Clinico-Etiological Spectrum and Functional Outcomes of Children with Pre-Status Dystonicus and Status Dystonicus (SD): A Descriptive Study.

Background: Status dystonicus (SD) is a life-threatening movement disorder emergency characterized by increasingly frequent and severe episodes of generalized dystonia, requiring urgent hospital admission. The diverse clinico-etiological spectrum, high risk of recurrence, and residual disabilities complicate functional outcomes. Aim: We aim to describe the clinico-etiological spectrum, radiology, therapeutic options, and follow-up of patients with pre-status dystonicus (pre-SD) and SD. Methodology: A cross-sectional retrospective study was carried out in a tertiary care referral center. The clinical, laboratory, and radiology data of all patients aged less than 18 years with pre-SD and SD from January 2010 to December 2020 were collected. The Dystonia Severity Assessment Plan (DSAP) scale for grading severity and the modified Rankin Scale (mRS) for assessing outcome were used at the last follow-up visit. Results: Twenty-eight patients (male:female: 2.1:1) experiencing 33 episodes of acute dystonia exacerbation were identified. The median age at the onset of dystonia and SD presentation was 8.71 (range: 0.25-15.75) and 9.12 (range: 1-16.75) years, respectively. Four patients experienced more than one episode of SD. The etiological spectrum of SD includes metabolic (Wilson's disease-13, L-aromatic amino acid decarboxylase deficiency-one, and Gaucher's disease-one), genetic (neurodegeneration with brain iron accumulation-three and KMT2B and THAP 1 gene-related-one each), structural-three, post-encephalitic sequelae (PES)-four, and immune-mediated (anti-NMDA receptor encephalitis-one). Five patients had pre-SD (DSAP grade 3), and 23 patients had established SD (DSAP grade 4-17 and DSAP grade 5-six). The Rapid escalation of chelation therapy precipitated SD in 11 patients with Wilson's disease. Febrile illness or pneumonia precipitated SD in nine patients. Twenty-three episodes of SD required midazolam infusion in addition to anti-dystonic medications. The median duration of hospital stay was 10 days (range: 3-29). Twenty-three patients had resolution of SD but residual dystonia persisted, while two patients had no residual dystonia at follow-up. Three patients succumbed owing to refractory SD and its complications. Conclusion: Early identification of triggers, etiology, and appropriate management are essential to calm the dystonic storm.

Childhood Neurological Disorders With Hyperhomocystinemia: A Case-Based Review.

Hyperhomocysteinemia is a rare neurometabolic syndrome with diverse manifestations in the pediatric age group, thereby posing a diagnostic challenge. Biochemical testing is imperative to guide plan of evaluation, which may include appropriate genetic testing, in inherited disorders. Through this case-based approach, we demonstrate the heterogeneity of clinical presentation, biochemical and genetic evaluation, and treatment strategies that may reverse this condition among children.

Case report of a rare purine synthesis disorder due to 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICAR) deficiency.

BACKGROUND: AICA (5-aminoimidazole-4-carboxamide) ribosiduria is an inborn error in purine biosynthesis caused due to biallelic pathogenic variants in the 5-aminoimidazole-4-carboxamide ribonucleotide-formyltransferase/imp cyclohydrolase (ATIC) gene located on chromosome 2q35. ATIC codes for a bifunctional enzyme, AICAR transformylase and inosine monophosphate (IMP) cyclohydrolase, which catalyse the last two steps of de novo purine synthesis. This disorder has been previously reported in only 4 cases worldwide, and herein, we report the first from India. CASE REPORT: The proband presented with global developmental delay, developmental hip dysplasia (DDH), acyanotic heart disease and nystagmoid eye movements. Whole exome sequencing (WES) identified compound heterozygous pathogenic variants in the ATIC. A novel splice site variant; c.1321-2A > G and a previously reported missense variant; c.1277A > G (p.Lys426Arg) were identified. Segregation analysis of parents showed the father to be a heterozygous carrier for the splice site variant and the mother, a heterozygous carrier for the missense variant. CONCLUSION: This case of a rare genetic disorder of purine biosynthesis of ATIC deficiency is the first case reported from India. Early diagnosis lead to early interventional therapy and genetic counselling.

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.

Clinicoradiological Spectrum of L-2-Hydroxy Glutaric Aciduria: Typical and Atypical Findings in an Indian Cohort.

CONTEXT: Neurometabolic disorders form an important group of potentially treatable diseases. It is important to recognize the clinical phenotype and characteristic imaging patterns to make an early diagnosis and initiate appropriate treatment. L-2-hydroxy glutaric aciduria (L2HGA) is a rare organic aciduria with a consistent and highly characteristic imaging pattern, which clinches the diagnosis in most cases. AIMS: The study aims to describe the clinical profile, magnetic resonance imaging (MRI) patterns, and outcome in a cohort of children with L2HGA and to assess the clinicoradiological correlation. MATERIALS AND METHODS: This is a retrospective descriptive study done at the Department of Radiodiagnosis and Neurological Sciences of our institution. Clinical and radiological findings of children diagnosed with L2HGA over an 8-year period (2010-2017) were collected and analyzed. Descriptive statistical analysis of clinical and imaging data was performed. RESULTS: There were six girls and four boys. A total of 14 MRI brain studies in 10 patients with the diagnosis were analyzed. MRI of all patients showed a similar pattern with extensive confluent subcortical white-matter signal changes with symmetrical involvement of dentate nuclei and basal ganglia. In two children who presented with acute decompensation, there was asymmetric cortical involvement and restricted diffusion, which are previously unreported. There was no significant correlation between the radiological pattern with the disease duration, clinical features, or course of the disease. CONCLUSION: MRI findings in L2HGA are highly consistent and diagnostic, which helps in early diagnosis, particularly in resource-constraint settings, where detailed metabolic workup is not possible. The article also describes novel clinical radiological profile of acute encephalopathic clinical presentation.

Revisiting magnetic resonance imaging pattern of Krabbe disease - Lessons from an Indian cohort.

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.

Novel Imaging Finding and Novel Mutation in an Infant with Molybdenum Cofactor Deficiency, a Mimicker of Hypoxic-Ischaemic Encephalopathy.

Molybdenum cofactor deficiency is a rare metabolic disorder manifesting with early onset seizures, developmental delay, microcephaly, and spasticity. In this report, we describe a three-month-old infant with neonatal onset, poorly controlled seizures, developmental delay, microcephaly, spastic quadriparesis and visual insufficiency. Magnetic resonance imaging of brain had shown cystic encephalomalacia involving bilateral parieto-occipital lobe and elevated lactate in magnetic resonance spectroscopy. Restricted diffusion noted along the corticospinal tract in our case is a novel imaging finding in patients with molybdenum cofactor deficiency. Low serum uric acid and elevated urine sulfite excretion were observed. A novel homozygous mutation was detected in exon 4 of molybdenum cofactor synthesis 2 (MOCS2) gene. Early infantile or neonatal onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking hypoxic-ischaemic encephalopathy should raise the suspect for molybdenum cofactor deficiency. Screening of all neonates for urinary sulfite metabolites would help in early diagnosis and management. Early diagnosis and treatment with cyclic pyranopterin monophosphate could arrest the progression of molybdenum cofactor deficiency type A. More research is needed to explore further treatment options in this otherwise lethal disorder.