/ID) with/without co-occurring conditions. Methods: The pathogenic copy number variation (pCNVs) findings on CMA of all children who presented with unexplained GDD/ID were categorized based on the clinical features. The karyotype results were compared with CMA. Results: The overall pCNV yield in children presenting with GDD/ID with or without comorbid conditions constituted 20.9%. Among the 17 pCNVs, 13 were losses and four were gains. Cardiac defect was the only co-morbidity in our study that demonstrated statistically significant prediction for pCNV (odds ratio 6.13, p value- 0.031). Six children who were karyotyped prior to CMA testing showed a structural abnormality. Conclusions: In our study, 20.9% of children with GDD/ID showed pCNVs on CMA. Cardiac defect alongside GDD/ID, emerged as the single strongest phenotype associated with pCNVs. CMA also provided vital information in previously karyotyped patients.

Phenotypic Pleiotropy in Arginase Deficiency: A Single Center Cohort.

Background: Arginase deficiency is considered a masquerader of diplegic cerebral palsy. The rarity of hyperammonemic crisis and the slowly progressive course has made it a unique entity among the urea cycle defects. Objectives: The aim of our study is to describe the varied phenotypic spectrum of children with arginase deficiency. Methodology: This retrospective study included children and adolescents aged <18 years with a biochemical or genetic diagnosis of arginase deficiency from May 2011 to May 2022. Data were collected from the hospital's electronic database. The clinical presentation, laboratory parameters at baseline and during metabolic decompensation, neuroimaging, electroencephalography findings, and molecular studies were analyzed. Results: About 11 children from nine families with biochemically or genetically proven arginase deficiency were analyzed. The male: female ratio was 2.7:1. Consanguineous parentage was observed in all children. The median age at presentation was 36 months (Range: 5 months-18 years). All children with onset of symptoms in early childhood had a predominant delay in motor milestones of varying severity. Metabolic decompensation with encephalopathy occurred in all except two children (n = 9, 81.8%). Pyramidal signs were present in all patients and additional extrapyramidal signs in two children. Positive family history was present in four probands. Seizures occurred in all children. Epilepsy with electrical status in slow wave sleep and West syndrome was noted in three children. All children had elevated ammonia and arginine at the time of metabolic crisis. The spectrum of neuroimaging findings includes periventricular, subcortical, and deep white matter signal changes and diffusion restriction. The mean duration of follow-up was 38.6 ± 34.08 months. All patients were managed with an arginine-restricted diet and sodium benzoate with or without ornithine supplementation. Conclusion: Spastic diparesis, recurrent encephalopathy, presence of family history, and elevated serum arginine levels must alert the clinician to suspect arginase deficiency. Atypical presentations in our cohort include frequent metabolic crises and epileptic encephalopathy. Early identification and management will ensure a better neurodevelopmental outcome.

Phosphoproteomic analysis reveals Akt isoform-specific regulation of cytoskeleton proteins in human temporal lobe epilepsy with hippocampal sclerosis.

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 GSK3ß, 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.

EEG lateralization and seizure outcome following peri-insular hemispherotomy for pediatric hemispheric epilepsy.

OBJECTIVE: To determine whether preoperative non-lateralizing scalp electroencephalography (EEG) influences seizure outcome following peri-insular hemispherotomy (PIH) in pediatric hemispheric epilepsy. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Congenital Myasthenic Syndrome: Spectrum of Mutations in an Indian Cohort.

OBJECTIVES: To investigate the mutational spectrum and genotype-phenotype correlation in Indian patients with congenital myasthenic syndrome (CMS), using next-generation sequencing of 5 genes. METHODS: CHRNE, COLQ, DOK7, RAPSN, and GFPT1 were sequenced in 25 affected patients. RESULTS: We found clinically significant variants in 18 patients, of which variants in CHRNE were the most common, and 9 were novel. A common pathogenic COLQ variant was also detected in 4 patients with isolated limb-girdle congenital myasthenia. CONCLUSIONS: Targeted screening of 5 genes is an effective alternate test for CMS, and an affordable one even in a developing country such as India. In addition, we recommend that patients with isolated limb-girdle congenital myasthenia be screened initially for the common COLQ pathogenic variant. This study throws the first light on the genetic landscape of CMSs in India.

A tropical menace of co-infection of Japanese encephalitis and neurocysticercosis in two children.

Japanese encephalitis (JE) is a mosquito borne encephalitis caused by Flavivirus. Neurocysticercosis (NCC) is a parasitic disease of the central nervous system caused by Taenia solium. In this report, we describe the clinical profile, imaging findings, and outcome of two children with JE and coexisting NCC. Eleven and thirteen-year-old boys from the same town of Jharkhand state were brought with history of fever, seizures, altered sensorium, and extrapyramidal symptoms. Dystonia, hypomimia, bradykinesia, and dyskinesia were observed. Meige syndrome observed in one of the children is a novel finding. Magnetic resonance imaging of the brain revealed findings suggestive of JE with cysticercal granulomas. There are few reports of coexistence of JE and NCC in children. Both children were treated with ribavirin, and follow-up imaging had shown significant resolution of signal changes. Both the children had shown marked clinical improvement. Ribavirin was found to beneficial in reducing the morbidity in our patients.

Acute necrotising encephalopathy in a child with H1N1 influenza infection: a clinicoradiological diagnosis and follow-up.

Acute necrotising encephalopathy of childhood (ANEC) is a fulminant disorder with rapid progressive encephalopathy, seizures and poor outcome. It has been reported in association with various viral infections. We describe the clinicoradiological findings and short-term follow-up in a child with H1N1 influenza-associated ANEC. Laminar, target or tricolour pattern of involvement of the thalami was seen on apparent diffusion coefficient images. Our patient had significant morbidity at discharge despite early diagnosis and management with oseltamivir and immunoglobulin. Repeat imaging after 3 months had shown significant resolution of thalamic swelling, but there was persistence of cytotoxic oedema involving bilateral thalami. She was pulsed with intravenous steroids and maintained on a tapering schedule of oral steroids. This report emphasises the need for a high index of suspicion to establish early diagnosis, promotion of widespread immunisation strategies to prevent influenza outbreak, and more research to establish standard treatment protocols for this under-recognised entity.

A Validation of an Examination Protocol for Cerebral Visual Impairment Among Children in a Clinical Population in India.

INTRODUCTION: Cerebral Visual Impairment (CVI) is a leading cause of vision impairment in developed and developing countries due to and increased survival of preterm and low birth weight infants. There are few data concerning the validity of protocols available to diagnose CVI. AIM: This study aimed to document the face, content and construct validity of an assessment protocol namely, a 15-domain, Structured Clinical Question Inventory (SCQI), which is based on structured history taking and clinical examination, for the diagnosis of CVI in a clinical population of India. MATERIALS AND METHODS: This study was a retro-spective chart analysis of all children below the age of 18years, referred to the CVI clinic of a tertiary care teaching hospital in Southern India from March 2011-Feb 2012. Clinical case-notes including the SCQI findings of all children referred to the clinic were reviewed. The data were extracted after Institutional Review Board approval. STATISTICAL ANALYSIS: Pearson correlation coefficient, Cronbach's alpha and exploratory factor analysis were used to document the content and construct validity of the examination protocol. RESULTS: A total of 342 children (35.7% male, 64.3% female), with a mean age of 3.8 years (range 0-17 years, the median was 3 years) were included in the study and their data were examined. The internal consistency of the SCQI was 0.93 suggesting it as an excellent tool to characterise and profile CVI and a 2-factor model (Dorsal Stream Dysfunction and Ventral Stream Dysfunction) based on a biologically plausible model explained 63% of the variance. CONCLUSION: The results of using the SCQI affirm published data and endorse a theoretical construct similar across cultures. The potential diagnostic accuracy, reliability and utility of this measure for CVI needs to be studied further. The clinical use of a short version of the SCQI may be helpful to contribute to the identification of CVI, especially for middle and low-income countries.

Neuroregression as an initial manifestation in a toddler with acquired pernicious anaemia.

The aetiology spectrum for neuroregression in infants and toddlers is diverse. Vitamin B12 deficiency-mediated neuroregression is less commonly considered as a differential. Prevalence of pernicious anaemia in the general population is 0.1% and is extremely rare in children. We describe a 35-month-old toddler with neuroregression, seizures, coarse tremors, bleating cry and neuropathy. His clinical symptomatology mimicked grey matter degenerative illness and infantile tremor syndrome, a nutritional deficiency-mediated movement disorder. His vitamin B12 level was low and serum homocysteine level was elevated. Haematological manifestations were not overt and anti-intrinsic factor antibody was positive. With parenteral vitamin B12 therapy, there was a dramatic response with clinical and laboratory translation. This report emphasises the need for a high index of suspicion and screening for markers of vitamin B12 deficiency in all children with unexplained acute or subacute neuroregression, seizures and movement disorders as it is potentially reversible.

Natural history of multiple sclerosis from the Indian perspective: Experience from a tertiary care hospital.

CONTEXT: Multiple sclerosis (MS) has a spectrum of heterogeneity, as seen in western and eastern hemispheres, in the clinical features, topography of involvement and differences in natural history. AIM: To study the clinical spectrum, imaging, and electrophysiological as well as cerebrospinal fluid (CSF) characteristics and correlate them with outcome. SETTINGS AND DESIGN: Retrospective analysis of MS patients during a period of 20 years. SUBJECTS AND METHODS: Cases were selected according to recent McDonald's criteria (2010), They were managed in the Department of Neurology, Christian Medical College, Vellore. STATISTICAL ANALYSIS USED: Chi-square and Fisher's exact tests were used for categorical variables. Multiple binary logistic regressions were done to assess significance. Kaplan-Meier curves were drawn to estimate the time to irreversible disability. RESULTS: A total of 157 patients with female preponderance (55%) were included. The inter quartile range duration of follow-up was 9.1 (8.2, 11) years for 114 patients, who were included for final outcome analysis. Relapsing remitting MS (RRMS) (54.1%) was the most common type of MS seen. RRMS had a significantly better outcome (odds ratio: 0.12, 95% confidence interval: 0.02-0.57, P = 0.008) compared to progressive form of MS (primary progressive, secondary progressive). The Expanded Disability Status Scale score of patients at presentation and at final follow-up was 4.4 ± 1.31 and 4.1 ± 2.31, respectively. During the first presentation, polysymptomatic manifestations like motor and sphincteric involvement, incomplete recovery from the first attack; and, during the disease course, bowel, bladder, cerebellar and pyramidal affliction, predicted a worse outcome. CONCLUSION: A high incidence of optico-spinal presentation, predominance of RRMS and a low yield on cerebrospinal fluid (CSF) studies are the major findings of our study. A notable feature was the analysis of prognostic markers of disability.

Subacute sclerosing panencephalitis in a child with human immunodeficiency virus (HIV) infection on antiretroviral therapy.

Subacute Sclerosing Panencephalitis (SSPE) in HIV-infected children is a scarcely reported entity with previous reports describing fulminant course. The impact of highly active antiretroviral therapy (HAART) in altering its course remains unknown. We describe a child with HIV infection, who developed measles at 5 months of age and later developed SSPE at 14 years of age, remaining stable at 7 month follow-up, while on HAART for WHO (World Health Organisation) stage IV disease. The dynamics of HIV-related immunosuppression has an impact on the clinical course of SSPE. Contrary to reported cases of fulminant progression, a classic presentation with slow progression can be expected in children on HAART. We reemphasize the recommendation of "early measles vaccination" to prevent measles infection and subsequent SSPE in these children with an increasingly good life expectancy in the era of HAART.

Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism (4H) Syndrome With Vertebral Anomalies: A Novel Association.

Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H) syndrome is a rare hypomyelination disorder with around 40 cases reported worldwide. Children with hypomyelination, hypodontia, hypogonadotropic hypogonadism syndrome present with varying degrees of developmental delay with a spastic ataxic syndrome with delayed eruption of teeth along with disruption in the eruption sequence, hypogonadotropic hypogonadism, and a fluctuating clinical course with intercurrent infections and varying periods of stability. The disorder is caused by mutations in POL3A and POL3B genes and is collectively termed as pol III-related leukodystrophies. Here we describe 2 children with hypomyelination, hypodontia, hypogonadotropic, hypogonadism syndrome and the association of multiple vertebral fusion anomalies in one of them, which has not been previously described in the literature. We conclude that the spectrum of the disorder is not limited to brain parenchyma alone and involves all the structures arising from neural ectoderm, and this needs further research.

Siblings with fucosidosis.

Fucosidosis is a rare lysosomal storage disorder due to deficiency of fucosidase enzyme, with around 100 cases reported worldwide. Here, we describe the clinical and imaging features in two siblings with fucosidosis. An 8-year-old girl presented with global developmental delay, followed by regression of acquired milestones from 3 years of age with bipyramidal, extrapyramidal involvement, coarse facies, telangiectatic lesions, dysostosis multiplex, characteristic magnetic resonance imaging finding along with undetectable levels of the fucosidase activity, which confirmed the diagnosis. Younger sibling has mild developmental delay with autistic traits with no neuroregression until now. He also has undetectable level of fucosidase enzyme activity and is being considered for stem cell transplantation. New case reports would expand the clinical spectrum, early diagnosis and help formulating appropriate therapy. Early diagnosis is crucial and hence sibling screening can be done, and those in the presymptomatic stage can undergo hematopoietic stem cell transplantation, which is potentially curable.

Magnetic resonance imaging findings in adult-form myotonic dystrophy type 1.

The adult form of myotonic dystrophy type 1 is a neuromuscular disorder with multisystem involvement, including the central nervous system (CNS). The presenting clinical features of this condition include distal muscle weakness, myotonia, intellectual decline, cataract, frontal baldness and testicular atrophy. Magnetic resonance (MR) imaging shows characteristic white matter changes in the CNS. The clinical presentation, characteristic white matter changes in the brain on MR imaging and electromyographic findings aid in the diagnosis of this disorder.

Outcomes of disconnective surgery in intractable pediatric hemispheric and subhemispheric epilepsy.

OBJECTIVES: To study the outcome of disconnective epilepsy surgery for intractable hemispheric and sub-hemispheric pediatric epilepsy. METHODS: A retrospective analysis of the epilepsy surgery database was done in all children (age <18 years) who underwent a peri-insular hemispherotomy (PIH) or a peri-insular posterior quadrantectomy (PIPQ) from April 2000 to March 2011. All patients underwent a detailed pre surgical evaluation. Seizure outcome was assessed by the Engel's classification and cognitive skills by appropriate measures of intelligence that were repeated annually. RESULTS: There were 34 patients in all. Epilepsy was due to Rasmussen's encephalitis (RE), Infantile hemiplegia seizure syndrome (IHSS), Hemimegalencephaly (HM), Sturge Weber syndrome (SWS) and due to post encephalitic sequelae (PES). Twenty seven (79.4%) patients underwent PIH and seven (20.6%) underwent PIPQ. The mean follow up was 30.5 months. At the last follow up, 31 (91.1%) were seizure free. The age of seizure onset and etiology of the disease causing epilepsy were predictors of a Class I seizure outcome. CONCLUSIONS: There is an excellent seizure outcome following disconnective epilepsy surgery for intractable hemispheric and subhemispheric pediatric epilepsy. An older age of seizure onset, RE, SWS and PES were good predictors of a Class I seizure outcome.