Managing pregnancy in a spinal muscular atrophy type III patient in Indonesia: a case report

Background Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower motor neurons, leading to progressive muscular atrophy and even paralysis. Spinal muscular atrophy usually associated with a defect of the survival motor neuron 1 (SMN-1) gene. Classification of spinal muscular atrophy is based on the age of onset and maximum motor function milestone achieved. Although spinal muscular atrophy can be screened for in newborns, and even confirmed earlier genetically, this remains difficult in Third World countries such as Indonesia. Case presentation A 28-year-old Asian woman in the first trimester of her second pregnancy, was referred to the neurology department from the obstetric department. Her milestone history showed she was developmentally delayed and the ability to walk independently was reached at 26 months old. At 8 years old, she started to stumble and lose balance while walking. At this age, spinal muscular atrophy was suspected because of her clinical presentations, without any molecular genetic testing. She was married at the age of 25 years and was soon pregnant with her first child. At the gestational age of 32 weeks, her first pregnancy was ended by an emergency caesarean section because of premature rupture of the membranes. In this second pregnancy, she was referred early to the general hospital from the district hospital to receive multidisciplinary care. She and her first daughter underwent genetic testing for spinal muscular atrophy, which has been readily available in our institution since 2018, to confirm the diagnosis and prepare for genetic counseling. Conclusions Managing pregnancy in a patient with spinal muscular atrophy should be performed collaboratively. In this case, genetic testing of spinal muscular atrophy and the collaborative management of this patient allowed the clinical decision making and genetic counseling throughout her pregnancy and delivery.

Analysis of clinical features of myasthenia gravis complicated with hyperthyroidism

Objectives: To investigate the clinical features of patients with myasthenia gravis complicated with and without hyperthyroidism. Methods: A total of 2083 patients with myasthenia gravis (MG) admitted in Center of Treatment of Myasthenia Gravis Hebei Province between January 2013 and July 2020 were retrospectively analyzed and divided into two groups: Group-A and Group-B, with 108 MG patients complicated with hyperthyroidism in Group-A and 1975 MG patients without thyroid disease in Group-B. The age of onset, gender, Osserman classification, acetylcholine receptor antibody and thymus status of the two groups were analyzed in the two groups. Independent-sample t test was used for intra-group comparison, and χ2 test was utilized for comparison of enumeration data. P<0.05 indicates a statistically significant difference. Results: The age of onset in Group-A was significantly lower than that in Group-B (p=0.000), the number of female patients was significantly higher than that in Group-B (p=0.037), and the level of Achrabs titer was significantly lower than that in Group-B (p=0.000). The incidence of thymoma in Group-A was significantly lower than that in Group-B (p=0.012), while the incidence of thymic hyperplasia was significantly higher than that in Group-B (p=0.000). Conclusion: Patients with MG complicated with hyperthyroidism are mainly female, with a lower age of onset, a lower level of acetylcholine receptor antibody, a lower incidence of thymoma, and a higher incidence of thymic hyperplasia. The clinical features of such patients are remarkably different from those of MG without thyroid disease. doi: https://doi.org/10.12669/pjms.38.3.4656 How to cite this:Wang Y, Qi G, Yang Y. Analysis of clinical features of myasthenia gravis complicated with hyperthyroidism. Pak J Med Sci. 2022;38(3):---------. doi: https://doi.org/10.12669/pjms.38.3.4656 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Universal Germline Panel Testing for Individuals with Pheochromocytoma and Paraganglioma Produces High Diagnostic Yield

Background Practice guidelines to identify individuals with hereditary pheochromocytomas and paragangliomas (PPGLs) advocate for sequential gene testing strategy guided by specific clinical features and predate the routine use of multigene panel testing (MGPT). Objective To describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort. Setting Commercial laboratory based in the United States. Methods Clinical data and test results were retrospectively reviewed in 1727 individuals who had targeted MGPT due to suspicion of hereditary PPGL from August 2013 through December 2019. Results Overall, 27.5% of individuals had a pathogenic or likely pathogenic variant (PV), 9.0% had a variant of uncertain significance, and 63.1% had a negative result. Most PVs were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.7%), and MAX (3.6%). PVs in FH, MEN1, NF1, SDHAF2, and TMEM127 collectively accounted for 6.5% of PVs. Clinical predictors of a PV included extra-adrenal location, early age of onset, multiple tumors, and positive family history of PPGL. Individuals with extra-adrenal PGL and a positive family history were the most likely to have a PV (85.9%). Restricting genetic testing to SDHB/C/D misses a third (32.8%) of individuals with PVs. Conclusion Our data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, and a substantial contribution to diagnostic yield from rare genes. These findings support universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.

Effect of maternal vitamin D supplementation on nasal pneumococcal acquisition, carriage dynamics and carriage density in infants in Dhaka, Bangladesh

Background Invasive pneumococcal disease is a major cause of infant morbidity and death worldwide. Vitamin D promotes anti-pneumococcal immune responses in vitro, but whether improvements in infant vitamin D status modify risks of nasal pneumococcal acquisition in early life is not known. Methods This is a secondary analysis of data collected in a trial cohort in Dhaka, Bangladesh. Acute respiratory infection (ARI) surveillance was conducted from 0 to 6 months of age among 1060 infants of women randomized to one of four pre/post-partum vitamin D dose combinations or placebo. Nasal swab samples were collected based on standardized ARI criteria, and pneumococcal DNA quantified by qPCR. Hazards ratios of pneumococcal acquisition and carriage dynamics were estimated using interval-censored survival and multi-state modelling. Results Pneumococcal carriage was detected at least once in 90% of infants by 6 months of age; overall, 69% of swabs were positive (2616/3792). There were no differences between any vitamin D group and placebo in the hazards of pneumococcal acquisition, carriage dynamics, or carriage density (p > 0.05 for all comparisons). Conclusion Despite in vitro data suggesting that vitamin D promoted immune responses against pneumococcus, improvements in postnatal vitamin D status did not reduce the rate, alter age of onset, or change dynamics of nasal pneumococcal colonization in early infancy. Trial registration Registered in ClinicalTrials.gov with the registration number of NCT02388516 and first posted on March 17, 2015.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohen's d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes

<b>Objective: </b>Type 2 diabetes (T2D) is a leading cause of end stage kidney disease (ESKD) worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease (DKD) in youth-onset than adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth-onset was associated with greater early tissue injury.<b></b> <p><b> </b></p> <p><b>Methods: </b>Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing and participants were stratified as youth-onset (<25 years) or adult-onset (≥25 years). Associations between clinical and morphometric parameters and age of onset were tested using linear models.<b></b></p> <p><b> </b></p> <p><b>Results: </b>At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1±9.9 <i>vs.</i> 51.4±10.2 years, <i>p</i><0.0001), but their diabetes duration was similar (19.3±8.1 <i>vs.</i> 17.0±7.8 years, <i>p</i>=0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25^th-75^th percentile, 17-470] <i>vs.</i> 27 [13-73] mg/g, <i>p</i>=0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552±128 nm <i>vs.</i> 490±114nm, <i>p</i>=0.002) and mesangial fractional volume (0.31±0.10 <i>vs</i>. 0.27±0.08, <i>p</i>=0.001) than adult-onset participants. Percentage glomerular sclerosis, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age of diabetes onset as a continuous variable.<b></b></p> <p><b> </b></p> <p><b>Conclusion: </b>Younger age of T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.</p>

Evaluation of Brain Structure Based on Voxel and Surface Morphology in Adults with MRI Negative Temporal Lobe Epilepsy

Background MRI-negative TLE (TLE-N) is a manifestation lacks visible MRI findings yet with detectable electrophysiological changes. In this study, differences of gray matter in drug-controlled MRI negative temporal lobe epilepsy (cTLE-N) and drug-resistant MRI negative temporal lobe epilepsy (rTLE-N) patients were calculated and analyzed by voxel-based morphology (VBM) and surface-based morphology (SBM), to discover the brain structural changes of TLE-N patients. Materials and methods Consecutive resident patients with 30 cTLE-N and 21 rTLE-N were recruited into respective groups, and 30 healthy controls’ structural MRI (sMRI) data collected as a control group. Open-source software based on VBM and SBM was deployed as gray matter volume (GMV) and cortical thickness (CT) analytic tools. Results VBM analysis showed that GMV of bilateral thalamus and right lingual gyrus of cTLE-N group, and left hippocampus, left fusiform gyrus and left thalamus of rTLE-N group were smaller compared to HC group(FDR corrected, P<0.05), while right cerebellum, inferior temporal gyrus, hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, orbital middle frontal gyrus, and left posterior central gyrus in cTLE-N group, and bilateral cerebellum and middle temporal gyrus, right fusiform gyrus, amygdala, hippocampus, and left middle occipital gyrus of rTLE-N group were greater than HC group(FDR corrected, P<0.05). SBM analysis showed that CT of the left medial orbitofrontal cortex and lateral occipital cortex in cTLE-N group, and thickness of the left medial orbitofrontal, temporal pole, middle temporal gyrus and right anterior superior cingulate cortex in rTLE-N group were thinner, compared to HC group. Correlation analysis showed that GMV and CT of different structures were correlated with age of onset, disease duration, and MoCA score. Conclusion This study utilized two different sMRI analytic tools and discovered several brain morphological changes in TLE-N. These morphological changes were also correlated with clinical variables. Further study may indicate the potential of these findings on the recognition of the TLE-N epilepsy network.

Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes

<b>Objective: </b>Type 2 diabetes (T2D) is a leading cause of end stage kidney disease (ESKD) worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease (DKD) in youth-onset than adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth-onset was associated with greater early tissue injury.<b></b> <p><b> </b></p> <p><b>Methods: </b>Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing and participants were stratified as youth-onset (<25 years) or adult-onset (≥25 years). Associations between clinical and morphometric parameters and age of onset were tested using linear models.<b></b></p> <p><b> </b></p> <p><b>Results: </b>At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1±9.9 <i>vs.</i> 51.4±10.2 years, <i>p</i><0.0001), but their diabetes duration was similar (19.3±8.1 <i>vs.</i> 17.0±7.8 years, <i>p</i>=0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25^th-75^th percentile, 17-470] <i>vs.</i> 27 [13-73] mg/g, <i>p</i>=0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552±128 nm <i>vs.</i> 490±114nm, <i>p</i>=0.002) and mesangial fractional volume (0.31±0.10 <i>vs</i>. 0.27±0.08, <i>p</i>=0.001) than adult-onset participants. Percentage glomerular sclerosis, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age of diabetes onset as a continuous variable.<b></b></p> <p><b> </b></p> <p><b>Conclusion: </b>Younger age of T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.</p>

Co-Mutation of FAT3 and LRP1B in Lung Adenocarcinoma Defines a Unique Subset Correlated With the Efficacy of Immunotherapy

Immunotherapy based on immune checkpoint inhibitors (ICIs) have demonstrated remarkable survival benefits and gained regulatory approval in non-small cell lung cancer (NSCLC) patients without an actionable driver mutation, but currently there is no well-established standard for how to screen the most suitable population for ICIs treatment. Here, we conducted a comprehensive analysis of the somatic mutation landscape of lung adenocarcinoma (LUAD) samples. After the stepwise screening of high-frequency mutated genes, two genes with prominent significance, FAT3 and LRP1B, were finally screened out. Through further analysis, we discovered that the co-mutation of FAT3 and LRP1B was associated with an earlier age of onset and occurred more frequently in Black/African American. Furthermore, co-mutation defines a unique subgroup of lung adenocarcinoma that can increase tumor mutational burden (TMB), boost cytotoxicity and tumor immunogenicity, and facilitate lymphocyte infiltration. The results of gene set enrichment analysis (GSEA) indicated that co-mutation can influence tumorigenesis through a variety of mechanisms. More strikingly, the subset of LUAD with co-mutation of FAT3 and LRP1B exhibited significantly prolonged immunotherapy progression free survival (PFS). In summary, co-mutation of FAT3 and LRP1B is a promising useful biomarker for predicting the efficacy of immunotherapy, which can improve the clinical efficiency of practicing precision medicine in lung adenocarcinoma patients.

Clinical and molecular spectrum associated with Polymerase-γ related disorders

Background POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. Methods Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. Results A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. Conclusions We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.