Sangeetha Yoganathan

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism–dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

Beta Propellar Protein-Associated Neurodegeneration: A Rare Cause of Infantile Autistic Regression and Intracranial Calcification.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of single gene disorders with distinguished clinical phenotypes and definitive imaging findings. Beta propeller protein-associated neurodegeneration (BPAN) is a subentity of NBIA with X linked dominant inheritance. In this report, we describe a girl with autistic regression, seizures, intracranial calcification, iron accumulation in substantia nigra, and globi pallidi, and diagnosis of BPAN was established based on the identification of previously described disease causing variant in WD repeat domain 45 (WDR45) gene encoding for β propeller protein. This is the first genetically proven case from India. BPAN is an underrecognized disorder and must be considered as a differential diagnosis in children with atypical Rett features and should be enlisted among the causes for autistic regression and intracranial calcification. Pediatricians must be aware of this rare entity for establishing early diagnosis, prognostication, and genetic counseling. Treatment is usually supportive. More research is needed to explore drugs in the management of BPAN that can facilitate the autophagy and promotes cytoprotection.

Eye of tiger sign mimic in an adolescent boy with mitochondrial membrane protein associated neurodegeneration (MPAN).

Neurodegeneration with brain iron accumulation (NBIA) refers to an inherited heterogeneous group of disorders pathologically characterized by focal brain iron deposition. Clinical phenotype, imaging findings and genotype are variable among the different types of this disorder. In this case report, we describe the imaging finding of an adolescent boy with mitochondrial membrane protein associated neurodegeneration (MPAN), a subentity of NBIA. Magnetic resonance imaging of brain revealed hypointensity of globi pallidi with medial medullary lamina appearing as a hyperintense streak in T2 weighted images. Mild cerebellar atrophy in T2 weighted images and blooming of substantia nigra and globi pallidi in susceptibility weighted images were also observed. Imaging findings in patients with MPAN mimics the eye of tiger appearance in patients with pantothenate kinase associated neurodegeneration. Classical phenotype and eye of tiger sign mimic in imaging of patients with NBIA should raise the suspect for MPAN. Genetic studies helps in the confirmation of diagnosis of this neurodegenerative disorder.

Predictors of outcome in children with status epilepticus during resuscitation in pediatric emergency department: A retrospective observational study

Objectives: To study the clinical profile and predictors of outcome in children with status epilepticus (SE) during resuscitation in pediatric emergency department. Materials and Methods: This retrospective study was carried out in a tertiary care teaching hospital. Admission and resuscitation data of children, aged between 1 month and 12 years, treated for SE, between September 2013 and August 2014, were extracted using a standard data collection form. Our SE management protocol had employed a modified pediatric assessment triangle to recognize and treat acute respiratory failure, cardiovascular dysfunction (CD), and subtle SE until all parameters resolved. Continuous positive airway pressure, fluid boluses based on shock etiology, inotropes, and cardiac safe anticonvulsants were the other modifications. Risk factors predicting mortality during resuscitation were analyzed using univariate and penalized logistic regression. Results: Among 610 who were enrolled, 582 (95.4%) survived and 28 (4.6%) succumbed. Grunt odds ratio (OR): 3.747 (95% confidence interval [CI]: 1.035−13.560), retractions OR: 2.429 (95% CI: 1.036−5.698), rales OR: 10.145 (95% CI: 4.027−25.560), prolonged capillary refill time OR: 3.352 (95% CI: 1.339−8.388), and shock requiring >60 mL/kg fluids OR: 2.439 (95% CI 1.040−5.721) were associated with 2−3 times rise in mortality. Inappropriate prehospital treatment and CD were the significant predictors of mortality OR: 7.82 (95% CI 2.10−29.06) and 738.71 (95% CI: 97.11−999), respectively. Resolution of CD was associated with improved survival OR: 0.02 (95% CI: 0.003−0.17). Conclusion: Appropriate prehospital management and treatment protocol targeting resolution of CD during resuscitation could reduce mortality in children with SE.

Study of refractory status epilepticus from a tertiary care center

Objectives: To determine the proportion of refractory status epilepticus (RSE) and super-RSE (SRSE) among patients with status epilepticus (SE) and to analyze RSE and non-RSE (NRSE) in terms of etiology and predictors for RSE. Materials and Methods: Patients were identified from discharge summaries database with keywords of SE and records of the portable electroencephalogram (EEG) machine from January 2011 to March 2016. Results: Two hundred and eighteen events were included in the study with 114 (52.3%) males, bimodal age preponderance age <5 years 30%, and second peak in age 15–65 years 52.8%, preexisting seizures were present in 34.4% (n = 75). Nearly 77.1% had NRSE (n = 168) and 22.9% had RSE (n = 50). This included 17 patients with SRSE (n = 17, 7.8% of all SE). Central nervous system (CNS) infection was a single largest etiological group in SE (69/218, 31.7%). In RSE, autoimmune encephalitis (17/50) and CNS infection (13/50) were the largest groups. De novo seizures (P = 0.007), low sensorium at admission (P = 0.001), low albumin at admission (P = 0.002), and first EEG being abnormal (P = 0.001) were risk factors on bivariate analysis. An unfavorable status epilepticus severity score (STESS) was predictive for RSE (P = 0.001). On multivariate analysis, de novo seizures (P = 0.009) and abnormal EEG at admission (P = 0.03) were predictive for RSE. Conclusions: Fifty patients had RSE (22.9%), of which 17 went on to become SRSE (7.8%). Unfavorable STESS score was predictive for RSE on bivariate analysis. On multivariate analysis, de novo seizures and abnormal initial EEG were predictors of RSE.

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.

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.

Teaching NeuroImages: Acute necrotizing encephalopathy of childhood: Neuroimaging findings

A 10-month-old infant was brought to the hospital in status epilepticus, preceded by a 2-day history of fever and loose stools. Brain MRI revealed swelling and T2 hyperintensity involving the thalami, white matter, and dorsal brainstem (figure 1). The thalamic lesions showed a trilaminar appearance on the diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) images, with hemorrhagic foci on susceptibility-weighted imaging (figures 1 and 2).

Menkes disease and response to copper histidine: An Indian case series

Background: Menkes disease (MD) is an X-linked recessive neurodegenerative disorder caused by mutations in ATP7A gene. Depending on the residual ATP7A activity, manifestation may be classical MD, occipital horn syndrome, or distal motor neuropathy. Neurological sparing is expected in female carriers. However, on rare occasions, females may manifest with classical clinical phenotype due to skewed X-chromosome inactivation, X-autosome translocation, and XO genotype. Here, we describe a small series of probands with MD and their response to copper histidine therapy. This series also includes a female with X-13 translocation manifesting neurological symptoms. Methods: The clinical profile, laboratory and radiological data, and follow-up of four children with MD were collected from the hospital database and are being presented. Results: All the four children in our series had developmental delay, recurrent respiratory tract infections, hair and skeletal changes, axial hypotonia, tortuous vessels on imaging, low serum copper, ceruloplasmin, and elevated lactate. Fetal hypokinesia and fetal growth retardation were present in two cases. Failure to thrive was present in three children and only one child had epilepsy. Subcutaneous copper histidine was administered to all children. The average time lapse in the initiation of treatment was 20.3 months, and average duration of follow-up was 14.3 months. Conclusion: We conclude that copper histidine therapy is beneficial in reversing the skin and hair changes, improving appendicular tone, socio-cognitive milestones, and improving weight gain, and immunity. Early diagnosis and management of MD are essential to have a better clinical outcome. More research is needed to explore and devise new strategies in the management of patients with MD.

Stroke in a child with dengue encephalopathy

Annals of Indian Academy of Neurology ¦ Volume 20 ¦ Issue 3 ¦ July-September 2017 329 Sir, Dengue is a mosquito-borne viral disease caused by dengue virus that belongs to the genus Flavivirus, transmitted by two mosquito vectors, namely, Aedes aegypti and Aedes albopictus.[1] Dengue with or without warning signs, and severe dengue are the categories of disease under the WHO recent classification.[1] This recent clinical case definition had stated to consider all patients with neurological manifestations under severe dengue. Here, we describe the clinical presentation, neuroimaging findings, and management of a child with dengue encephalopathy manifesting with seizures and stroke. Neuroimaging had shown pontine bleed and watershed infarcts in this child.