Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease

Background Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by deficiency of the branched-chain α-ketoacid dehydrogenase complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. This study presents the clinical and molecular characterizations of four MSUD patients. Methods Clinical data of patients were retrospectively analyzed, and genetic mutations were identified by whole-exome sequencing. CLUSTALX was employed to analyzed cross-species conservation of the mutant amino acid. The impact of the mutations was analyzed with PolyPhen-2 software. The I-TASSER website and PyMOL software were used to predict the protein three-position structure of the novel mutations carried by the patients. Results Vomiting, irritability, feeding difficulties, seizures, dyspnoea, lethargy and coma were the main clinical presentations of MSUD. Cranial MRI showed abnormal symmetrical signals in accordance with the presentation of inherited metabolic encephalopathy. Seven mutations were detected in four patients, including three novel pathogenic mutations in the BCKDHA (c.656C>A), BCKDHB (deletion of a single-copy of BCKDHB) and DBT (c.1219dup) genes. Structural changes were compatible with the observed phenotypes. Conclusions Different types of MSUD can display heterogeneous clinical manifestations. Exhaustive molecular studies are necessary for a proper differential diagnosis. The newly identified mutation will play a key role in the prenatal diagnosis of MSUD in the future.

Association of the Verbal Component of the GCS With Mortality in Patients With Encephalopathy Who Are Not Undergoing Mechanical Ventilation

Background and Objectives:The utility of the Glasgow Coma Scale (GCS) in intubated patients is limited due to reliance on language function evaluation. The Full Outline of UnResponsiveness (FOUR) Score was designed to circumvent this shortcoming, instead adding evaluations of brainstem reflexes (FOUR B) and specific respiratory patterns (FOUR R). We aimed to determine if the verbal component of the GCS (GCS V) among encephalopathic non-intubated patients significantly contributes to mortality prediction and to assess GCS vs. FOUR Score performance.Methods:All prospectively consented patients ≥18 years admitted to the Internal Medicine service at Zambia’s University Teaching Hospital from October 3rd, 2017 to May 21st, 2018 with a GCS of ≤10 have undergone simultaneous GCS and FOUR Score assessments. The patients were not eligible for mechanical ventilatory support per local standards. Patients’ demographics and clinical characteristics were presented as either percentage frequencies or numerical summaries of spread. The predictive power of the GSC without Verbal component vs. total GCS vs. FOUR Score on mortality were estimated using the area under the receiver operating characteristic (AU-ROC).Results:235 patients (50% women; mean age 47.5 years) were enrolled. All patients were Black. Presumed etiology was CNS infection (64; 27%), stroke (63; 27%), systemic infection (39; 16.6%), metabolic encephalopathy (3; 14.5 %), 14.9% unknown. In-hospital mortality was 83%. AU ROC for GCS Eye+Motor (0.662) vs. total GCS (0.641) vs. total FOUR Score (0.657) did not differ. Odds ratio mortality for GCS > 6 vs. < 6 was 0.32, 95% CI 0.14-0.72 (p 0.01); for FOUR Score >10 vs. <10 was 0.41, 95% CI 0.19-0.86 (p 0.02).Conclusion:Absence of a verbal component of GCS had no significant impact on total GCS’s performance and either GCS or FOUR Score are acceptable scoring tools for mortality prediction in the resource-limited setting. These findings need further validation in the countries with readily available mechanical ventilatory support.Classification of Evidence:This study provides Class I evidence that the verbal component of the GCS does not significantly contribute to a total GCS score in mortality prediction among encephalopathic patients who are not intubated.

Autoimmune Encephalitis Post-SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes

Background and objectives:Autoimmune encephalitis (AE) cases post-SARS-CoV-2 infection have been reported, but the frequency is unknown. We aimed to determine the frequency and diagnostic features of COVID-19 related AE.Methods:Residual sera from 556 consecutive Mayo Clinic Rochester patients (laboratory cohort) who underwent autoimmune encephalopathy neural IgG evaluation were tested for total antibodies against the SARS-CoV-2 spike glycoprotein using an FDA-authorized chemiluminescence assay (October 2019-December 2020). Clinical records from patients with a positive SARS-CoV-2 antibody result and available research consent were reviewed. This laboratory cohort was cross-referenced with the Department of Neurology’s COVID-related consultative experience (encephalopathy cohort, n=31).Results:Eighteen of the laboratory cohort (3%) were SARS-CoV-2 antibody positive (April-December 2020). Diagnoses were: AE, 2; post-acute sequelae of SARS CoV-2 infection [PASC], 3; toxic-metabolic encephalopathy during COVID-19 pneumonia, 2; diverse non-COVID-19 relatable neurological diagnoses, 9; unavailable, 2. Five of the encephalopathy cohort had AE (16%, including the 2 laboratory cohort cases which overlapped) representing 0.05% of 10,384 patients diagnosed and cared for with any COVID-19 illness at Mayo Clinic Rochester in 2020. The 5 patients met definite (n=1), probable (n=1), or possible (n=3) AE diagnostic criteria; median symptom onset age was 61 years (range, 46-63), 3 were women. All 5 were neural IgG negative and 4 tested were SARS-CoV-2 PCR/IgG index negative in CSF. Phenotypes (and accompanying MRI and EEG findings) were diverse (delirium [n=5], seizures [n=2], rhombencephalitis [n=1], aphasia [n=1], and ataxia [n=1]). No ADEM cases were encountered. The 3 patients with possible AE had spontaneously resolving syndromes. One with definite limbic encephalitis was immune therapy responsive but had residual mood and memory problems. One patient with probable autoimmune rhombencephalitis died despite immune therapy. The remaining 26 encephalopathy cohort patients had toxic-metabolic diagnoses.Discussion:We encountered occasional cases of AE in our 2020 COVID-19 experience. Consistent with sporadic reports and small case series during the COVID-19 pandemic, and prior experience of postinfectious AE, our cases had diverse clinical presentations and were neural IgG and CSF viral particle negative. Application of diagnostic criteria assists in differentiation of AE from toxic-metabolic causes arising in the setting of systemic infection.

Study of Clinical Profile and Outcome of Metabolic Encephalopathy in Patients Admitted at HSK Hospital, Bagalkot, Karnataka

BACKGROUND Metabolic encephalopathy (ME) is one of the most frequently encountered and broadly defined diagnoses by the physicians in the intensive care setting. ME is a clinical state characterized by cerebral dysfunction in the absence of structural brain disease. The causes are many and often multifactorial. The purpose of study was to evaluate various causes, clinical profile, and outcome in patients with ME. METHODS This is a hospital based, observational, cross sectional study, conducted in ICU of Department of General medicine, S.N. Medical College, Bagalkot. Patients with head trauma, organic causes of altered sensorium, psychiatric conditions were excluded. RESULTS Mean age was 51.22 ± 17.24 years. Majority were males. Diabetes was the most common comorbidity found followed by cirrhosis of liver and hypertension. Septic causes were found to be the most common aetiology. 80.7 % recovered from the disease and death was noted in 19.3 % patients. CONCLUSIONS All the patients with ME had altered level of consciousness with fever being the most common symptom. Most of them were males, most common aetiology was septic cause, and recovery was seen in about 80.7 % of patients. KEYWORDS Metabolic Encephalopathy, Altered Sensorium, Sepsis

Autoimmune Antibody in Encephalopathic Patients: A Pilot Study

Objective: To investigate the specificity of the antibodies related to autoimmune encephalitis and to identify possible associated factors with the false-positive result. Materials and Methods: The present study was a prospective observational study, conducted at the Ramathibodi Hospital between June and December 2019. All patients, who had acute to subacute encephalopathy from any causes, were recruited to the study. Their serum or cerebrospinal fluid (CSF) were taken to analyze for autoimmune encephalitis assays and anti-thyroid antibodies. The authors did not interfere with the primary physicians on any management of the patients. Clinical and laboratory data were systematically reviewed and collected from medical records. The clinical outcome was evaluated one month after the onset. Results: Fifty-one patients were recruited. Only one patient had autoimmune encephalitis related to anti-CV2/CRMP5 antibody. Seventeen out of the remaining fifty patients had positive tests for anti-thyroid antibodies of which five had Hashimoto’s thyroiditis and one of them did not have the document of thyroid status. Eleven remaining patients appeared to have false-positive test since their medical conditions were all clearly explained by other causes. Comparison of clinical and laboratory data between patients with false-positive test and patients with true negative test did not show any significant difference except the duration of the symptoms, which was significantly shorter in the false-positive group. Conclusion: False-positive anti-thyroid antibodies appear to be common in patients with acute encephalopathy. The occurrence of serum/CSF antibody in acute encephalopathy may be a true association, but it may not be the cause of encephalopathy. Therefore, the diagnosis of autoimmune encephalopathy based on anti-thyroid antibodies should be carefully made and excluded from all other possible causes. Keywords: Autoimmune encephalitis; Metabolic encephalopathy; Hashimoto’s encephalopathy; False positive

STUDY OF NON TRAUMATIC COMA IN CHILDREN AT TERTIARY HOSPITAL.

Introduction: Non-traumatic coma can have varied etiology and clinical characteristics. These may determine the management and outcome of the patients. We aimed to study the etiology and outcomes of children diagnosed and treated for non-traumatic coma in our hospital. Methodology: Medical records of children aged 2 months to 18 years, diagnosed with non-traumatic coma from January 2020 till December 2020 were reviewed retrospectively. The nal outcome was determined by patient's death or neurological condition at the time of discharge. Results: In the present study, out of 45 patients of NTC, 44% of the patients were in the age group 2 months to 5 years, 31% in 6 years to 12 years and 24% in 13 years to 18 years and 42% were Males & 57% were Females. In etiology, Infectious and Non-infectious causes contributed equally. Among the infectious causes, the most common ones were acute encephalitis (22%), acute pyogenic meningitis (9%), TBM (9%) and remaining infectious causes contributed to 9%. Among the non-infectious causes, diabetic ketoacidotic coma (22%), epileptic encephalopathy and metabolic encephalopathy contributed to 7% each. In outcome of the sample of 45 patients, 39 (87%) were discharged home and mortality was observed in 6 (13%). Among the total patients discharged (87%), 53% were neurologically normal, 7% had mild disability, 9% had moderate disability and 18% had severe disability. In our study, mortality was 3% in children with moderate brain injury, 33% mortality in children with severe brain injury (p value < 0.01). Conclusions: In our study, mortality rate was high with severe brain injury as compared to mild and moderate brain injury as assessed by GCS at admission.