Compressive Myelopathy Secondary to TRPV4 Skeletal Dysplasia: Spondylometaphyseal Dysplasia, Kozlowski Type.

Transient receptor potential vanilloid 4 channel ( TRPV4 ) gene mutations have been described in skeletal system and peripheral nervous system pathology. The case described here is a 9-year-old male child patient, born to a nonconsanguineous marriage with normal birth history who had difficulty in walking and stiffness of joints for the last 7 years, and progressive weakness of all four limbs and urine incontinence for 1 year following falls. Physical examination showed below-average weight and height and short trunk. Musculoskeletal examination revealed bony prominence bilaterally in the knee joints and contractures in knee and elbow joints with brachydactyly; muscle tone was increased, with brisk deep tendon reflexes. Skeletal survey showed platyspondyly with anterior beaking with metaphyseal dysplasia. Magnetic resonance imaging of the spine revealed atlantoaxial instability with hyperintense signal changes at a cervicomedullary junction and upper cervical cord with thinning and spinal canal stenosis suggestive of compressive myelopathy with platyspondyly and anterior beaking of the spine at cervical, thoracic and lumbar vertebrae. Exome sequencing revealed a heterozygous de novo variant c.2389G > A in exon 15 of TRPV4 , which results in the amino acid substitution p.Glu797Lys in the encoded protein. The characteristics observed indicated spondylometaphyseal dysplasia, Kozlowski type (SMD-K). The child underwent surgical intervention for compressive myelopathy by reduction of atlantoaxial dislocation with C1 lateral mass and C2 pars fusion using rib graft and fixation using screws and rods. To conclude, for any child presenting with progressive kyphoscoliosis, short stature, platyspondyly, and metaphyseal changes, a diagnosis of SMD-K should be considered and the patient and family should be advised to avoid spinal injuries.

Idiopathic Hypereosinophilic Syndrome Presenting with Recalcitrant Oral and Genital Ulcers Responding Well to Thalidomide.

Hypereosinophilic syndrome is a myeloproliferative disorder characterized by abnormal accumulation of eosinophils in the blood or peripheral tissues. It is uncommonly seen in children. We describe a 14-year-old girl diagnosed with idiopathic hypereosinophilic syndrome presenting with recurrent, painful oral and genital ulcers, hepatosplenomegaly along with consistently high eosinophil count and leucocytosis. Genetic studies showed negative for FIPIL-PDGFRA fusion gene. Mucosal ulcers were recalcitrant to conventional therapy and responded well to thalidomide.

Case Series of Ethylmalonic Encephalopathy from Southern India.

Ethylmalonic encephalopathy is a rare neurometabolic disorder with central nervous system involvement and vasculopathy. It is presented in infancy with developmental delay, acrocyanosis, petechiae, chronic diarrhea, and early death. This was a retrospective study of confirmed cases of ethylmalonic aciduria from a tertiary care hospital over a period of 5 years from January 2015 to December 2020. Case details including analysis of clinical history, investigations, and outcomes are presented. Of six cases, male-to-female ratio was 4:2. Mean age of presentation was 35.5 months (range: 14-83 months). Consanguinity, global developmental delay, failure to thrive, skin rashes, microcephaly, hypotonia, and exaggerated deep tendon reflexes were observed in all cases. Chronic diarrhea was presented in five cases. The serum levels of C4 carnitine and urinary levels of ethylmalonic acid were increased in all cases. Magnetic resonance imaging (MRI) of the brain showed heterogenous bilateral symmetrical changes in the basal ganglia in five cases, and in one case, MRI could not be done. Genetic testing in two cases showed a homozygous variant in ETHE1 gene. Four children died, while the other two cases showed a decreased in recurrent encephalopathies and diarrhea after starting metronidazole. All children had global developmental delay, failure to thrive, skin rashes, central hypotonia, increased C4 carnitine levels in the serum, and increased ethylmalonic acid in the urine. Chronic diarrhea, acrocyanosis, and basal ganglia change in the MRI of the brain also give important clues for diagnosis. Metronidazole is useful in preventing recurrent episodes of encephalopathy.

Infantile Systemic Hyalinosis Presenting as Pseudo-Paralysis in Infancy: Study of Six Cases.

Infantile systemic hyalinosis is a very rare fatal autosomal recessive genetic disorder with a mutation in capillary morphogenesis gene-2- CMG2 /Human anthrax toxin-2 ANTXR2 resulting in spindle cell proliferation, altered collagen metabolism along with extensive deposition of hyaline material in the skin and several tissues. To date only a few cases have been reported in the literature, hence we reported this series. This study is a retrospective chart review of infants diagnosed with infantile systemic hyalinosis from January 2015 through December 2020 at a tertiary care children's hospital in South India. The mean age of presentation was 9.4 months, with a male to female ratio of 1:5. All children were born of consanguineous marriage except one child. All children had symptoms at birth, painful limb movements, multiple joint stiffness, gingival thickening, skin lesions around perianal, perioral areas, and frog-like position. Three (50%) children had stiff skin. Routine tests including complete blood count, liver function test, renal function test, creatine phosphokinase, nerve conduction studies, and metabolic tests were normal in all children. Skin biopsy showed hyalinized collagenous tissue in the dermis. Genetic study results of two cases revealed pathogenic variants in ANTXR2 gene. Infantile systemic hyalinosis should be considered in infants presenting with painful limb movements. The diagnosis helped in avoiding unnecessary investigations and prognostications. The genetic information from proband mutation helped in prenatal diagnosis in two families.

Childhood movement disorders: Clinicoetiological pattern and long-term follow-up at tertiary care center from South India.

Objectives: Movement disorders are common neurological problems. There is a considerable delay in the diagnosis of movement disorders which indirectly indicates their under-recognition. The studies regarding relative frequencies and their underlying etiology are limited. Describing and classifying them with a diagnosis helps in treating the condition. To study the clinical pattern of various movement disorders in children and to establish their etiology and outcome. Materials and Methods: This observational study was conducted in tertiary care hospital from January 2018 to June 2019. Children from 2 mo. to 18 years of age presenting with involuntary movements on the first Monday of every week were included in the study. History and clinical examination were carried out with a pre-designed proforma. A diagnostic workup was done, results were analyzed to find the common movement disorders and their etiology, and follow-up was analyzed for 3 years. Results: A total of 100 cases out of 158 with known etiology were included in the study of which 52% were females and 48% were males. The mean age at presentation was 3.15 years. The various movement disorders are dystonia-39(39%), choreoathetosis-29(29%), tremors-22(22%), gratification reaction-7(7%), and shuddering attacks-4(4%). Ballismus and myoclonus were found in 3(3%) children each. Tics, stereotypes, and hypokinesia were found in 2(2%) children each. A total of 113 movement disorders were found in 100 children. Etiologically, perinatal insult was the most common cause 27(27%), followed by metabolic/genetic/hereditary causes 25(25%). Infantile tremor syndrome due to Vitamin B12 deficiency-16/22(73%), was a major contributor in children with tremors. Rheumatic chorea was less in our study 5(5%). Out of the 100 study subjects, 72 cases were followed up. Out of which 26 children have completely recovered. Based on the modified Rankins score(MRS), 7 children belong to category I, 2 children belong to category II, 1 child to category III, 6 children to category IV, and 14 children to category V of MRS. A total of 16 children have died (MRS VI). Conclusion: Perinatal insult and Infantile tremor syndrome are more important and preventable causes. Rheumatic chorea is found to be less common. A significant number of children had more than one type of movement disorder, which warrants the need to look for varied types of movement disorders in the same child. Long-term follow-up shows complete recovery in one-fourth of children and the remaining surviving with disability.

Cohort of Phenotype, Genotype, and Outcome of SCN Developmental and Epileptic Encephalopathies from Southern Part of India.

The SCN encephalopathies are one of the rare early childhood intractable epileptic encephalopathies associated with pleomorphic seizures, cognitive decline, motor, and behavioral abnormalities that begin in early infancy. There is a dearth of data on phenotype and genotype of SCN encephalopathies from the Indian subcontinent, hence we are reporting clinical and molecular profile and outcome of SCN developmental and epileptic encephalopathies. This is a retrospective chart review of SCN developmental and epileptic encephalopathies in a tertiary care center, Bangalore, India between January 2015 and March 2020. All children with clinical features of SCN developmental and epileptic encephalopathies and confirmed with pathogenic variants were included. A total of 50 cases of SCN developmental and epileptic encephalopathies were analyzed, 31 of them were male and the mean age of presentation was 7.8 months. Precipitating factors for the first episode of seizure were fever and vaccination accounting for 33 and 8 children, respectively. Forty (80%) children had prolonged seizures and 15 (30%) had epileptic spasms. All children had a normal birth history and normal development before the onset of seizures, which was followed by developmental delay and regression. Thirty (60%) children had behavioral difficulties, notable hyperactivity, and autistic features. Neuroimaging and the initial electroencephalogram (EEG) were normal in all patients. The mean age of abnormal EEG was 14 months. The various subtypes of SCN variants were SCN1A in 31 children followed by SCN2A and SCN9A in eight children each and SCN1B in three children. Frameshift and nonsense mutations were associated with more severe phenotype and poor outcome compared with missense mutations. Thirty-four patients partially responded to treatment and the rest were refractory. The results of genetic testing were used to guide treatment; sodium channel blocking antiepileptic drugs were discontinued in 15 patients and sodium channel blocking agents were started in 3 patients with partial response. Three out of four children on stiripentol had a partial response. The SCN developmental and epileptic encephalopathies can present with epileptic spasms in addition to other types of seizures. Epileptic spasms are more common in nonsense and frameshift mutations. The outcome is poor in children with epileptic spasms compared with those without epileptic spasms. Genetic testing helps to select antiepileptic drugs that lead to seizure reduction.

Basal Ganglia Autoimmune Encephalitis Following Leptospirosis.

Basal ganglia encephalitis is a part of the spectrum of autoimmune basal ganglia disorders. We are reporting a child who had a fever with focal seizures followed by behavioral problems, rigidity, bradykinesia, and dystonia. His parkinsonism-like features were increasing day by day up to the level that the child was non-ambulatory. His initial Magnetic Resonance Imaging (MRI) of the brain showed asymmetrical T2 hyperintensities involving both the caudate nuclei and putamina. Later, with progressive symptoms, repeat MRI revealed a swelling and symmetrical signal change in both the caudate nuclei and putamina in the form of T2 and Fluid-attenuated inversion recovery (FLAIR) hyperintensities. In addition, there was T2 hyperintensity involving bilateral substantia nigra. Serum basal ganglia antibody, Leptospira Immunoglobulin M (IgM) antibody was positive, and Cerebrospinal Fluid (CSF) oligoclonal band was positive. So, the child was diagnosed with post-leptospirosis autoimmune basal ganglia encephalitis. He was managed with immunomodulatory agents and significant improvement in the symptoms with mild residual extrapyramidal symptoms were noted.

A Treatable Cause of Myelopathy: Biotinidase Deficiency Presenting as Acute Flaccid Paralysis.

Biotinidase deficiency (BD) is a rare treatable cause of neurometabolic disorders. It is an autosomal recessive disorder that manifests with cutaneous and neurological manifestations. Spinal cord involvement is uncommon with only a few cases reported in the literature. A 6-year-old female child presented with progressive difficulty in walking since 2 months. At 6 months of age, the child was elsewhere evaluated for global developmental delay and suspected as metabolic disorders and started on megavitamins, following which the child was improved. For the past 2 years, she has stopped medicines. On examination, irritable, alopecia, eczema, hypotonia, and power of two-fifths in all four limbs, and exaggerated deep tendon reflexes. The magnetic resonance imaging (MRI) brain and spine showed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities in periaqueductal gray matter, dorsal midbrain, pons, medulla, and cervical cord. She was suspected to have BD and confirmed by low enzyme levels and pathogenic variant in BTD . She was started on biotin supplements that resulted clinically dramatic improvement and MRI became normal within 4 weeks. Any child presenting with acute flaccid paralysis with brainstem and spinal cord noncompressive lesions on MRI, rare treatable conditions like BD should be considered in developing countries, like India, where still no universal newborn screening facilities are available.

A Randomized Controlled Trial on the Study of Effectiveness and Safety of Hormonal (ACTH) Treatment Alone versus Hormonal (ACTH) with Levetiracetam for Epileptic Spasms.

Background West's syndrome (WS) is a triad of epileptic spasms (ESs), psychomotor delay, and hypsarrhythmia. The treatment of ESs is still controversial. Hence, we designed a randomized controlled trial (RCT) to compare the outcomes in children with WS treated with adrenocorticotropic hormone (ACTH) alone versus ACTH and levetiracetam (LEV). Objectives To compare the treatment outcomes and side effects in children treated with ACTH alone versus ACTH and LEV. Methods This prospective randomized controlled trial was conducted from December 2017 to May 2019 in tertiary care center, Bangaluru. Children from 2 months to 5 years of age, diagnosed with WS were included. Fifty children in each group were analyzed for efficacy and side effects. Results There was no difference in the baseline characteristics in both groups. There was no difference in spasms response at the end of 2 weeks between the groups (88 vs. 82%) with p -value of 0.813. The relapse rates were less in ACTH and LEV group (20%) compared with ACTH alone (22%) but statistically not significant ( p > 0.1). There was no difference observed in subsequent epilepsy rates (18%) in ACTH versus 19% in ACTH with LEV group ( p > 0.1) and side effects. There was improvement in milestones 48% in ACTH with LEV group versus 37% in ACTH alone however statistically not significant ( p > 0.1). Conclusion There was no difference in children treated with ACTH alone versus ACTH and LEV in terms of control of spasms and subsequent epilepsy rates. The relapse rate is less, and developmental outcome is better in ACTH with LEV group but statistically not significant.

Clinical Profile and Outcome in Children with Post Diphtheritic Paralysis in a Tertiary Care Hospital in Southern India.

Objectives: Post-Diphtheritic Paralysis (PDP), one of the most severe complications of diphtheria, is caused by exotoxin of Corynebacterium diphtheria. This study was planned since there has been a resurgence of diphtheria in India in recent years due to a number of epidemiological factors. Materials & Methods: Thirty-five children with PDP were studied in a tertiary care hospital in Southern India. Result: Neurological complications occurred in 38.5% of 91 patients with faucial diphtheria. Of the patients, 13 (37.1%) were unimmunized, 12 (34.3%) were partially immunized, two (5.7%) were completely immunized, and eight (22.6%) had unknown status. Isolated bulbar palsy and bulbar palsy followed by limb weakness were seen in 20 (57.1%) and 15 (42.9%) of the patients, respectively. The first symptoms of PDP occurred 5-34 days after the onset of local diphtheria infection. Eleven (31.4%) out of the 35 patients had received antitoxin between days 5-7 of illness. Ventilation-dependent respiratory failure occurred in three (8.6%) patients with PDP. Nine (25.7%) patients had evidence of co-existent myocarditis, while myocarditis with renal failure was seen in two (5.7%) patients. Four (11.4%) patients died, three from severe cardiomyopathy and one from aspiration. Demyelinating neuropathy was noted in 64% of the patients. Children with bulbar palsy recovered in 4-7 weeks, while limb symptoms improved in 6-17 weeks. Conclusion: PDP should be considered in any child presenting with bulbar palsy/quadriparesis following previous history of fever/sore throat. Awareness and availability with timely administration of ADS within 48 hours are essential to reduce PDP, as antitoxin seems ineffective if administered after the second day of diphtheritic symptoms.

Clinical and Laboratory Profile of Gangliosidosis from Southern Part of India.

Gangliosidoses are progressive neurodegenerative disorders caused by the deficiency of enzymes involved in the breakdown of glycosphingolipids. There are not much data about gangliosidosis in India; hence, this study was planned. The aim is to study the clinical, biochemical, and molecular profile of gangliosidosis. A retrospective chart review, in the pediatric neurology department from January 2015 to March 2020, was performed. Children diagnosed with Gangliosidosis were included. The disorder was confirmed by reduced activity of enzymes and/or pathogenic or likely pathogenic variants in associated genes. We assessed age at presentation, gender, parental consanguinity, clinical manifestations, neuroimaging findings, enzyme level, and pathogenic or likely pathogenic variants. Clinical data for 32 children with gangliosidosis were analyzed, which included 12 (37.5%) with GM1 gangliosidosis, 8 (25%) with Tay-Sachs disease (TSD), 11 (34.37%) with Sandhoff disease (SD), and 1 AB variant of GM2 gangliosidosis that occurs due to GM2 ganglioside activator protein deficiency. Twenty-four (75%) children were the offspring of consanguineous parents. Thirty-one (97%) had developmental delay. The median age at presentation was 15.5 months. Nine (28.12%) had seizures. Five children (41.6%) with GM1 gangliosidosis and two with SD had extensive Mongolian spots. Ten children with GM1 gangliosidosis (83.3%) had coarse facial features. Cherry red spot was found in 24 out of 32 children (75%). All children with GM1 gangliosidosis and none with TSD had hepato-splenomegaly. Two children (2/8; 25%) with TSD and seven (7/11; 63%) with SD had microcephaly. One child with SD had coarse facies and three did not have hepato-splenomegaly. Neuroimaging findings revealed bilateral thalamic involvement in 20 (62.5%) patients and periventricular hypomyelination in all cases. One child had a rare AB variant of GM2 gangliosidosis. GM2 Gangliosidoses are more common compared with GM1 variety. All of them had infantile onset except one child with TSD. Microcephaly can be present while usually megalencephaly is reported in the literature. The absence of hepato-splenomegaly does not rule out SD. Extensive Mongolian spots can be seen in GM2 gangliosidosis. AB variant of GM2 gangliosidosis should be considered when the enzyme is normal in the presence of strong clinical suspicion.

Scrotal ulcers in an infant with multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2 infection.

The majority of cases of multisystem inflammatory syndrome in children (MIS-C) manifest non-specific mucocutaneous features. We report the case of a 3-month-old infant presenting with purpura, acral desquamation, and scrotal ulcers. Scrotal ulcers have not been previously reported in MIS-C and add to the spectrum of cutaneous findings associated with the disorder.

Profile of Indian Children with Childhood Ataxia and Central Nervous System Hypomyelination/Vanishing White Matter Disease: A Single Center Experience from Southern India.

Background Childhood ataxia with central nervous system hypomyelination (CACH) is a recently described childhood inherited white matter disease, caused by mutations in any of the five genes encoding eukaryotic translation initiation factor ( eIF2B ). Methods Retrospective review of the charts of children with CACH was performed from January 2014 to March 2020 at tertiary care center from Southern India. Diagnosis was based on magnetic resonance imaging (MRI) criteria or genetic testing. Results Total number of children with CACH enrolled were 18. Male/female ratio was 10:8. Mean age of presentation was 37.11 months (range = 6-144 months). Affected siblings were seen in five (28%) cases. All children had spasticity, ataxia, and diffuse white matter changes with similar signal as cerebrospinal fluid on all pulse sequences on MRI brain. Of the 18 children, only nine are alive. Duration of illness among deceased children was 9.6667 months (range = 2-16 months). Waxing and waning of symptoms were seen in seven cases. Genetic analysis of EIF2B gene was performed in five cases, among which three mutations were novel. Conclusion A diagnosis of childhood ataxia with central nervous system hypomyelination should be considered in patients presenting with acute onset neuroregression following infection or trauma with associated neuroimaging showing classical white matter findings.

Canavan Disease: Clinical and Laboratory Profile from Southern Part of India.

BACKGROUND: Canavan disease (CD) is an autosomal recessively inherited leukodystrophy. It affects one in 6,400 to 13,500 people in the Jewish population. However, prevalence and presentation of the disease in India is largely unknown; hence, we are reporting this series. METHODS: This is a retrospective chart review in a tertiary care hospital from January 2015 to March 2020. CD was confirmed by elevated N- acetyl aspartate (NAA) levels in urinary gas chromatography and mass spectrometry (GCMS)/increased NAA peak in magnetic resonance spectroscopy (MRS) and/or detection of mutations. The data was extracted in a predesigned proforma and analyzed. RESULTS: We had 12 children with mean age at presentation being 6.8 months (range 3 months to 10 months.). Males were more commonly affected (83.3%, n = 10). Ten children (83.3%) were born out of consanguineous parentage. All of them had visual impairment and pyramidal signs. Seizures were noted in five (42%) children. Normal head size in three (25%) and microcephaly in two (16.66%) cases were noted. Magnetic resonance imaging (MRI) revealed signal changes with bilateral symmetric T2W white matter (WM) hyperintensities in subcortical U fibers in all cases. MRS was done in ten children, all of which showed increased NAA peak. Increased level of NAA in urinary GCMS was noted in six out of eight children. Six cases had homozygous pathogenic variants in ASPA gene. Antenatal diagnosis helped in prevention of recurrence in three families. CONCLUSION: Urinary NAA and MRS showing NAA peak are useful in diagnosis of CD. Macrocephaly is not a necessary finding to diagnose CD. Early diagnosis helps in genetic counseling and prevention of subsequent conceptions.

Clinical Profile and Outcome of Indian Children with Aromatic L-Amino Acid Decarboxylase Deficiency: A primary CSF Neurotransmitter Disorder Mimicking as Dyskinetic Cerebral Palsy.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a disorder of neurotransmitter synthesis. It presents with psychomotor delay, dystonia, oculogyric crisis, and autonomic features. There is paucity of literature on this disorder. Hence, we are reporting this series with an objective to study profile and outcome of Indian children with AADC deficiency. In this retrospective review, all case records of genetically confirmed cases of AADC deficiency at the pediatric neurology department in a tertiary care hospital, from March 2014 to March 2020, were analyzed. The data were extracted in a predesigned proforma and analyzed. Out of seven cases, five were males. Median age of onset of symptoms was 4 months but median age of diagnosis was 12 months. All of them had developmental delay, oculogyric crisis, dystonia, increased sweating, intermittent fever, feeding and sleep disturbance, irritability, failure to thrive, axial hypotonia with dyskinetic quadriparesis, and normal magnetic resonance imaging (MRI) of brain and electroencephalogram (EEG). All of them were treated with pyridoxal 5-phosphate, trihexyphenidyl and pramipexole and six cases, in addition, were given bromocriptine. One case was additionally treated with selegiline. One case showed good improvement, five showed partial improvement, and one case expired. In conclusion, AADC deficiency should be suspected in any child with dyskinetic quadriparesis, oculogyric crisis, autonomic disturbances like increased sweating, intermittent fever, and sleep disturbance with normal neuroimaging.