Role of physical therapy intervention in acute disseminated encephalomyelitis.

We reported a case of a school-going child, diagnosed with acute disseminated encephalomyelitis (ADEM) who presented with symptoms such as high fever, acute hemiplegia and ataxia and was referred for physiotherapeutic intervention. This case report aims to document the assessment and management of ADEM from the intensive care unit to the home setting by physical therapy. Also, the child developed ventilator-associated pneumonia and a right lower motor neuron facial injury for which the child was referred to paediatric physical therapy. Since then, continuing for 8 months has helped the child to be independent in all aspects of mobility with no complaints. The child showed improvement in WeeFIM scores and Sunnybrook facial grading after 99 sessions of intensive physical therapy for approximately 83 hours along with the home programme. It has been proven an efficient treatment method along with other medical lines of treatment for neurological impairment associated with ADEM.

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype.

Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic ATP7A variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic ATP7A variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed ATP7A transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of ATP7A mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant ATP7A splicing, expands the understanding of intronic variation on the ATP7A-related disease spectrum.

Biallelic variants in CENPF causing a phenotype distinct from Strømme syndrome.

Biallelic loss-of-function (LoF) variants in CENPF gene are responsible for Strømme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from -2.9 SDS to -5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted-V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Strømme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case-series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Strømme syndrome.

Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. DESIGN: Cohort study. SETTING: National Health Service, England, including secondary and tertiary care. PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis. RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

Appraisal of Critically Ill COVID-19 Patients at a Dedicated COVID Hospital.

PURPOSE: To study the pattern of severe COVID-19 to reduce morbidity and mortality. METHODS: It was an observational cohort study for comprehensive clinical analysis of critically ill COVID-19 patients at a dedicated COVID public hospital. RESULTS: Total 373(13.6%) patients were critically ill with 254(68.1%) males and 119(31.9%) females (including 25 pregnant) and death occurred in 69(18.5%) patients. Mean of parameters associated with critical COVID illness and having significant difference among dead and recovered were; age (47.08,p= 5.67E- 09), SpO2 (86.08), blood sugar(168.47,p= 1.86E-08), IL-6(210.5,p=0.0058) D-dimer(0.753,p= 0.00178). All the patients were given oxygen by non invasive technique, in 46(12.3%) intubation and invasive ventilation required. Use of hydroxychloroquin in 284(76.1%) (p=0.041,OR0.555,95%CI 0.314-0.981), lopinavir/ ritonavir in 283(75.9%) (p=4.222E-009,OR0.198, 95%CI0.114-0.345), tocilizumab in 124(33.2%) patients, (p=3.27E006, OR0.150, 95%CI0.063-0.358) were associated with recovery. Factors that influenced mortality were presence of co-morbidities (p=0.088,OR1.784,95%CI0.911-3.492), hypertension(p=0.0031,OR2.432,95% CI1.370 -4.318), low SpO2 (p=3.91E-010,OR0.017,95%CI0.002-0.137), high blood sugar(p=7.75E-009,OR8.514,95%CI 3.776-19.201), high LDH(p=0.00064,OR2.7 22,95%CI1.545-4.798) high ferritin(p=0.00014,OR4.606,95%CI 2.035-10.422), high D-dimer(p=2.85E-007,OR4.090,95%CI 2.371-7.056), low PFR(p=4.84E-008), and endotracheal intubation(p=3.14E-043,OR165.936,95%CI48.160-571.731). Using binary logistic regression, elevated IL-6(0.02441), low PFR(0.00082), and endotracheal intubation(2.04E-10) were statistically significant predictors of death. CONCLUSION: "Happy Hypoxia", hyperglycemia, high inflammatory markers (IL-6, ferritin), and ARDS were hallmark of critical COVID-19, early detection of factors associated with severity and mortality and starting the multipronged management with oxygen in prone position, hydroxychloroquin, antiviral, methylprednisolone, anticoagulants, tocilizumab early may help in halting the worsening of COVID and reduce morbidity and mortality.

Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes.

INTRODUCTION: Fetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential. METHODS: We reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service. RESULTS: Seven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10). CONCLUSIONS: This study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

Effects of Intraperitoneal Local Anaesthetics Bupivacaine and Ropivacaine versus Placebo on Postoperative Pain after Laparoscopic Cholecystectomy: A Randomised Double Blind Study.

INTRODUCTION: Laparoscopic Cholecystectomy (LC) is the most frequently performed elective daycare surgery and provision of postoperative pain relief is of importance. After laparoscopic cholecystectomy shoulder and abdominal pain causes considerable distress. Visceral pain during coughing, respiration and mobilization increases morbidity, hospital stay and costs. AIM: To compare the analgesic efficacy of intraperitoneally instilled equipotent concentrations of bupivacaine and ropivacaine versus placebo in relieving postoperative pain after laparoscopic cholecystectomy when used as a part of multimodal analgesia. MATERIALS AND METHODS: In this randomised, prospective, double blind, placebo controlled study, 90 ASA Class I or II patients were randomly divided into three groups of 30 each. Group S received intraperitoneal infiltration with 35 ml of 0.9% normal saline, Group B with 35 ml of 0.25% bupivacaine and Group R with 35 ml of 0.375% ropivacaine. All groups received standard general endotracheal anaesthesia and analgesia with IV paracetamol 15 mg/kg and diclofenac 1.5 mg/kg. Numerical Rating Scale (NRS) score of analgesia at rest and on cough/movement, duration of analgesia, haemodynamic parameters, need for a rescue analgesic (IV tramadol 1 mg/kg) was recorded and adverse effects of procedure and drugs if any were monitored. Data was analysed with SPSS statistical software version 21.0. One way ANOVA or the Kruskal-Wallis test was used to compare continuous data across all three groups as appropriate. Subsequent analysis of continuous data between two groups was achieved by Tukey's post hoc test. Significance was accepted as p<0.05. RESULTS: The mean NRS was <5 till only four hours in Group S, till eight hours in Group B and till 16 hours in Group R. The duration of analgesia was 13.47±1.38 hours in Group R, 7.93±1.44 hours in Group B and 4.47±0.86 hours in Group S. CONCLUSION: Intraperitoneal infiltration of LA significantly reduces pain intensity scores in the early postoperative period after LC surgery and helps in improving the postoperative recovery profile and outcome. This makes LC surgery more amenable to day care surgical setup. Ropivacaine (0.375%) is more efficacious, longer acting with a higher intensity of postoperative analgesia than bupivacaine (0.25%).

Evaluation of the Efficacy of Bupivacaine (0.5%) alone or with Clonidine (1µg/kg) Versus Control in a Single Level Paravertebral Blockin Patients Undergoing PCNL Procedure.

INTRODUCTION: Percutaneous Nephrolithotomy (PCNL) is a widely used procedure to remove complex upper tract renal calculi by means of a nephroscope. Although less invasive, PCNL is associated with significant pain owing to soft tissue injury. Most of these patients have mild to moderately compromised renal function. An anaesthesia plan that reduces intraoperative requirement of anaesthetics, analgesics, muscle relaxants and postoperative requirement of systemic analgesics is essential. Paravertebral Block (PVB) in combination with general anaesthesia may be an ideal technique for achieving all the goals. AIM: To evaluate the efficacy of Bupivacaine (0.5%) alone or with Clonidine (1ug/kg) versus control in a single level paravertebral block for intra-operative and postoperative analgesia in patients undergoing PCNL procedure. MATERIALS AND METHODS: In this prospective, randomized, observer blind study we evaluated the intraoperative as well as postoperative analgesic effects of paravertebrally administered Bupivacaine (0.5%) alone or Bupivacaine±Clonidine (1µg/kg) versus Control (Conventional analgesia with IV Paracetamol). We also evaluated requirement of propofol, haemodynamic parameters, need for rescue analgesics & incidence of adverse effects. Collected data was analysed with SPSS statistical software. One way ANOVA test was applied. All pair wise multiple comparison procedures were analysed by Tukey's Method if equal sample size and by Dunnett's Method if unequal sample size in all groups. RESULTS: It was observed that paravertebral block is an effective method for providing intra and postoperative analgesia for PCNL surgery. It reduced the requirement of intraoperative propofol, maintained stable intra and postoperative haemodynamics without any adverse effects or complications. Addition of Clonidine as an adjuvant to Bupivacaine enhanced the quality of paravertebral block with better haemodynamic stability, greater reduction in the intraoperative propofol requirement and provided significantly longer postoperative analgesia without any incident of bradycardia, hypotension, sedation or respiratory compromise. CONCLUSION: In conclusion, 0.5% Bupivacaine±1µg/kg Clonidine in a single level paravertebral block is useful, effective and safe for providing intra as well as postoperative analgesia during PCNL surgeries.

3p interstitial deletion: novel case report and review.

3p interstitial deletions have emerged in recent years as a new cause of neurodevelopmental delay and intellectual disability. Since the first report of this condition in 1979, 16 cases have been described in the literature, delineating it as a presumptive syndrome. Here, we add a novel case presenting severely delayed neurodevelopment and psychomotor development; facial dysmorphism (square facies, broad forehead, short palpebral fissures, epicanthic folds, broad nasal bridge, and low-set malformed ears); cerebral, cardiac, and genital malformations; hand and feet anomalies; sacral sinus; and hearing impairment. Genetic investigations revealed a del(3)(p12.3p14.1) of 12.5 Mb, including 31 ORFs, among which ROBO2, PDZRN3, MITF, and FOXP1 are known to act in neurodevelopment. The clinical features of our patient are compared with those previously reported in the literature, thus providing further support for the delineation of the 3p interstitial deletion syndrome.

Type 1 collagenopathy presenting with a Russell-Silver phenotype.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. It exhibits a broad spectrum of clinical severity, ranging from multiple fractures in utero and perinatal death, to normal adult stature and low fracture incidence. Extra-skeletal features of OI include blue sclera, hearing loss, skin hyperlaxity, joint hyperextensibility, and dentinogenesis imperfecta. The proα1(I) and proα2(I) chains of collagen 1 are encoded by the COL1A1 and COL1A2 genes, respectively; quantitative or qualitative defects in type I collagen synthesis usually manifest as types of OI or some sub-types of EDS. The majority of patients (about 90%) with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes, which shows an autosomal dominant pattern of inheritance. Six other genes, CRTAP, LEPRE1, FKBP10, PP1B, SP7/Osterix (OSX), and SERPINH1, are associated with autosomal recessive forms of OI. However, other, rare phenotypes have also been described. There are many differential diagnoses of the short, syndromic child, including chromosomal, single gene, and multifactorial causes. However, one condition of particular relevance in the context of this report is the Russell-Silver syndrome (RSS). As originally described, the RSS is a very specific condition. However, it has subsequently become an umbrella term for a heterogeneous group of conditions presenting with short stature and triangular shape to the face. A significant proportion of these are now believed to be due to imprinting defects at 11p15. However, the cause in many cases remains unknown. We describe two cases with a phenotypic overlap between OI and RSS who both have COL1A1 mutations. Thus, a type 1 collagenopathy should be considered in the differential diagnosis of syndromic short stature.

The pathogenic m.3243A>T mitochondrial DNA mutation is associated with a variable neurological phenotype.

The m.3243A>G point mutation in the mitochondrial tRNA(Leu(UUR)) (MTTL1) gene is a common cause of mitochondrial DNA disease and is associated with a variety of clinical presentations. A different mutation occurring at the same site - an m.3243A>T transversion - is less prevalent, but has previously been observed in two patients with encephalopathy and lactic acidosis. We report the investigations of a further two patients with the m.3243A>T mutation who presented with either a chronic progressive external ophthalmoplegia (CPEO) phenotype or sensorineural hearing loss, with single fibre mutation studies confirming segregation of the m.3243A>T mutation with COX deficiency.

Visual impairment and prolonged survival in a girl with Marshall-Smith syndrome.

Marshall-Smith syndrome is characterized by overgrowth, advanced bone age, failure to thrive, respiratory problems, dysmorphic facial features and variable mental retardation. Respiratory problems are a major cause of early morbidity and mortality. Ocular features have been mentioned in previous reports, but details are limited. This report describes the clinical features of a child with typical features of Marshall-Smith syndrome with emphasis on visual function. She had megalocornea, hypoplastic optic discs and was partially sighted. Aggressive management of the early respiratory and feeding problems improved survival in this child.