Clinical Spectrum Research Articles

Amidst Cytokine Storm in Metabolic Diseases: Can 2-deoxy-D-glucose (2-DG) Cure COVID-19?

Abstract: The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2)-related pandemic disease COVID-19, which began in China in 2019, became the leading cause of fatalities globally. The transmission rate of the virus is directly proportional to the so-called ‘dance dynamic’ energy of the spike protein as this phenomenon favours the ligand-receptor binding. The clinical spectrum of the COVID-19 disease, which includes (inflammation, cytokine storm, and multi-organ dysfunction), puts Corona Warriors active in various aspects of the disease, such as the efficient management of critically ill COVID-19 patients, in danger of losing their lives. Due to its effects on an ancient oxygen-independent glycolytic pathway, anti-inflammatory properties, and competitive interaction with viral proteins, 2-deoxy-D-glucose (2-DG), which is being developed in India at the Defence Research and Development Organization (DRDO), has emerged as a ground-breaking agent for COVID-19 treatment. After a virus gains entry into host cells, it is found that metabolic reprogramming takes place to meet the nutritional and energy requirements for virus reproduction. The recent approval of 2-DG for adjunctive emergency usage by the Drug Controller General of India (DCGI) may mark a turning point in the management of mild to moderate COVID-19 infection.

ATP1A3 Disease Spectrum Includes Paroxysmal Weakness and Encephalopathy Not Triggered by Fever.

Heterozygous pathogenic variants in ATP1A3, which encodes the catalytic alpha subunit of neuronal Na+/K+-ATPase, cause primarily neurologic disorders with widely variable features that can include episodic movement deficits. One distinctive presentation of ATP1A3-related disease is recurrent fever-triggered encephalopathy. This can occur with generalized weakness and/or ataxia and is described in the literature as relapsing encephalopathy with cerebellar ataxia. This syndrome displays genotype-phenotype correlation with variants at p.R756 causing temperature sensitivity of ATP1A3. We report clinical and in vitro functional evidence for a similar phenotype not triggered by fever but associated with protein loss-of-function. We describe the phenotype of an individual with de novo occurrence of a novel heterozygous ATP1A3 variant, NM_152296.5:c.388_390delGTG; p.(V130del). We confirmed the pathogenicity of p.V130del by cell survival complementation assay in HEK293 cells and then characterized its functional impact on enzymatic ion transport and extracellular sodium binding by two-electrode voltage clamp electrophysiology in Xenopus oocytes. To determine whether variant enzymes reach the cell surface, we surface-biotinylated oocytes expressing N-tagged ATP1A3. The proband is a 7-year-old boy who has had 2 lifetime episodes of paroxysmal weakness, encephalopathy, and ataxia not triggered by fever. He had speech regression and intermittent hand tremors after the second episode but otherwise spontaneously recovered after episodes and is at present developmentally appropriate. The p.V130del variant was identified on clinical trio exome sequencing, which did not reveal any other variants possibly associated with the phenotype. p.V130del eliminated ATP1A3 function in cell survival complementation assay. In Xenopus oocytes, p.V130del variant Na+/K+-ATPases showed complete loss of ion transport activity and marked abnormalities of extracellular Na+ binding at room temperature. Despite this clear loss-of-function effect, surface biotinylation under the same conditions revealed that p.V130del variant enzymes were still present at the oocyte's cell membrane. This individual's phenotype expands the clinical spectrum of ATP1A3-related recurrent encephalopathy to include presentations without fever-triggered events. The total loss of ion transport function with p.V130del, despite enzyme presence at the cell membrane, indicates that haploinsufficiency can cause relatively mild phenotypes in ATP1A3-related disease.

Sentinel Enhanced Dengue Surveillance System - Puerto Rico, 2012-2022.

Dengue is the most prevalent mosquitoborne viral illness worldwide and is endemic in Puerto Rico. Dengue's clinical spectrum can range from mild, undifferentiated febrile illness to hemorrhagic manifestations, shock, multiorgan failure, and death in severe cases. The disease presentation is nonspecific; therefore, various other illnesses (e.g., arboviral and respiratory pathogens) can cause similar clinical symptoms. Enhanced surveillance is necessary to determine disease prevalence, to characterize the epidemiology of severe disease, and to evaluate diagnostic and treatment practices to improve patient outcomes. The Sentinel Enhanced Dengue Surveillance System (SEDSS) was established to monitor trends of dengue and dengue-like acute febrile illnesses (AFIs), characterize the clinical course of disease, and serve as an early warning system for viral infections with epidemic potential. May 2012-December 2022. SEDSS conducts enhanced surveillance for dengue and other relevant AFIs in Puerto Rico. This report includes aggregated data collected from May 2012 through December 2022. SEDSS was launched in May 2012 with patients with AFIs from five health care facilities enrolled. The facilities included two emergency departments in tertiary acute care hospitals in the San Juan-Caguas-Guaynabo metropolitan area and Ponce, two secondary acute care hospitals in Carolina and Guayama, and one outpatient acute care clinic in Ponce. Patients arriving at any SEDSS site were eligible for enrollment if they reported having fever within the past 7 days. During the Zika epidemic (June 2016-June 2018), patients were eligible for enrollment if they had either rash and conjunctivitis, rash and arthralgia, or fever. Eligibility was expanded in April 2020 to include reported cough or shortness of breath within the past 14 days. Blood, urine, nasopharyngeal, and oropharyngeal specimens were collected at enrollment from all participants who consented. Diagnostic testing for dengue virus (DENV) serotypes 1-4, chikungunya virus, Zika virus, influenza A and B viruses, SARS-CoV-2, and five other respiratory viruses was performed by the CDC laboratory in San Juan. During May 2012-December 2022, a total of 43,608 participants with diagnosed AFI were enrolled in SEDSS; a majority of participants (45.0%) were from Ponce. During the surveillance period, there were 1,432 confirmed or probable cases of dengue, 2,293 confirmed or probable cases of chikungunya, and 1,918 confirmed or probable cases of Zika. The epidemic curves of the three arboviruses indicate dengue is endemic; outbreaks of chikungunya and Zika were sporadic, with case counts peaking in late 2014 and 2016, respectively. The majority of commonly identified respiratory pathogens were influenza A virus (3,756), SARS-CoV-2 (1,586), human adenovirus (1,550), respiratory syncytial virus (1,489), influenza B virus (1,430), and human parainfluenza virus type 1 or 3 (1,401). A total of 5,502 participants had confirmed or probable arbovirus infection, 11,922 had confirmed respiratory virus infection, and 26,503 had AFI without any of the arboviruses or respiratory viruses examined. Dengue is endemic in Puerto Rico; however, incidence rates varied widely during the reporting period, with the last notable outbreak occurring during 2012-2013. DENV-1 was the predominant virus during the surveillance period; sporadic cases of DENV-4 also were reported. Puerto Rico experienced large outbreaks of chikungunya that peaked in 2014 and of Zika that peaked in 2016; few cases of both viruses have been reported since. Influenza A and respiratory syncytial virus seasonality patterns are distinct, with respiratory syncytial virus incidence typically reaching its annual peak a few weeks before influenza A. The emergence of SARS-CoV-2 led to a reduction in the circulation of other acute respiratory viruses. SEDSS is the only site-based enhanced surveillance system designed to gather information on AFI cases in Puerto Rico. This report illustrates that SEDSS can be adapted to detect dengue, Zika, chikungunya, COVID-19, and influenza outbreaks, along with other seasonal acute respiratory viruses, underscoring the importance of recognizing signs and symptoms of relevant diseases and understanding transmission dynamics among these viruses. This report also describes fluctuations in disease incidence, highlighting the value of active surveillance, testing for a panel of acute respiratory viruses, and the importance of flexible and responsive surveillance systems in addressing evolving public health challenges. Various vector control strategies and vaccines are being considered or implemented in Puerto Rico, and data from ongoing trials and SEDSS might be integrated to better understand epidemiologic factors underlying transmission and risk mitigation approaches. Data from SEDSS might guide sampling strategies and implementation of future trials to prevent arbovirus transmission, particularly during the expansion of SEDSS throughout the island to improve geographic representation.

Assessing the applicability of the 2023 international MOGAD panel criteria in real-world clinical settings.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified demyelinating disorder with a diverse clinical spectrum. Diagnosing MOGAD traditionally relies on clinical judgment, highlighting the necessity for precise diagnostic criteria. Banwell et al. proposed criteria, aiming to refine the diagnostic spectrum. This study evaluates these criteria in a real-life cohort, comparing their performance with clinical judgment and describe the cohort of MOGAD patients. This retrospective study, conducted at Hadassah Medical Center, included 88 patients with MOG-IgG antibodies. Patients with a positive or borderline MOG-IgG antibodies by cell-based assay were included. Demographics, clinical and MRI data were recorded. Cases were divided into definite MOGAD and Non-MOGAD groups as determined by the treating physician. We assessed the sensitivity and specificity of the new criteria in comparison to treating physicians' evaluations. Additionally, we examined clinical differences between the MOGAD and Non-MOGAD groups. We observed a strong concordance (98%) between the new MOGAD criteria and treating physicians' diagnoses. Clinical disparities between MOGAD and Non-MOGAD groups included lower EDSS scores, normal MRI scans, preserved brain volume, negative OCB results, and distinct relapse patterns. Also, compared to relapsing patients, monophasic MOGAD patients have greater brain volume and a lower age at onset. The study demonstrates robust accuracy of new MOGAD criteria, emphasizing their potential to enhance diagnostic precision. Treatment response integration into the MOGAD diagnosis is crucial, as it could aid in distinguishing MOGAD from other demyelinating disorders. Distinct clinical profiles highlight the importance of informed decisions in managing MOGAD and similar disorders.

Hypoparathyroidism, deafness and renal dysplasia syndrome with bilateral cataract and bicornuate uterus caused by a de novo GATA3 mutation

Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare genetic disorder caused by haploinsufficiency of the GATA3 gene. A very limited number of cases have been reported in the literature to date. Diagnosis is challenging as the phenotypic expression has wide heterogeneity due to variable penetrance of the underlying genetic mutation. Although the condition is inherited in an autosomal dominant pattern, sporadic cases do occur. This report presents a case of a 22-year-old female diagnosed with HDR syndrome, featuring bilateral cataract and bicornuate uterus. The GATA3 mutation detected in the patient was not identified in the family, suggesting it to be arising de novo. The present case report describes the rare phenotypic findings of bilateral cataract and bicornuate uterus associated with HDR, thus expanding the clinical spectrum of the syndrome.

#664 Childhood Takayasu arteritis: a multicentre retrospective study

Abstract Background and Aims Takayasu arteritis (TA) is a rare, large vessel vasculitis affecting mainly the aorta and its major branches. Data on paediatric TA (pTA) is very scarce. The aim of this study was to characterize clinical presentation, therapy and outcome of pTA in a global study population. Method We conducted an international multicentre retrospective observational study of children diagnosed with pTA. Inclusion criteria were an age of less than 18 years at initial presentation in the year 2000 or more recently. Clinical data were collected from patients’ charts by the treating paediatric rheumatologist or nephrologist; data were fully anonymised for analysis purposes. Follow-up data was collected up to 2 years after diagnosis. Results 198 patients from 20 countries were included (76% female). The median age at disease onset was 12 years. Arterial hypertension (67%), a difference in pulses between limbs (65%) and fatigue (66%) were the most common symptoms at presentation. The gastrointestinal system was the second most affected organ system. The median eGFR (estimated glomerular filtration rate) at baseline was 105 ml/min/1.73 m2. Renal artery stenosis was documented in 58% of all patients and in 37% there was need for an invasive renovascular procedure. In 25 of 32 (78%) patients who had either a positron emission tomography–magnetic resonance imaging (PET-MRI) or PET-computed tomography (CT) there was evidence of active inflammation mainly of the aorta. 67% of all patients showed thickened wall abnormalities and 31% had arterial dilatations in a major vessel on any one or more anatomical imaging modality such as ultrasound, CT or MRI. Immunosuppressive treatment was primarily steroids, cyclophosphamide and methotrexate, 37% of all patients were treated with monoclonal antibodies of which 65% received an anti-tumor necrosis factor (TNF) antibody, 31% an anti-Interleukin 6 (IL-6) antibody and 4% an anti-B-cell antibody. Dialysis was necessary in 7% and one patient underwent kidney transplantation. Seven patient deaths (4%) were documented at the most recent follow-up. The renal function after two years was median eGFR 102 ml/min/1.73 m2, with 67% showing normal function, 31% presenting with chronic kidney disease (CKD) stage 1, 1% with stage 2, 1% with stage 3 and no patients showed stages 4 and 5. A quarter of the patients (27%) were still symptomatic at the 2-year follow-up. The median systolic blood pressure was 117 (interquartile range 107–125) mmHg. 64% of all patients still had antihypertensive treatment, and 87% were still on immunosuppressive therapy. Conclusion Our study represents the largest paediatric cohort of children diagnosed with Takayasu arteritis. Several organ systems were involved at onset and the clinical spectrum was highly variable. We will in our further analyses in more detail describe the outcome in relation to presenting symptoms and treatment.

#555 Acute graft pyelonephritis in a kidney transplant recipient—a single centre experience in northern India

Abstract Background and Aims Urinary tract infections (UTI) are the most common infections after kidney transplantation. Although clinical spectrum of pyelonephritis after kidney transplantation remain less clear. This study was conducted to evaluate the prevalence, clinical and microbiological profile with antibiogram of post-transplant pyelonephritis. Method We retrospectively reviewed and analysed the charts of 1684 patients, who underwent kidney transplantation at Medanta—The Medicity between January 2015 and May 2023. Patients were screened for the diagnosis of pyelonephritis and their clinical characteristics and outcome were evaluated. Results 93/1684 (5.5%) patients with a mean age of 41 ± 13.57 years had developed at least one episode of Pyelonephritis. 68 were males and 25 females. Older age, female gender, hyperglycaemia, use of induction immunosuppression were the risk factors for Pyelonephritis. Median time of occurrence was 44 days after transplantation. Most common symptoms were fever (n=64) followed by dysuria (n=40), and abdominal pain (n=11). Most common organism isolated was Escherichia coli (51.6%) followed by Klebsiella pneumonia (30.1%), and Pseudomonas aeruginosa (11.8%). This study showed a high percentage of resistance to commonly used antibiotics like Carbapenems (61.3%), third generation cephalosporin (49.5%). 41/93 (44%) patients had acute graft dysfunction at the time of presentation. Median duration of hospital stay was 7 days. 90/93 patients had graft recovery and one patient lost his graft after episode of UTI. Conclusion Pyelonephritis is a common cause of morbidity after kidney transplantation and occurs in an early post-transplant period. Gram negative bacilli are the major pathogens and carbapenems as an empirical therapy might be useful choice for management of Pyelonephritis and coverage of majority pathogens.

#3033 IgA vasculitis: a unexpected diagnosis of pulmonary renal syndrome

Abstract Background IgA vasculitis is an inflammatory condition affecting blood vessels that poses a significant diagnostic and therapeutic challenge in clinical practice. Characterized by the deposition of immunoglobulin A (IgA) on vessel walls, this pathology can manifest in various ways, presenting a broad and sometimes complex clinical spectrum. Ninety percent of cases occur in the pediatric age group. Severe lung involvement, such as pulmonary hemorrhage, is rare in patients with IgAV. We present a case of a 33-year-old patient with pulmonary renal syndrome and without purpura, an atypical presentation of IgA vasculitis. Case Report We describe the case of a 33-year-old patient with no relevant medical history or regular medication, who presented to the emergency department in November 2022 with symptoms of hemoptysis, fatigue, myalgias, and pallor. On physical examination, the patient was conscious, cooperative, normotensive, tachycardic, afebrile, with bilateral axillary adenopathies, and scattered crackles on lung auscultation. Laboratory tests revealed anemia with a hemoglobin level of 5.8 g/dL, non-oliguric acute kidney injury with a creatinine level of 2.25 mg/dL, microscopic hematuria (>50/hpf), and proteinuria (UPCR of 2.8 mg/mg and UACR of 1.6 mg/mg). A chest CT scan showed bilateral and scattered ground-glass opacities consistent with alveolar hemorrhage. The patient was admitted to the Nephrology service, underwent 3 sessions of plasma exchange, and started therapy with methylprednisolone 1000 mg for 3 days. A renal biopsy revealed 24 glomeruli, with 3 showing segmental sclerosis and 1 with fibrocellular crescents, mild interstitial nephritis; immunofluorescence showed IgA+++, C3++, IgM, and IgG+- Oxford Classification: M1 E0 S1 T0 C1. Bronchofibroscopy showed a rosy bronchoalveolar lavage and macrophages with hemosiderin pigment deposition. The patient continued with prednisolone at 1 mg/kg. In January 2023 (after two months), there was a >25% reduction in albuminuria with resolution of acute kidney injury. A gradual reduction of prednisolone was initiated, and it was definitively discontinued in October 2023. In the last outpatient visit in January 2024, the patient maintained normal renal function, with no hematuria, UPCR of 100 mg/g, UACR of 70 mg/g, and no further episodes of alveolar hemorrhage. Conclusion This case stands out for its atypical presentation: an adult with alveolar hemorrhage and without other more classical manifestations of IgA vasculitis, such as purpura. This is yet another case that emphasizes the importance of the broad spectrum of diagnoses that a nephrologist should consider in the face of acute kidney injury.

#2078 Study of spectrum of renal dysfunction in cancer patients on ICPI as mono or combination with conventional chemo in north India

Abstract Background and Aims Although use of ICPI's have revolutionized the treatment of cancer patient with significantly improving the longevity of these patients but it also is associated with various adverse reactions known as iRAE's related to its use, which in due course is being revealed gradually. Kidney related iRAE's are important and also limitation to therapy, which could be a detrimental factor for these patients availing the beneficial effects of these revolutionary medications. Previous literature on these therapeutics had the limitations of being retrospective, small case series and case reports and evaluating only one or two parameters of kidney dysfunction, also the criteria used for evaluations had the limitation of standardization. With this we aimed to study the spectrum of renal dysfunction in cancer patients, receiving ICPI with or without conventional chemotherapy using standard criteria. Method Study involved patients with malignancy who had received at least 1 dose of ICPI as mono or combination with conventional chemotherapy. The primary end-point was 6 month assess the clinical spectrum & outcome of renal dysfunction, and the secondary end-points were the patient-level risk factors for renal dysfunction, the impact of renal dysfunction on clinical outcomes. Results Conducted through October 2021-2022, enrolled N = 156 (66 male & 90 females) & followed up for 6 months. 109 (69.9%) subjects developed KDIGO–AKI—Stage I (51.4%) & Stage II (35.8%) & non required RRT. The median duration for onset of AKI was 131 days. Proteinuria was observed in n = 143 (91.67%). n = 116 (74.3%) developed new-onset proteinuria. n = 40 (25.6%) were proteinuric at the start of the study & 27/40 (67.5%) were observed to have >50% increase in proteinuria, qualifying for proteinuria with therapy. 92/143 proteinuric subjects (64.3%) developed >1 g/day proteinuria. On subcategorizing proteinuria it was observed that 82/92 (57.3%) had 1–3 g/day proteinuria and ≥3.0 g/day proteinuria was observed in 10/92 (7.0%). Definitive ICPI–AKI could be attributed to only 2 subjects, as they underwent kidney biopsy for their kidney dysfunction and significant proteinuria. Secondary amyloid deposits in the glomeruli and mesangium was found in 1 subject & the other subject showed acute tubulointerstitial deposits with granular cast. Proteinuria and kidney dysfunction resolved with stoppage of the ICPI and steroids administration, which was consistent with the limited literature available for the management of ICPI related amyloidosis & iRAE. n = 88 had partial recovery of kidney dysfunction following an AKI event & complete recovery was seen in n = 3 (2.7%). >50% recovery in eGFR was observed in n = 41 (37.6%). Electrolyte abnormality commonly observed were hyponatremia, hypokalemia & hypomagnesemia & was seen in distributed almost equally, followed by hypocalcemia. Hypernatremia, hyperkalemia, hypermagnesemia & hypercalcemia were less commonly reported. Lastly mortality was also observed in n = 16 (10.2%), but could not be directly attributed to ICPI use, kidney dysfunction, malignancy type, comorbid conditions & other concomitants medication use. Conclusion To conclude this present prospective cohort study is a comprehensive assessment of the spectrum of renal dysfunction in cancer patients, among recipients of ICPI with or without conventional chemotherapy using standard criteria to the best of our knowledge, which has been the limitation of previous literature. We have shown a vast spectrum of kidney dysfunction possibly attributed to the ICPI's in malignancy patients. Viewed in respect to better QoL with ICPI therapy in malignancy patients, kidney related iRAE's could limit the patients from their beneficial effects. A possible persistent immune injury might have led to partial recovery of kidney dysfunction in majority. An unusual finding of secondary amyloid deposits with pembrolizumab, which possible might have occurred due to persistence of high levels of inflammatory markers due to these drugs. Thus underscoring the need for a close follow-up and recommend kidney biopsy to better & definitively identify the glomerular pathology & treatment accordingly.

#2613 Clinical spectrum and prognosis of the atypical polycystic kidney disease caused by monoallelic loss-of-function IFT140 variants

Abstract Background and Aims Monoallelic loss-of-function (LoF) variants in IFT140, which protein product is involved in retrograde ciliary trafficking and ciliary entry of membrane protein, have been recently linked to ADPKD spectrum, with 44 pedigrees reported so far [1]. The aim of this study was to characterize the disease presentation and renal outcome of individuals with monoallelic LoF variants of IFT140. Method Clinical information, family history and imaging data were collected for individuals with LoF IFT140-variants identified amongst 2800 individuals recruited in the Genkyst and Cystic ADPKD patients cohorts, and in different French, Spanish, and German centers. Targeted massive parallel sequencing of cystic genes or whole exome sequencing was performed. Newly identified and recently reported cases were combined to evaluate the influence of sex on eGFR using linear regression taking age into account. In addition, data of the Genome Aggregation (GnomAD) v4.0 and of the 100k Genomes project were respectively used to explore genetic prevalence and disease penetrance and expressivity. Results A total of 75 individuals from 61 pedigrees were identified (median age at last follow-up 56 years, 52% females). Forty-one different LoF IFT140-variants were identified: 14 nonsense, 7 splice-site, 14 frameshifting deletions or insertions and 6 large deletions, and no additional pathogenic variant was identified in any other gene. A majority of the individuals presented with large, exophytic cysts, median total kidney volume 688 (n = 35, range 201-4139) ml, and 90.9% were classified in Mayo Class 2A. Although 70.4% of the individuals had stage 1 or 2 chronic kidney disease (CKD) at the last follow up, proportion of CKD stage 3-5 was significantly higher (56.3% vs 7.7%, p < 0.00001) after 60 years of age. Adjusted for age, males exhibited lower eGFR (linear regression, p = 0.038, Fig. 1). Median age at diagnosis of hypertension was 63 years. Liver cysts were present in 12% of affected individuals with no case of symptomatic polycystic liver disease, and intracranial aneurysms in three of 10 screened patients. The genetic prevalence of monoallelic LoF IFT140 variants was estimated to be 19.56 (0.95 CI 18.60-20.53) per 10,000 in the entire GnomAD population (n = 280 in 807,162) and 29.4 (0.95 CI 25.4-33.8) per 10,000 in the 100kG (n = 190 in 64,185). Amongst the latter, kidney cysts were reported in 26.8% and diagnosis cystic kidney disease (Q61) was established in 18.4%. No obvious extra renal manifestations were identified, and out of total of 730 phenotype association tests conducted, only Q61 was associated with pLOF IFT140 variants (p = 2.9 × 10−9, OR = 5.6 (3.3-9.2)). Conclusion Individuals with monoallelic LoF variants of IFT140 are likely to develop kidney cysts and/or atypical forms of ADPKD. However, a large proportion may remain asymptomatic or undiagnosed. There is no evidence to recommend cascade screening using genetic testing in young at risk relatives. Follow-up of blood pressure and eGFR after 50 years of age should be advised.

#234 Clinical spectrum and genetic variants of Alport syndrome and thin basement membrane nephropathy—single center experience

Abstract Background and aims Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are genetically heterogeneous kidney diseases that manifest with kidney involvement, AS also with hearing and visual impairment. Electron microscopic examination shows characteristic ultrastructural changes in the glomerular basement membrane (GBM) in AS and TBMN, but cannot reliably distinguish between the two entities. Therefore, molecular genetic studies and the identification of individual pathogenic variants in the target genes are crucial to confirm the diagnosis. The aim of our study is to determine the significance of the genetic variants associated with the ultrastructural changes of GBM found in the renal biopsy. Method We retrospectively analyzed records of patients from the University Medical Centre Ljubljana in which ultrastructural GBM changes characteristic for AS and TBMN were found in the renal biopsy, including their clinical, laboratory and histological features. Molecular genetic investigations were made using the new generation sequencing method (NGS) to determine germline pathogenic variants in genes directly related to AS and TBMN (COL4A3, COL4A4 and COL4A5) and in genes that are important in syndromes with a related clinical picture (COL4A6, CD151, LMX1B, MYH9, FN1 and MYO1E). The pathogenicity of variants was determined according to the Clinical Molecular Genetic Society best practice guidelines. Results The study included 73 patients with ultrastructurally confirmed thin GBM. Indications for kidney biopsy were chronic nephritis syndrome in 33 patients (45%), acute worsening of renal function in 16 (22%), nephrotic syndrome in 9 (12%), nephrotic proteinuria and chronic kidney disease in 6 (8%), isolated proteinuria in 5 (7%) and suspected vasculitis in 4 patients (6%). At the time of kidney biopsy average age was 50 ± 16 years, average creatinine 112 ± 70 µmol/L and average estimated glomerular filtration rate (eGFR) 65 ± 24 ml/min/1.73 m2, 7 patients had eGFR below 30 ml/min/1.73 m2. Average daily proteinuria was 2.4 ± 3.3 gr and 88% of patients had hematuria. 38% of them have hearing impairment and 43% had positive familiar history of kidney disease. We recorded 33 patients (45%) with genetic variants associated with AS or TBMN: 22 patients (67%) with pathogenic variants, 2 patients (6%) with likely pathogenic and 9 patients (27%) with variants of uncertain significance. The presence of a positive genetic analysis was associated with a higher level of hematuria (p = 0.003), a lower level of proteinuria (p = 0.004) and a positive family history of kidney disease (p < 0.001). It was also associated with hearing loss, but the association was not statistically significant (p = 0.099). Patients with genetic variants had similar eGFR to those with negative genetics (63.9 ml/min/1.73 m2 (58.3-69.4) vs 66.2 ml/min/1.73 m2 (60.0-72.3)), p = 0.698. We also found no differences in GBM thickness in patients without compared to those with identified gene variants (213 nm (160-315) vs. 209 nm (140-410)), p = 0.761. 32 patients (44%) had only focal chronic changes and ultrastructural changes of thin GBM present on kidney biopsy and 41 patients (56%) had also been diagnosed with other renal pathology. When comparing these two groups, patients without associated pathology had lower daily proteinuria (p = 0.048), higher level of hematuria (p = 0.021), frequent hearing impairment (p = 0.008) and also positive genetics analysis (p = 0.016). Conclusion We have shown that in patients with proven ultrastructural alterations in GBM, the presence of so far recognized genetic variants associated with AS and TBMN is 45%, and corresponds to the frequency of other phenotypic characteristics of AS, including hearing impairment and positive family history. In the future, additional clinical tools will be required to accurately determine the role of coexistent thin GBM on the prognosis of patients with other relevant kidney pathology and other genetic tools beyond NGS should be employed to explore other pathologic genetic variants associated with the AS spectrum.

Cutaneous Reactions in Pediatric Patients Treated with MEK Inhibitors- A Retrospective Single Center Study.

Introduction MEK inhibitors are in use for several indications for adults and children. Cutaneous toxicities are among the most common adverse effects. We aimed to describe the spectrum of cutaneous adverse events, its frequency and severity in a cohort of pediatric patients. Methods We reviewed all records of patients in our tertiary treatment center treated with MEK inhibitors between January 2016 and January 2023 for all indications. Results Among 33 patients, 76% reported cutaneous adverse effects. The highest prevalence was in the group of patients treated with trametinib (90%), followed by the group treated with selumetinib (50%) and the group treated with combination of trametinib and BRAF inhibitor (dabrafenib, 34%). Xerosis, dermatitis, paronychia and hair heterochromia were most frequently reported. Severity was graded 1 or 2 for most adverse events, and 237 visits to the dermatology clinic related to these adverse events were recorded. Conclusions Cutaneous adverse events are common in the pediatric population as in adults, but the clinical spectrum is different. Although considered as mild, multiple dermatological consultations reflect the distress caused by these events. Dermatologists have a central role in the multidisciplinary care of pediatric patients receiving these agents.

A rare case of congenital right lobar segmental hepatic hypoplasia complicated by portal hypertension: a radiologic perspective

Abstract Background Segmental hypoplasia of liver is an infrequently encountered congenital anomaly which is clinically indolent and detected incidentally on cross sectional imaging or abdominal surgery which can have a myriad of surgical and medical implications. The unique radiological manifestations and associated complications makes it a diagnostically challenging entity. Case presentation We report a case of a middle-aged female presenting with complaints of non-specific abdominal pain for two years in which we reported the presence of segmental hypoplasia of right lobe complicated by development of portal hypertension incidentally detected on ultrasound examination which was followed up and confirmed on cross sectional imaging. Conclusions In this case report, we present a unique instance of congenital segmental hypoplasia of the liver, highlighting the intricacies of its radiological presentation, potential clinical implications, and the challenges associated with its diagnosis. By examining this rare anomaly, we aim to contribute to the growing body of knowledge surrounding hepatic developmental disorders, fostering a deeper understanding of the clinical spectrum, and facilitating improved patient care through enhanced diagnostic awareness.

Simpson-Golabi-Behmel syndrome.

The Simpson-Golabi-Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X-linked semi-dominant trait, with variable expressivity in males and reduced penetrance and expressivity in females. The clinical spectrum is broad, ranging from mild manifestations in both males and females to multiple malformations and neonatal death in the more severely affected cases. An increased risk of neoplasia is reported, requiring periodical surveillance. Intellectual development is normal in most cases. SGBS is caused by a loss-of-function mutation of the GPC3 gene, either deletions or point mutations, distributed all over the gene. Notably, GPC3 deletion/point mutations are not found in a significant proportion of clinically diagnosed SGBS cases. The protein product GPC3 is a glypican functioning as a receptor for Hh at the cell surface, involved in the Hh-Ptc-Smo signaling pathway, a regulator of cellular growth.

Clinical, Hormonal, and Genetic Spectrum of 46 XY Disorders of Sexual Development (DSD) Patients.

To evaluate the clinical,hormonaland genetic characteristics of 46XY disorders of sexual development (DSD) patients from South India. 46XY DSD patients with a provisional diagnosis of 17β-hydroxysteroid dehydrogenase 3 (17BHSD3) deficiency, 5 alpha-reductase type 2 deficiency (5ARD2) or partial androgen insensitivity syndrome (PAIS) based on clinical and hormonal analysis were included in this study. All the patients underwent detailed clinical and hormonal evaluations. Targeted next-generation sequencing for all three genes (AR, HSD17B3, and SRD5A2) in parallel was carried out for all the included patients and their parents. Based upon the clinical and hormonal analysis, among the 37 children with 46XY DSD in the present study, 21 children were diagnosed with 5ARD2, 10 with PAIS, and six with 17BHSD3 deficiency. However, genetic analysis revealed pathogenic mutations in nine patients - six in the AR gene, two in the SRD5A2 gene, and one in the HSD17B3 gene. The concordance rate between provisional hormonal and genetic diagnosis was only 22.2%. Two out of six subjects with AR gene variants were positive for somatic mosaicism. In the present study, a positive genetic diagnosis was detected in nine patients (24%), including five novel variants. In this study, mutations in the AR gene was the most reported. The authors did not find the testosterone: dihydrotestosterone (T: DHT) ratio to be an accurate hormonal diagnostic tool.

From Atherosclerosis to Spontaneous Coronary Artery Dissection: Defining a Clinical and Genetic Risk Spectrum for Myocardial Infarction.

Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease. Recent studies have revealed several associated variants with varying effect sizes for SCAD, giving rise to a complex genetic architecture. Associated genes highlight an important role for arterial cells and their extracellular matrix in the pathogenesis of SCAD, as well as notable genetic overlap between SCAD and other systemic arteriopathies such as fibromuscular dysplasia and vascular connective tissue diseases. Further investigation of individual variants (including in the associated gene PHACTR1) along with polygenic score analysis have demonstrated an inverse genetic relationship between SCAD and atherosclerosis as distinct causes of AMI. SCAD represents an increasingly recognized cause of AMI with opposing clinical and genetic risk factors from that of AMI due to atherosclerosis, and it is often associated with complex underlying genetic conditions. Genetic study of SCAD on a larger scale and with more diverse cohorts will not only further our evolving understanding of a newly defined genetic spectrum for AMI, but it will also inform the clinical utility of integrating genetic testing in AMI prevention and management moving forward.

Modeling social cognition in alcohol use disorder: lessons from schizophrenia.

A better understanding of social deficits in alcohol use disorder (AUD) has the potential to improve our understanding of the disorder. Clinical research shows that AUD is associated with interpersonal problems and the loss of a social network which impedes response to treatment. Translational research between animal models and clinical research may benefit from a discussion of the models and methods that currently guide research into social cognition in AUD. We propose that research in AUD should harness recent technological developments to improve ecological validity while maintaining experimental control. Novel methods allow us to parse naturalistic social cognition into tangible components, and to investigate previously neglected aspects of social cognition. Furthermore, to incorporate social cognition as a defining element of AUD, it is critical to clarify the timing of these social disturbances. Currently, there is limited evidence to distinguish factors that influence social cognition as a consequence of AUD, and those that precede the onset of the disorder. Both increasing the focus on operationalization of social cognition into objective components and adopting a perspective that spans the clinical spectrum will improve our understanding in humans, but also possibly increase methodological consistency and translational dialogue across species. This commentary underscores current challenges and perspectives in this area of research.

Expanding the genetic and phenotypic relevance of CLCN4 variants in neurodevelopmental condition: 13 new patients.

CLCN4 variations have recently been identified as a genetic cause of X-linked neurodevelopmental disorders. This study aims to broaden the phenotypic spectrum of CLCN4-related condition and correlate it with functional consequences of CLCN4 variants. We described 13 individuals with CLCN4-related neurodevelopmental disorder. We analyzed the functional consequence of the unreported variants using heterologous expression, biochemistry, confocal fluorescent microscopy, patch-clamp electrophysiology, and minigene splicing assay. We identified five novel (p.R41W, p.L348V, p.G480R, p.R603W, c.1576 + 5G > A) and three known (p.T203I, p.V275M, p.A555V) pathogenic CLCN4 variants in 13 Chinese patients. The p.V275M variant is found at high frequency and seen in four unrelated individuals. All had global developmental delay (GDD)/intellectual disability (ID). Seizures were present in eight individuals, and 62.5% of them developed refractory epilepsy. Five individuals without seizures showed moderate to severe GDD/ID. Developmental delay precedes seizure onset in most patients. The variants p.R41W, p.L348V, and p.R603W compromise the anion/exchange function of ClC-4. p.R41W partially impairs ClC-3/ClC-4 association. p.G480R reduces ClC-4 expression levels and impairs the heterodimerization with ClC-3. The c.1576 + 5G > A variant causes 22bp deletion of exon 10. We further define and broaden the clinical and mutational spectrum of CLCN4-related neurodevelopmental conditions. The p.V275M variant may be a potential hotspot CLCN4 variant in Chinese patients. The five novel variants cause loss of function of ClC-4. Transport dysfunction, protein instability, intracellular trafficking defect, or failure of ClC-4 to oligomerize may contribute to the pathophysiological events leading to CLCN4-related neurodevelopmental disorder.

Disease spectrum and prognostic factors in patients treated for tuberculous meningitis in Shaanxi province, China

BackgroundTuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) and can be difficult to diagnose and treat. We aimed to describe the clinical presentation, diagnosis, disease spectrum, outcome, and prognostic factors of patients treated for TBM in China.MethodsA multicenter retrospective study was conducted from 2009 to 2019 enrolling all presumptive TBM patients referred to Xijing tertiary Hospital from 27 referral centers in and around Shaanxi province, China. Patients with clinical features suggestive of TBM (abnormal CSF parameters) were included in the study if they had adequate baseline information to be classified as “confirmed,” “probable,” or “possible” TBM according to international consensus TBM criteria and remained in follow-up. Patients with a confirmed alternative diagnosis or severe immune compromise were excluded. Clinical presentation, central nervous system imaging, cerebrospinal fluid (CSF) results, TBM score, and outcome—assessed using the modified Barthel disability index—were recorded and compared.FindingsA total of 341 presumptive TBM patients met selection criteria; 63 confirmed TBM (25 culture positive, 42 Xpert-MTB/RIF positive), 66 probable TBM, 163 possible TBM, and 49 “not TBM.” Death was associated with BMRC grade III (OR = 5.172; 95%CI: 2.298–11.641), TBM score ≥ 15 (OR = 3.843; 95%CI: 1.372–10.761), age > 60 years (OR = 3.566; 95%CI: 1.022–12.442), and CSF neutrophil ratio ≥ 25% (OR = 2.298; 95%CI: 1.027–5.139). Among those with confirmed TBM, nearly one-third (17/63, 27.0%) had a TBM score < 12; these patients exhibited less classic meningitis symptoms and signs and had better outcomes compared with those with a TBM score ≥ 12. In this group, signs of disseminated/miliary TB (OR = 12.427; 95%CI: 1.138–135.758) and a higher TBM score (≥15, OR = 8.437; 95%CI: 1.328–53.585) were most strongly associated with death.ConclusionTBM patients who are older (>60 years) have higher TBM scores or CSF neutrophil ratios, have signs of disseminated/miliary TB, and are at greatest risk of death. In general, more effort needs to be done to improve early diagnosis and treatment outcome in TBM patients.

Myelin Oligodendrocyte Glycoprotein-Antibody Associated Disease: An Updated Review of the Clinical Spectrum, Pathogenetic Mechanisms and Therapeutic Management

Clinical syndromes associated with antibodies against myelin oligodendrocyte glycoprotein (MOG) are now recognized as a distinct neurological disease entity, and are gaining increasing attention. The pathogenic mechanisms underlying MOG-antibody disease (MOGAD) remain incompletely understood. Case series, facilitated by registries, and observational studies over the past few years have shed increasing light on the clinical aspects and therapeutic approaches of MOGAD. MOGAD may manifest with a variety of clinical syndromes, including acute disseminated encephalomyelitis (ADEM), autoimmune encephalitis, optic neuritis (ON) and transverse myelitis (TM). MOGAD can be either monophasic or relapsing. This review aims to provide a comprehensive updated description of the clinical spectrum, paraclinical features, and prognosis of MOG-antibody disease, as well as summarize its therapeutic considerations. Randomized clinical trials, standardized diagnostic criteria and treatment guidelines are the steps forward.