Publications by authors named "Lokesh Lingappa"

41 Publications

The spectrum of acute leukoencephalopathy with restricted diffusion (ALERD): A case series and review of literature.

Eur J Paediatr Neurol 2021 Jun 6;33:86-93. Epub 2021 Jun 6.

Department of Pediatric Neurology, Rainbow Children's Hospital, Hyderabad, Telangana, India. Electronic address:

Introduction: The clinico-etiological spectrum of Acute leukoencephalopathy with restricted diffusion (ALERD) is not well known in Indian population. This is likely to vary between populations and ethnicities.

Methods: We retrospectively reviewed the clinicoetiological spectrum of ALERD at a tertiary care pediatric center, and described the clinical, imaging, etiological spectrum and short-term outcomes.

Results: Eleven out of 78 children with non-traumatic encephalopathy presenting to our center had a final diagnosis of ALERD. The mean age at presentation was 34.9 months (6-80 months) and 63.6% were males. The monophasic course (72.7%) and the diffuse pattern (63.6%) on neuroimaging were predominant in these children. Dengue haemorrhagic fever was the commonest underlying/triggering infection (5 of 11 children). Ten children required mechanical ventilation in view of neurogenic respiratory failure, with mean duration of ventilation of 6.4 days (Range 2-10 days). The duration of hospital stay varied from 11 to 25 days (Mean - 15.3 days). One child (9 %) died, 6 children (54.5 %) had varying degrees of cognitive impairment and 4 (36.3 %) children had a normal outcome. Children with a shorter duration of ventilation seemed to have a better outcome.

Conclusion: Dengue haemorrhagic fever was the commonest cause, and diffuse imaging pattern with monophasic course was the commonest presentation in Indian children with ALERD. The clinical presentation and factors influencing outcome are possibly different from previously described literature.
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http://dx.doi.org/10.1016/j.ejpn.2021.05.017DOI Listing
June 2021

Clinical Profile, Yield of Cartridge-based Nucleic Acid Amplification Test (GeneXpert), and Outcome in Children with Tubercular Meningitis.

J Pediatr Neurosci 2020 Jul-Sep;15(3):224-230. Epub 2020 Nov 6.

Department of pediatric Neurology and Neuro-rehabilitation, Rainbow Children's Hospital and Perinatal Centre, Hyderabad, Telangana, India.

Background: GeneXpert MTB/RIF is a test for early, rapid diagnosis of tubercular meningitis (TBM).

Aim: The aim of this article was to study the clinical profile, radiological features, yield of GeneXpert, neurosurgical interventions, and outcome of TBM in children.

Settings And Design: This was a retrospective and prospective observational study.

Materials And Methods: Diagnosis was based on the uniform research definition criteria and was staged according to the British Medical Research Council. Mantoux test, analysis of cerebrospinal fluid (CSF), CSF GeneXpert, and radiological investigations were performed.

Results: Of 36 patients, 50% were aged 1-5 years. Fever (100%), headache (82%), altered sensorium (80%), and vomiting (66%) were common features. Twelve (33%) had contact with active case of tuberculosis; 32 received Bacille Calmette Guarin vaccination. Neurological features included severe deterioration in sensorium (Glasgow Coma Scale < 8) (38%), mild and moderate deficit in sensorium (31%), hemiparesis (41%), and involvement of sixth (25%) and seventh (22%) cranial nerves. Cerebral vision impairment (25%), papilledema (25%), and dystonia (22%) were other findings. CSF GeneXpert was positive in 37% (12/33) patients. Hydrocephalus and basal exudates (75%) were noted on neuro-imaging. Surgical intervention was performed in children with hydrocephalus (13/27). Omayya reservoir was placed in seven children, of which five needed conversion to ventriculoperitoneal (VP) shunt; direct VP shunt was carried out in six (6/13). Good outcome was noted in 78% at discharge. Stage III TBM ( = 0.0001), cerebral infarcts ( = 0.0006), and motor deficits ( = 0.03) were associated with poor outcome. Sequelae included learning difficulties with poor scholastic performance (31.5%).

Conclusion: GeneXpert has high diagnostic specificity, but negative results do not rule out TBM. CSF GeneXpert provided quick results. Placement of Ommaya reservoir in TBM stage II and III with hydrocephalus was not successful. Hydrocephalus was managed conservatively with success (53%).
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http://dx.doi.org/10.4103/jpn.JPN_92_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847089PMC
November 2020

Herbal Medicine-Induced Seizures in Children: Single-Center Experience Over 18 Months.

Indian Pediatr 2021 01;58(1):71-73

Department of Neurology, Rainbow Children's Hospital, Banjara Hills, Hyderabad 500 034, Andhra Pradesh, India.

Many common household herbal preparations may have seizurogenic ingredients. We report 15 children with seizures following exposure to such compounds: oral ingestion of liquid preparation in 13, and local application of balm and Eucalyptus oil ingestion in one each. All children, except one, had generalized seizures. This study highlights the need to address this history during evaluation of first seizure, and increase awareness of seizurogenic potential of such preparations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840423PMC
January 2021

Psychological outcomes, coping and illness perceptions among parents of children with neurological disorders.

Psychol Health 2020 Dec 15:1-17. Epub 2020 Dec 15.

Department of Liberal Arts, Indian Institute of Technology Hyderabad, Hyderabad, India.

Objective: To assess the Common Sense Model among parents of children with neurological disorders, by determining the prevalence of symptoms of anxiety and depression, and how illness perceptions relate to symptoms of anxiety and depression both directly, and indirectly via coping.

Design: 205 parents of children with neurological disorders in Hyderabad, India completed questionnaires.

Main Outcome Measures: Hospital Anxiety and Depression Scale, Brief Illness Perception Questionnaire and Coping Health Inventory for Parents. We used multiple regressions and PROCESS for SPSS to assess direct and indirect relationships.

Results: Mild to severe symptoms of anxiety (41.0%) and depression (39.5%) were common. Symptoms of anxiety and/or depression were related to perceived treatment control over the illness, perceived understanding of the illness, perceived personal control over the illness (anxiety only), and perceived timeline of the illness (depression only). The coping strategy 'maintaining social support' mediated the relationship between symptoms of depression and four illness perceptions: perceived consequences (95%CI=.03,-.21), timeline (95%CI=.01,-.25), perceived personal control (95%CI=.02-.24), and treatment control (95%CI=.01-.34).

Conclusion: Our findings have implications for education interventions to improve community attitudes of child neurological disorders. Such interventions may allow families' social networks to provide more support to parents, which could aid parents' coping strategies.
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http://dx.doi.org/10.1080/08870446.2020.1859113DOI Listing
December 2020

Persistent Craniopharyngeal Canal: A Rare Cause for Recurrent Meningitis in Pediatric Population.

Ann Indian Acad Neurol 2020 Jul-Aug;23(4):545-548. Epub 2019 Mar 5.

Department of Pediatric Hemato-Oncology, Rainbow Children's Hospital, Hyderabad, Telangana, India.

We present the case of a 5-year-old girl who had six episodes of meningitis. She also had panhypopituitarism and was found to have a persistent craniopharyngeal canal (CPC) as the cause of her recurrent meningitis. Role of neuroradiology and a high index of suspicion by the clinical team are highlighted here. Persistent CPC is a rare cause of recurrent meningitis. We discuss the approach to the child with recurrent meningitis.
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http://dx.doi.org/10.4103/aian.AIAN_411_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657271PMC
March 2019

Newborn screening and single nucleotide variation profiling of TSHR, TPO, TG and DUOX2 candidate genes for congenital hypothyroidism.

Mol Biol Rep 2020 Oct 15;47(10):7467-7475. Epub 2020 Sep 15.

Department of Biotechnology, Vignan's Foundation for Science, Technology & Research (Deemed to be University), Vadlamudi, Guntur, Andhra Pradesh, 522213, India.

High prevalence of congenital hypothyroidism (CH) among Indian newborns prompted us to establish population-specific reference ranges of TSH and to explore the contribution of the common genetic variants in TSHR, TPO, TG and DUOX2 genes towards CH. A total of 1144 newborns (593 males and 551 females) were screened for CH. SNV profiling (n = 22) spanning three candidate genes, i.e. TSHR, TPO and TG was carried out in confirmed CH cases (n = 45). In screen negative cases (n = 700), ten TSHR variants were explored to establish association with CH. No mutation found in DUOX2. The 2.5th to 97.5th percentiles of TSH in these newborns were 0.5 to 12.2 mU/L. In newborns with optimal birth weight, the cut-off was 10 mU/L. Lower or higher birth weight resulted in slightly higher TSH. Two TSHR variants, i.e. rs7144481 and rs17630128 were associated with agenesis, hypoplasia and goiter. The rs2268477 was associated with agenesis and hypoplasia. The rs1991517, rs2075176 and rs2241119 were associated with agenesis only. The rs7144481, rs17630128, rs1991517 and rs2268477 were associated with 2.17, 4.62, 2.91 and 2.29-fold increased risk for CH, respectively. Among the TPO variants, rs867983 and rs2175977 were associated with agenesis and goiter, respectively. Among the TG variants, rs2076740 showed association with agenesis and goiter. Two rare variants i.e. TPO g.IVS14-19 G>C and TG c.1262 C>T were observed in CH cases. No genetic variant identified in the two exons of DUOX2. To conclude, the current study established Indian population-specific normative values for TSH and demonstrates specific genotype-phenotype correlations among three candidate genes.
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http://dx.doi.org/10.1007/s11033-020-05803-xDOI Listing
October 2020

KCNT1-related epilepsy: An international multicenter cohort of 27 pediatric cases.

Epilepsia 2020 04 13;61(4):679-692. Epub 2020 Mar 13.

Neurology Division, Department of Pediatrics, Lady Harding Medical College and Kalawati Saran Children's Hospital, New Delhi, India.

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.
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http://dx.doi.org/10.1111/epi.16480DOI Listing
April 2020

Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders.

Pediatr Neurol 2020 05 4;106:43-49. Epub 2020 Feb 4.

Department of Pediatric Neurology, Rainbow Children Hospital, Hyderabad, India.

Background: Joubert syndrome and related disorders are a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosis. Joubert syndrome is a clinically and genetically heterogeneous disorder involving mutations in 35 ciliopathy-related genes. We present a large cohort of 59 patients with Joubert syndrome from 55 families. Molecular analysis was performed in 35 families (trio).

Methods: Clinical exome analysis was performed to identify causal mutations, and genotype-phenotype correlations were evaluated.

Results: All of the cases were stratified into pure Joubert syndrome (62.7%), Joubert syndrome with retinal disease (22.0%), polydactyly (8.5%), and liver (1.7%) and kidney (1.7%) involvement. Joubert syndrome-related disorders include Meckel-Gruber syndrome in 5.1% cases and Leber congenital amaurosis (1.7%). Of the 35 Joubert syndrome-related genes, 11 were identified in these patients, i.e., CEP290, C5ORF, TCTN1, CC2D2A, RPGRP1L, TCTN3, AHI1, INPP5E, TCTN2, NPHP1, and TMEM237. For the first time, we identified a ciliopathy gene, CCDC28B, as a causal gene in Joubert syndrome in one family. CEP290 accounted for 37.8% cases of pure Joubert syndrome, Joubert syndrome with retinal and renal disease, and Meckel-Gruber syndrome. The p.G1890∗ allele in CEP290 is highly recurrent. Of the six families with Joubert syndrome who had a prenatal diagnosis, one fetus was normal, two were carriers, and three were affected.

Conclusions: This is the largest study of Joubert syndrome from India. Although a high degree of locus and allelic heterogeneity was observed, CEP290 variants were the most common among these patients.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.01.012DOI Listing
May 2020

Identification and Characterization of a Novel CASK c.2546T>C (p.V849A) Mutation in a Male Infant with Pontocerebellar Hypoplasia.

Ann Indian Acad Neurol 2019 Oct-Dec;22(4):523-524. Epub 2019 Oct 25.

Department of Biochemical Genetics and Pharmacogenomics, Sandor Speciality Diagnostics Pvt Ltd, Banjara Hills, Road No: 3, Hyderabad, Andhra Pradesh, India.

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http://dx.doi.org/10.4103/aian.AIAN_2_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839305PMC
October 2019

An Unusual Combination of Neurological Manifestations and Sudden Vision Loss in a Child with Familial Hyperphosphatemic Tumoral Calcinosis.

Ann Indian Acad Neurol 2019 Jul-Sep;22(3):327-331

Department of Neurology and Hemato-Oncology, Rainbow Children's Hospital and Birthright, Hyderabad, Telangana, India.

Hyperphosphatemia in the absence of renal failure is an unusual occurrence, particularly in children, but is a common primary feature of familial hyperphosphatemic tumor calcinosis. We report a child with hyperphosphatemia who presented with multiple episodes of neurologic dysfunction involving lower motor neuron facial nerve palsy along with sequential visual loss. He also had an episode of stroke. There was an extensive metastatic calcification of soft tissue and vasculature. Hyperphosphatemia with normal serum alkaline phosphatase, calcium, parathyroid hormone, and renal function was noted. He was managed with hemodialysis and sevelamer (3 months) without much success in reducing serum phosphate level, requiring continuous ambulatory peritoneal dialysis (3 years). Intact fibroblast growth factor 23 () was undetectable, with C-terminal fragments significantly elevated (2575 RU/ml, normal <180 RU/ml). Sequencing demonstrated homozygous c.486C >A (p.N162K) mutation in , confirming the diagnoses of primary deficiency, the first case to be reported from India.
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http://dx.doi.org/10.4103/aian.AIAN_191_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613414PMC
July 2019

Association of Child Neurology-Indian Epilepsy Society Consensus Document on Parental Counseling of Children with Epilepsy.

Indian J Pediatr 2019 07 8;86(7):608-616. Epub 2019 Jun 8.

Department of Pediatric Neurology, Madhukar Rainbow Children's Hospital, Malviya Nagar, Delhi, 110017, India.

When a child is diagnosed with epilepsy, counseling regarding the same is done by the treating doctor. Most parents are frightened and have poor knowledge about epilepsy. Therapeutic advice including drug dosage, administration and side effects takes up the major part of physician's time, thereby neglecting important issues like home seizure management, follow up and others. These lacunae in knowledge require systematic patient and family education. To address these issues, an expert group meeting of pediatric neurologists and epileptologists in India along with social workers/epilepsy educators, legal experts, parents, and teachers was held. The various aspects regarding parental counseling in children with epilepsy were discussed and a consensus document was formulated. Here authors present the group consensus statement on counseling parents and caregivers of children with epilepsy. This document is intended to help physicians and pediatricians counsel the families when a child is diagnosed with epilepsy.
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http://dx.doi.org/10.1007/s12098-019-02946-zDOI Listing
July 2019

Immunodeficiency, Motor Delay, and Hypouricemia Caused by a Novel Mutation of Purine Nucleoside Phosphorylase Gene in an Indian Infant.

Ann Indian Acad Neurol 2019 Apr-Jun;22(2):231-233

Department of Clinical Genetics, MedGenome Laboratory, Bengaluru, Karnataka, India.

We describe an 11-month-old boy who presented with recurrent respiratory infections from 6 months of age. His elder sister died at 10 months with severe septicemia and meningitis. The boy had a mild motor delay. Investigations revealed T cell deficiency and very low serum uric acid suggestive of purine nucleoside phosphorylase (PNP) deficiency - a rare variant of severe combined immunodeficiency disease. A novel homozygous missense mutation of c.597C>G(p. S199R) of exon 5 on PNP gene confirmed the diagnosis. We suggest that uric acid should be a part of investigation profile for unidentified motor delay, as recurrent infections can be late presentation.
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http://dx.doi.org/10.4103/aian.AIAN_430_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472228PMC
April 2019

Ictal FDGPET and SPECT in hemifacial seizures due to cerebellar epilepsy-Case report.

Neurol India 2019 Jan-Feb;67(1):169-172

Department of Neurosurgery, Krishna Institute of Medical Sciences, Secunderabad, Telangana, India.

The role of cerebellum in seizure generation is debatable. Semiology and electroencephalography (EEG) findings are non-specific and sometimes misleading, posing further difficulty in proving the epileptogenicity in pre-surgical workup. We report two cases of cerebellar lesions who presented with hemifacial seizures since the neonatal period and were refractory to antiepileptic drugs (AEDs). Both inter-ictal and ictal EEGs were non-contributory. Magnetic resonance imaging (MRI) showed a lesion in the cerebellum, in proximity to cerebellar peduncle in both the patients. (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and ictal single photon emission computed tomography (SPECT) showed focal hypermetabolism and hyperperfusion respectively, corresponding to the lesion on MRI in both the cases. Intraoperative electrocorticography showed rhythmic spikes confirming the epileptogenic nature of the lesion. Both patients were operated with a favorable surgical outcome. Histopathology was suggestive of a ganglioglioma in one child and a low-grade glioma in the other. Both cases illustrate that FDG-PET and SPECT can act as surrogate markers for invasive recordings to prove the epileptogenicity of cerebellar lesions, especially in resource limited settings.
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http://dx.doi.org/10.4103/0028-3886.253622DOI Listing
December 2019

Juvenile idiopathic inflammatory myopathies: A clinicopathological study with emphasis on muscle histology.

Indian J Pathol Microbiol 2019 Jan-Mar;62(1):61-66

Department of Neurology, Institute of Neurological Sciences, Care Hospital, Hyderabad, Telangana, India.

Background: Juvenile idiopathic inflammatory myopathies (JIIM) are rare and heterogeneous. Subtype identification is important for treatment.

Materials And Methods: Patients below 18 years diagnosed as idiopathic inflammatory myopathy (IIM) according to the Bohan and Peter criteria between January 2010 and May 2015 were evaluated with muscle biopsy in the four domains: muscle fiber, inflammation, connective tissue, and vascular, with basic panel of histochemical stains as per recommendations of the European Neuromuscular center (ENMC) workshop 2015. Immunohistochemistry with CD 31 was done to assess capillary density.

Results: JIIM constituted 15.25% of IIM with juvenile dermatomyositis (JDM) being the most common subgroup (24/27) followed by juvenile overlap myositis (JOM) (3/27) in association with systemic lupus erythematosus (2) and systemic sclerosis (1). Muscle biopsy in JDM was characterized by perifascicular atrophy, necrosis, degeneration, and regeneration in all and the other features included perivascular inflammation (21), lymphoid aggregates (2), mitochondrial abnormalities (9), sarcoplasmic vacuoles (6), capillary dropout (5), capillary dilatation (6), and perimysial fibrosis (14). JOM was characterized by auto-antibodies and perivascular inflammation.

Conclusion: JIIMs were rare and JDM was the most common subtype. Muscle biopsy evaluation as per ENMC criteria characterized the subgroups.
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http://dx.doi.org/10.4103/IJPM.IJPM_387_17DOI Listing
May 2019

Case Reports: Survival from Rabies: Case Series from India.

Am J Trop Med Hyg 2019 01;100(1):165-169

Department of Pediatrics and Pediatric Intensive Care Unit, Seth G.S. Medical College and KEM Hospital, Mumbai, India.

Rabies, a zoonotic viral encephalitis, continues to be a serious public health problem in India and several other countries in Asia and Africa. Survival is rarely reported in rabies, which is considered to be almost universally fatal. We report the clinical and radiological findings of eight patients with laboratory-confirmed rabies who survived the illness. With the exception of one patient who recovered with mild sequelae, all survivors had poor functional outcomes. The reported survival from rabies in recent years may reflect an increased awareness of the disease and greater access to better critical care facilities in rabies-endemic countries. Nonetheless, there is an urgent need to focus on preventive strategies to reduce the burden of this dreadful disease in rabies-endemic countries.
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http://dx.doi.org/10.4269/ajtmh.18-0711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335910PMC
January 2019

Identification of Two Novel Mutations in Aminomethyltransferase Gene in Cases of Glycine Encephalopathy.

J Pediatr Genet 2018 Sep 6;7(3):97-102. Epub 2018 Jul 6.

Department of Biochemical Genetics, Sandor Lifesciences Pvt. Ltd., Banjara Hills, Hyderabad, Telangana, India.

In this study, we report three cases of nonketotic hyperglycinemia (NKHG) diagnosed biochemically and molecularly. Clinical exome analysis in two families revealed two novel mutations in the aminomethyltransferase (AMT) gene, that is, c.14_15insT (p.Ser6LysfsTer22) and c.259-2A > T, both of them adversely affecting the protein. This is the first report of AMT gene mutations in NKHG from India. Prenatal diagnosis in the first family showed an unaffected fetus in the third pregnancy. The role of AMT protein is pivotal for the synthesis of 5,10-methylene tetrahydrofolate, the first metabolite in one-carbon metabolism that regulates DNA synthesis, repair, and methylation.
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http://dx.doi.org/10.1055/s-0038-1667036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087477PMC
September 2018

A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy.

Mol Genet Genomic Med 2018 03 22;6(2):282-287. Epub 2017 Dec 22.

Medgenome Labs, Bommasandra, Bangalore, India.

Background: Several genes have been implicated in a highly variable presentation of developmental delay with psychomotor retardation. Mutations in EMC1 gene have recently been reported. Herein, we describe a proband born of a consanguineous marriage, who presented with early infantile onset epilepsy, scaphocephaly, developmental delay, central hypotonia, muscle wasting, and severe cerebellar and brainstem atrophy.

Methods: Genetic testing in the proband was performed using custom clinical exome and targeted next-generation sequencing. This was followed by segregation analysis of the variant in the parents by Sanger sequencing and evaluation of the splice variant by RNA sequencing.

Results: Clinical exome sequencing identified a novel homozygous intronic splice variant in the EMC1 gene (chr1:19564510C>T, c.1212 + 1G>A, NM_015047.2). Neither population databases (ExAC and 1000 genomes) nor our internal database (n = 1,500) had reported this rare variant, predicted to affect the splicing. RNA sequencing data from the proband confirmed aberrant splicing with intron 11 retention, thereby introducing a stop codon in the resultant mRNA. This nonsense mutation is predicted to result in the premature termination of protein synthesis leading to loss of function of the EMC1 protein.

Conclusion: We report, for the first time the role of aberrant EMC1RNA splicing as a potential cause of disease pathogenesis. The severe epilepsy observed in our study expands the disease-associated phenotype and also emphasizes the need for comprehensive screening of intronic splice mutations.
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http://dx.doi.org/10.1002/mgg3.352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902391PMC
March 2018

Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability.

Eur J Med Genet 2018 Feb 1;61(2):100-103. Epub 2017 Aug 1.

Paediatric Neurologist, Rainbow Children Hospital, Hyderabad, 500082, India.

In this study we present the first two cases from India of a rare inborn error of metabolism manifesting as dystonia and 3-methylglutaconic aciduria and a Leigh like lesions in the brain MRI associated with SERAC1 gene mutation, a phenotype characteristic of MEGDEL syndrome. A four base pair duplication in exon 15 i.e.NM_032861.3 (SERAC1) c. 1643_1646 dup ATCT (p.(Leu550SerfsX19)) and another with a homozygous missense variation in exon 15 i.e. NM_032861.3 (SERAC1) c.1709 G > A (p.(Gly526Glu)) were detected and both were novel mutations. Hepatopathy was observed in the neonatal period with lactic acidosis in one child and at the age of 5yrs in the other. These cases add to the existing number of patients identified till today and additional mutations in the SERAC1 gene.
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http://dx.doi.org/10.1016/j.ejmg.2017.07.013DOI Listing
February 2018

Light Microscopy and Polarized Microscopy: A Dermatological Tool to Diagnose Gray Hair Syndromes.

Int J Trichology 2017 Jan-Mar;9(1):38-41

Department of Pediatrics, Division of Pediatric Neurology, Rainbow Children's Tertiary Care Centre, Hyderabad, Telangana, India.

Gray hair syndromes are rare syndromes which have an autosomal recessive inheritance and are characterized by pigmentary dilution of skin and hair, defects in immunological function, and nervous system defects. They comprise three disorders namely Chediak-Higashi syndrome (CHS), Griscelli syndrome (GPS), and Elejalde syndrome. Clinically, it is difficult to distinguish these disorders as their clinical features may overlap. Hence, to make a correct diagnosis and differentiate between CHS and GPS light microscopic examination of skin and hair shafts as well as peripheral blood smear evaluations should be done. In cases where the diagnosis is not possible chromosomal analysis for specific mutations can be done. In resource-poor settings where chromosomal analysis is not possible, and light microscopy findings are inconclusive, polarized microscopy can serve as a useful tool to distinguish between CHS and GPS. We report three cases with gray hair syndromes where the diagnosis on light microscopy and polarized microscopy of hair shaft correlated with the bone marrow examination findings and chromosomal analysis, thus emphasizing the importance of a noninvasive, cost-effective, and time-saving alternative in the diagnosis of these syndromes.
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http://dx.doi.org/10.4103/ijt.ijt_21_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514796PMC
August 2017

Spinal muscular atrophy with respiratory distress syndrome (SMARD1): Case report and review of literature.

Ann Indian Acad Neurol 2016 Jul-Sep;19(3):395-8

Department of Pediatric Critical Care, Rainbow Children's Hospital, Banjara Hills, Hyderabad, Telangana, India.

Spinal muscular atrophy with respiratory distress syndrome (SMARD1) is a rare cause of early infantile respiratory failure and death. No cases have been currently described from India. Two low-birth-weight infants presented prior to 6 months of age with recurrent apnea and respiratory distress. Both required prolonged ventilation, and had distal arthrogryposis and diaphragmatic eventration. Nerve conduction study revealed motor sensory axonopathy. Genetic testing confirmed mutations in immunoglobulin mu binding protein (IGHMBP2). These two cases establish presence of SMARD1 in our population. Both infants died on discontinuation of ventilation. Antenatal diagnoses done in one pregnancy. Though rare, high index of suspicion is essential in view of poor outcome and aid antenatal counseling.
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http://dx.doi.org/10.4103/0972-2327.168635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980968PMC
August 2016

Congenital muscular dystrophy with inflammation: Diagnostic considerations.

Ann Indian Acad Neurol 2016 Jul-Sep;19(3):356-9

Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.

Background And Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD) vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α2 deficiency on immunohistochemistry (IHC).

Material And Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E), enzyme and immunohistochemistry (IHC) with laminin α2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α2 deficiency.

Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones) and three showed discontinuous, and less intense staining.

Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones.
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http://dx.doi.org/10.4103/0972-2327.186814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980959PMC
August 2016

Rare clinical presentation of diffuse large B-cell lymphoma as otitis media and facial palsy.

J Pediatr Neurosci 2016 Jan-Mar;11(1):58-60

Surya Fertility Centre, Banjara Hills, Hyderabad, Telangana, India.

Extra nodal presentation of Non Hodgkins Lymphoma (NHL) is a rare entity, and data available about the NHL that primarily involves of middle ear and mastoid is limited. We report a case of diffuse large B cell lymphoma (DLBCL), in a 2 year 8 month old boy, who developed otalgia and facial palsy. Computed tomography revealed a mass in the left mastoid. Mastoid exploration and histopathological examination revealed DLBCL. This case highlights the importance of considering malignant lymphoma as one of the differential diagnosis in persistent otitis media and/facial palsy.
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http://dx.doi.org/10.4103/1817-1745.181252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862291PMC
May 2016

Clinical profile and outcome of refractory convulsive status epilepticus in older children from a developing country.

Seizure 2016 Mar 1;36:31-35. Epub 2016 Feb 1.

Department of Neurology, Krishna Institute of Medical Sciences, Hyderabad, India.

Purpose: The current study evaluates the etiology, clinical course and outcome of refractory convulsive status epilepticus (CSE) in older children.

Methods: Retrospective analysis of data of 73 children with CSE, aged ≥2 and ≤12 years was performed. Odds ratios were calculated between variables for clinical course and outcome. Mortality of the group was analyzed using survival analysis.

Results: Thirty three (45.2%) children progressed to refractory status epilepticus (RSE). The most common etiology for CSE was acute symptomatic in 44 (60.3%) of which 37 had presumed CNS infections. The odds of progressing to RSE were higher in children with acute symptomatic etiology (OR 2.62; CI - 95%; 0.99-7.14; p=0.041). Progression to RSE increased the chances of severe sepsis by six times (OR 6.08; CI - 95%; 1.19-31.02; p=0.036) and acidosis by nearly 15 times (OR 14.77; CI - 95%; 1.19-31.02; p=0.020). Overall mortality was 13.7%, higher in RSE (21.2% vs.7.5%). Amongst the 63 surviving children followed for 1 year from discharge, progression to RSE increased the odds of disability by seven times (OR 7.08; CI 29.31; p=0.004).

Conclusion: Acute symptomatic etiology was the commonest cause of CSE among older children from developing country and increased the odds of progressing to RSE. RSE was significantly associated with disability at 1 year from discharge.
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http://dx.doi.org/10.1016/j.seizure.2016.01.014DOI Listing
March 2016

Congenital Disorder of Glycosylation (CDG) Presenting as Non-immune Hydrops Fetalis.

Indian J Pediatr 2016 Apr 14;83(4):359-60. Epub 2015 Sep 14.

Department of Neonatology, Rainbow Children's Hospital, Hyderabad, Andhra Pradesh, 500 034, India.

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http://dx.doi.org/10.1007/s12098-015-1895-zDOI Listing
April 2016

Teaching NeuroImages: Fetal deep medullary vein thrombosis presenting as progressive intracerebral hemorrhage.

Neurology 2015 Jul;85(1):e5-6

From the Departments of Neurology (R.K., N.S., L.L.) and Fetal Medicine (C.R.), Rainbow Hospital for Women and Children; and the Department of Neuroradiology (D.R.V.), Mediciti Hospitals, Hyderabad, India.

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http://dx.doi.org/10.1212/WNL.0000000000001719DOI Listing
July 2015

Spectrum of mutations in Glutaryl-CoA dehydrogenase gene in glutaric aciduria type I--Study from South India.

Brain Dev 2016 Jan 10;38(1):54-60. Epub 2015 Jun 10.

Pediatric Neurology, Rainbow Children Hospital, India.

Background: Glutaric aciduria type I is an autosomal recessive organic acid disorder. The primary defect is the deficiency of Glutaryl-CoA dehydrogenase (EC number 1.3.99.7) enzyme that is involved in the catabolic pathways of the amino acids l-lysine, l-hydroxylysine, and l-tryptophan. It is a treatable neuro-metabolic disorder. Early diagnosis and treatment helps in preventing brain damage.

Methods: The Glutaryl-CoA dehydrogenase gene (GCDH) gene was sequenced to identify disease causing mutations by direct sequencing of all the exons in twelve patients who were biochemically confirmed with GA I.

Results: We identified eleven mutations of which nine are homozygous mutations, one heterozygous and two synonymous mutations. Among the eleven mutations, four mutations p.Q162R, p.P286S, p.W225X in two families and p.V410M are novel. A milder clinical presentation is observed in those families who are either heterozygous or with a benign synonymous SNP. Multiple sequence alignment (MSA) of GCDH with its homologues revealed that the observed novel mutations are not tolerated by protein structure and function.

Conclusions: The present study indicates genetic heterogeneity in GCDH gene mutations among South Indian population. Genetic analysis is useful in prenatal diagnosis and prevention. Mutation analysis is a useful tool in the absence of non-availability of enzyme assay in GA I.
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http://dx.doi.org/10.1016/j.braindev.2015.05.013DOI Listing
January 2016

Michels syndrome: the first case report from India and review of literature.

Indian J Ophthalmol 2014 Sep;62(9):954-8

Pediatric Ophthalmology and Strabismus Sevices, Jasti V Ramanamma Children's Eye Care Center, L. V. Prasad Eye Institute, Hyderabad, Andhra Pradesh, India.

A 2-year 7-month-old girl born out of a consanguineous marriage, presented at our facility with clinical features characterized by the eyelid triad of blepharophimosis, blepharoptosis and epicanthus inversus in association with hypertelorism, cleft palate and craniosynostosis. This constellation of features is suggestive of Michels syndrome. At the time of writing this report, there were only ten reported cases worldwide and to the best of our knowledge, there have been no published reports from India.
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http://dx.doi.org/10.4103/0301-4738.143946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244746PMC
September 2014

Lingappa et al. reply.

Authors:
Lokesh Lingappa

Dev Med Child Neurol 2014 Jul 19;56(7):699-700. Epub 2014 Apr 19.

Rainbow Hospital for Women and Children, Hyderabad, India.

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http://dx.doi.org/10.1111/dmcn.12451DOI Listing
July 2014