NDUFV1-Related Mitochondrial Complex-1 Disorders: A Retrospective Case Series and Literature Review.

BACKGROUND: Pathogenic variants in the NDUFV1 gene disrupt mitochondrial complex I, leading to neuroregression with leukoencephalopathy and basal ganglia involvement on neuroimaging. This study aims to provide a concise review on NDUFV1-related disorders while adding the largest cohort from a single center to the existing literature. METHODS: We retrospectively collected genetically proven cases of NDUFV1 pathogenic variants from our center over the last decade and explored reported instances in existing literature. Magnetic resonance imaging (MRI) patterns observed in these patients were split into three types-Leigh (putamen, basal ganglia, thalamus, and brainstem involvement), mitochondrial leukodystrophy (ML) (cerebral white matter involvement with cystic cavitations), and mixed (both). RESULTS: Analysis included 44 children (seven from our center and 37 from literature). The most prevalent comorbidities were hypertonia, ocular abnormalities, feeding issues, and hypotonia at onset. Children with the Leigh-type MRI pattern exhibited significantly higher rates of breathing difficulties, whereas those with a mixed phenotype had a higher prevalence of dystonia. The c.1156C>T variant in exon 8 of the NDUFV1 gene was the most common variant among individuals of Asian ethnicity and is predominantly associated with irritability and dystonia. Seizures and Leigh pattern of MRI of the brain was found to be less commonly associated with this variant. Higher rate of mortality was observed in children with Leigh-type pattern on brain MRI and those who did not receive mitochondrial cocktail. CONCLUSIONS: MRI phenotyping might help predict outcome. Appropriate and timely treatment with mitochondrial cocktail may reduce the probability of death and may positively impact the long-term outcomes, regardless of the genetic variant or age of onset.

Disseminated phaeohyphomycosis due to Cladophialophora bantiana in an immunocompetent child.

A 3-year-old boy presented with acute headache, vomiting and right focal clonic seizures without history of fever, joint pain or altered sensorium. Neuroimaging showed multifocal contrast enhancing lesions with significant perilesional edema. CECT chest and abdomen showed multiple variable sized nodules in the lungs and hypodense lesion in liver with mesenteric lymphadenopathy. There was persistent eosinophilia with maximum upto 35 %. Liver biopsy and brain biopsy revealed Cladophialophora bantiana. He was treated with IV liposomal amphotericin and voriconazole for 6 weeks with repeat neuroimaging showing more than 50 % resolution of the intracranial lesions. He was transitioned to oral combination of flucytosine and voriconazole. At 14 months follow-up, he remained symptom free with complete radiological resolution of the lesions and no eosinophilia. High suspicion, an aggressive approach in obtaining microbiological diagnosis and timely combination antifungal therapy may give satisfactory outcome without surgery.

Rare paediatric disorders in Indian healthcare settings with focus on neuromuscular disorders: Diagnostic and management challenges.

Rare diseases form the bulk of the financial expenditure of any developing or developed economy. Among the various rare diseases, paediatric neuromuscular disorders form a major portion, with a worldwide survey estimating a prevalence of 1 in 3500 individuals. In a lower middle-income country (LMIC) like India, malnutrition still accounts for most of the under-5 mortality. However, the economic burden of rare paediatric neuromuscular disorders cannot be underestimated. The treating physician should have a basic understanding of how to approach a child presenting with weakness and how to utilise the available tests which are affordable in an LMIC setting. History and examination still form the core, and with new diagnostic methods like nextgeneration sequencing, more and more rare disorders are getting diagnosed. It is important for the treating physician to know about basic supportive care, recent advancements, and available treatment options for these conditions. With exciting new treatment options being available for these disorders, the perception of these diseases as being not treatable is gradually changing. This review aims to be of guidance to clinicians from an LMIC setting like India and to empower them to manage such rare paediatric neuromuscular disorders.

Incident Breakthrough Seizures, Serum Matrix Metalloproteinase-9 and Perfusion Magnetic Resonance Imaging Parameters in a Cohort of Children and Adolescents With Neurocysticercosis: A Longitudinal Observational Study.

BACKGROUND: The current study estimated incident breakthrough seizures, serum matrix metalloproteinase-9 (MMP-9), and perfusion magnetic resonance imaging (MRI) parameters in five- to 18-year-olds with neurocysticercosis (NCC) from colloidal or vesicular through calcified stages over at least 24 months' follow-up. METHODS: Single, colloidal, or vesicular parenchymal NCC cases were treated with albendazole and steroids and followed at a tertiary care north Indian hospital. Serum MMP-9 was estimated in colloidal or vesicular treatment-naive state and in a subset of calcified cases at six-month follow-up. The same subset of calcified cases also underwent perfusion MRI of the brain at six-month follow-up. RESULTS: Among 70 cases, 70% calcified at six-month follow-up. Over a median follow-up of 30 months, the incidence of breakthrough seizures was 48.6% (61.2% in calcified and 19.2% in resolved, P = 0.001; 32.9% early [within six months] and 15.7% late [beyond six months], P = 0.02). Serum MMP-9 levels were higher in colloidal and vesicular compared with calcified stage (242.5 vs 159.8 ng/mL, P = 0.007); however, there was no significant association with breakthrough seizures and/or calcification in follow-up. In a subgroup of calcified cases (n = 31), the median relative cerebral blood volume on perfusion MRI in and around the lesion was lower in those with seizures (n = 12) than in those without (n = 19) (10.7 vs 25.2 mL/100 g, P = 0.05). CONCLUSIONS: In post-treatment colloidal or vesicular NCC, incident breakthrough seizures decrease beyond six months. In calcified NCC with remote breakthrough seizures, significant perilesional hypoperfusion is seen compared with those without seizures.

A Novel Neuroimaging Phenotype in the X-Linked Intellectual Disability with a Missense Mutation of CNKSR2 Gene.

Background: Mental retardation, X-linked, syndromic, Houge type (MRXSHG) is a form of mental retardation characterized by intellectual disability, speech and language impairments, and early-onset seizures. It has been recently recorded in Online Mendelian Inheritance in Man (OMIM), and only 10 cases have been reported in the literature so far. Objective: To highlight the novel neuroimaging findings in the pediatric X-linked intellectual disability with a missense mutation of connector enhancer of kinase suppressor of RAS2 (CNKSR2) gene. Material and Methods: We present a case of intellectual disability, refractory epilepsy, speech and language delay with subtle dysmorphism, and behavioral issues in an 11-year-old boy with novel neuroimaging findings in a CNKSR2 gene with missense mutation. Results: Brain MRI revealed involvement of the basal ganglia, predominantly the neostriatum, and along with the subependymal aspects with focal cavitations involving, especially the bilateral caudate heads. There was relative sparing of the globus pallidi and posterior putamina bilaterally. Whole-exome sequencing identified a hemizygous missense pathogenic variant in the CNKSR2 gene. The mother was found to be an asymptomatic carrier. Conclusion: This case report highlights the rare missense mutation in the CNKSR2 gene and abnormal neuroimaging findings, which further provide information about the phenotypic characteristics of X-linked syndromic intellectual disability.

Assessment of knowledge, attitude and practice (KAP) of parents/caregivers towards epilepsy in children - A cross- sectional observational study.

Objectives: The study aimed to assess the knowledge, attitude, and practice (KAP) of parents/caregivers toward epilepsy in paediatric patients at a tertiary care centre of North India. Methods: A cross sectional study was carried out among 418 parents or caregivers using convenience sampling technique with 16-item questionnaire in English language and also translated to local language that is Hindi. Children with epilepsy who visited the paediatric outpatient department within a year were included in the study (January 2021-22). A total of 450 children visited the clinic, 32 of whom were excluded for various reasons, and the final analysis was conducted among the 418 parents or caregivers who completed the questionnaire. Results: The male and female patients were 56.7% (n = 237) and 43.3% (n = 181) respectively. The age distribution of patients with less than 5 years, 6-10 years and more than 10 years were 35.6% (n = 149), 54.5% (n = 228), 9.8% (n = 41) respectively. Only one third of parents and caregivers did not consider epilepsy as psychiatric illness. Most of the parents and caregivers think that epilepsy affects school performance (77.2%) and hinders family life (71.0%). More than half of the parents or caregivers believes that the society discriminates against person with epilepsy and around 46.6% consider that alternative medicine can cure epilepsy. The parents or caregivers felt financial burden due to epilepsy was in 72.5% and approximately 78.5% perceived that their work is affected because of their child's epilepsy. Perception of epilepsy as a psychiatric illness was found to be significantly higher in parents with primary and secondary level education, when compared to parents who were graduates. The practice of the parents or caregivers towards administration of drugs to their child was good, however around 36.6% (n = 153) missed the dose of anti-seizure medications. Conclusion: The study highlights the substantial knowledge, attitude and practice gap amongst parents and caregivers for children with epilepsy which indirectly has huge impact on the management of epilepsy. Thus it becomes utmost important to educate the family as well as the community regarding epilepsy which will help in improving the therapeutic outcomes, overall quality of life and interpersonal and social relationships of these children.

Socio-cultural Adaptation and Validation of Ages and Stages Questionnaire (ASQ 3) in Indian Children Aged 2 to 24 Months.

OBJECTIVE: To socio-culturally adapt and validate a Hindi language version of ASQ-3 in Indian children aged 2-24 months. METHODS: This cross-sectional study was conducted at a tertiary-care center between March, 2017 and April, 2019. Children "at-risk" for developmental delay of either gender aged 2-24 months. Socio-cultural adaptation was done through interaction among 37 subject experts followed by validation. After piloting in 20 children, modified ASQ-3 was validated in 568 at-risk children (4 age-groups: 2-7, 7-13, 13-19 and 19-24 months). Validation was done against Development assessment scale for Indian infants (DASII). RESULTS: Results: After screening 654 children, 568 were enrolled. Among these, 420 had developmental delay on DASII while 18 failed to be identified on ASQ (4.3%). Overall sensitivity and specificity of Hindi language Indian-adaptation of ASQ-3 in detecting developmental delay were 95.9% (95%CI: 93.6%-97.5%) and 81.7% (95%CI: 74%-87.9%), respectively with a positive predictive value (PPV) of 94.6% (95%CI: 92%-96.5%) and negative predictive value (NPV) of 85.6% (95%CI: 78.2%-92.2%). The sensitivity and specificity for motor delay were 96.1% (93.8%-97.7%) and 92.4% (86.4%-96.3%) [PPV: 97.7% (95.8%-98.9%); NPV: 87.7% (81%-92.7%)]. Sensitivity and specificity for mental delay were 95.5% (93.1%-97.2%)and 95.3% (90.1%-98.3%) [PPV: 98.6% (97%-99.5%); NPV: 85.9% (79.1%-91.2%)]. CONCLUSION: The Hindi language Indian-adaptation of ASQ-3 had good psychometric properties with high sensitivity for developmental delay (95.9%), mental delay (95.5%), and motor delay (96.1%), suggesting it to be a good screening tool for neurodevelopmental delay.

Tumefactive demyelination in pediatrics: An unusual late neurological complication of hematopoietic stem cell transplant.

Immune-mediated demyelination is a rare posttransplant complication. Here, we report an 8.5-year-old boy who developed left hemiparesis, 18 months post matched sibling donor hematopoietic stem cell transplant (HSCT) for relapsed acute myeloid leukemia and was diagnosed to have tumefactive demyelination. The diagnosis was established based on clinical and radiological features. The complete resolution of the lesions with steroids further established the immune-mediated pathophysiology.