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1.
Isolated nephrocalcinosis due to compound heterozygous mutations in renal outer medullary potassium channel.
Khandelwal, P, Sabanadesan, J, Sinha, A, Hari, P, Bagga, A
CEN case reports. 2020;(3):232-236
Abstract
Identification of a monogenic etiology is possible in a proportion of patients with childhood-onset nephrolithiasis or nephrocalcinosis. Bartter syndrome (BS), a hereditary tubulopathy characterized by polyuria, hypokalemic alkalosis and growth retardation that rarely presents with isolated nephrocalcinosis. Patients with defect in renal outer medullary potassium channel, encoded by the KCNJ1 gene causing BS type 2, typically present during the neonatal period. We describe a 14-year-old girl with mild late-onset BS type 2 with reported pathogenic compound heterozygous variations in exon 2 of KCNJ1 (c.146G > A and c.657C > G). This patient presented with isolated medullary nephrocalcinosis due to hypercalciuria; absence of hypokalemia and metabolic alkalosis was unique. This case highlights the importance of screening the KCNJ1 gene in patients with hypercalciuria and nephrocalcinosis, even in older children.
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2.
Links between metabolic syndrome and the microbiome.
Gildner, TE
Evolution, medicine, and public health. 2020;2020(1):45-46
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Metabolic syndrome (MetS) is a cluster of co-occurring pathological conditions, characterised by insulin resistance, abdominal obesity, hypertension and dyslipidaemia One possible factor contributing to MetS risk is change in microbiome composition. Diets high in processed foods appear to alter microbiome composition in ways that promote higher fat mass and insulin resistance. Additionally, a sedentary lifestyle decreases microbiome diversity, elevating inflammation and metabolic disease risk. Research on how the microbiome responds to modest, attainable changes in diet and physical activity will help identify which dietary adjustments and exercise types have the greatest potential to protect patients from MetS.
Abstract
Metabolic syndrome (MetS) is a cluster of harmful conditions which occur together, such as insulin resistance, abdominal obesity, and hypertension. The global prevalence of MetS is growing rapidly, with some estimates suggesting over one billion people worldwide experience increased morality and disease rates linked with this syndrome. One possible factor contributing to MetS risk is changes in microbiome composition. Approximately 100 trillion bacteria and other microbes reside in the human intestinal tract, collectively termed the gut microbiome. Humans and microbes share a long evolutionary history, with many of these microbes influencing human health outcomes. However, environmental conditions have changed dramatically with human technological innovations; many of these changes (e.g., diets high in processed foods and sedentary lifestyles) appear to impact human-microbe relationships. In general, recent changes in diet and activity patterns have been linked to decreased microbiome diversity, elevating inflammation and metabolic disease risk and likely promoting the development of MetS. Targeting patient diet or exercise patterns may therefore help doctors better treat patients suffering from MetS. Still, additional work is needed to determine how the microbiome responds to changes in patient activity and diet patterns across culturally and biologically diverse human populations.
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Intramyocellular Lipids, Insulin Resistance, and Functional Performance in Patients with Severe Obstructive Sleep Apnea.
Chien, MY, Lee, PL, Yu, CW, Wei, SY, Shih, TT
Nature and science of sleep. 2020;12:69-78
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Obstructive sleep apnoea syndrome (OSA) is characterized by repeated occlusion of the upper airway during sleep, resulting in periods of intermittent hypoxemia [low level of oxygen in blood]. The aim of this study was to (a) investigate the intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL), biochemical data, and functional performance in patients with severe OSA versus controls, and (b) examine the correlations between intra-muscular lipid contents and biochemical and performance variables. This study is a clinical trial that recruited 20 patients with OSA and body mass index(BMI)-matched controls. Results demonstrate that patients with OSA had significantly lower IMCL and EMCL values when compared with their age-, and BMI-matched controls without OSA. Furthermore, compared with controls, patients with OSA had significantly reduced functional performance and exhibited abnormal biochemical data, including glucose and insulin levels and lipid profiles. Authors conclude that additional large-scale clinical trials are required to further explore the complex mechanism between OSA, muscle metabolism, and insulin action.
Abstract
PURPOSE An increasing number of studies have linked the severity of obstructive sleep apnea (OSA) with metabolic dysfunction. However, little is known about the lipid compartments (intramyocellular [IMCL] and extramyocellular [EMCL] lipids) inside the musculature in these patients. The present study was designed to investigate the IMCL and EMCL, biochemical data, and functional performance in patients with severe OSA, and to examine the correlations between intramuscular lipid contents and test variables. PARTICIPANTS AND METHODS Twenty patients with severe OSA (apnea-hypopnea index [AHI]: ≥30/h; body mass index [BMI]: 26.05±2.92) and 20 age- and BMI-matched controls (AHI <5/h) were enrolled. Proton magnetic resonance spectroscopy was used to measure the IMCL and EMCL of the right vastus lateralis muscle. Biochemical data, including levels of fasting plasma glucose, insulin, lipid profiles, and high-sensitivity C-reactive protein (hsCRP), were measured. Insulin resistance index (IR) was calculated using the homeostasis model assessment method. Performance tests included a cardiopulmonary exercise test and knee extension strength and endurance measurements. RESULTS Patients with severe OSA had significantly (P<0.05) lower values of IMCL (14.1±5.4 AU) and EMCL (10.3±5.8 AU) compared to the control group (25.2±17.6 AU and 14.3±11.1 AU, respectively). Patients with severe OSA had significantly higher hsCRP, IR, and dyslipidemia compared with controls (all P<0.05). Furthermore, IMCL was negatively correlated with AHI, cumulative time with nocturnal pulse oximetric saturation lower than 90% (TSpO2<90%) (ρ=-0.35, P<0.05), IR (ρ=-0.40, P<0.05), glucose (ρ=-0.33, P<0.05), and insulin (ρ=-0.36, P<0.05), and positively correlated with lowest oximetric saturation (ρ=0.33, P<0.01). CONCLUSION Skeletal muscle dysfunction and metabolic abnormalities were observed in patients with OSA that did not have obesity. IMCL was positively correlated with aerobic capacity and muscular performance, but negatively correlated with AHI and IR. Large-scale clinical trials are required to explore the complicated mechanism among OSA, intramuscular metabolism, and insulin action. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00813852.
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Significant Impact of the Ketogenic Diet on Low-Density Lipoprotein Cholesterol Levels.
Salas Noain, J, Minupuri, A, Kulkarni, A, Zheng, S
Cureus. 2020;12(7):e9418
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Ketogenic diet includes food with a very low-carbohydrate and high-fat content that aims to drastically reduce carbohydrate intake and replace it with fat, hence inducing ketosis. This study is a case report which presents a case of a rapid increase, followed by a rapid correction of low-density lipoprotein cholesterol (LDL-C) in a patient following a ketogenic diet. The patient is a 56-year-old Hispanic female who showed a rapid increase in LDL-C and total cholesterol after only 30-40 days of following a ketogenic diet. She was directed to follow a balanced diet and take statin medication. Results showed that the patient's BMI, four weeks after the discontinuation of ketogenic diet, did not change despite a marked improvement in her LDL-C. Authors conclude that due to the unpredictable response of LDL-C levels to a ketogenic diet, close monitoring of patients with a high risk of cardiovascular disease should be considered.
Abstract
It is well known, based on the previous research, that a ketogenic diet leads to an improvement in the lipid profile and decreases cardiovascular risk factors such as hypertension. However, recent studies have also reported increased levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) as a result of this diet. It has been postulated that this elevation in LDL-C would not likely increase cardiovascular complications due to the large LDL-C particle size. In this case report, we present a case of a rapid increase, followed by a rapid correction of LDL-C, in a patient following a ketogenic diet. A 56-year-old Hispanic female with a past medical history of hypertension and fibromyalgia presented to the outpatient clinic for evaluation of fatigue. She reported that she had been following a strict ketogenic diet along with daily regular exercise for approximately 30-40 days prior to this visit. Her diet consisted of low-carbohydrate vegetables, seafood, avocados, eggs, and coconut oil. The patient's physical exam was unremarkable. At the time of the visit, her BMI was calculated at 28 kg/m2, with a weight loss of approximately six to seven pounds since starting the ketogenic diet. Her fasting lipid profile showed a total cholesterol of 283 mg/dl, LDL-C of 199 mg/dl, high-density lipoprotein cholesterol (HDL-C) of 59 mg/dl, and triglycerides levels of 124 mg/dl. She was instructed to stop the ketogenic diet and to incorporate a balanced diet, which includes a higher amount of carbohydrates and lower fat. She was also started on high-intensity atorvastatin. However, she reported experiencing myalgias soon after initiating atorvastatin; therefore, the medication was switched to rosuvastatin 10 mg at bedtime. During her follow-up appointment, she reported not having consistently taken rosuvastatin due to the concern of worsening myalgias. Her lipid profile, after four weeks of ketogenic diet discontinuation and inconsistent use of statins, showed significant improvement resulting in a total cholesterol level of 190 mg/dl and LDL-C of 106 mg/dl. Statin therapy was discontinued, and the patient maintained optimal LDL-C levels on subsequent testing. This patient showed a rapid increase in LDL-C and total cholesterol after only 30-40 days of the ketogenic diet. Her drastic elevation in LDL-C could also be explained due to the rapid weight loss, as cholesterol in the adipose tissue is known to mobilize as the fat cells shrink. Interestingly, her BMI four weeks after the discontinuation of the ketogenic diet did not change despite a marked improvement in her LDL-C. Therefore, we believe the acute onset and resolution of hyperlipidemia was secondary to the ketogenic diet itself. This study helps to better understand expectations when recommending a ketogenic diet to patients and its consequences. There is currently no statistically significant study that proves this elevation of LDL-C would not increase cardiovascular risks. Furthermore, the necessity for statin therapy in a ketogenic diet-induced hyperlipidemia remains unknown.
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Primary creatine deficiency syndrome as a potential missed diagnosis in children with psychomotor delay and seizure: case presentation with two novel variants and literature review.
Rostami, P, Hosseinpour, S, Ashrafi, MR, Alizadeh, H, Garshasbi, M, Tavasoli, AR
Acta neurologica Belgica. 2020;(3):511-516
Abstract
Creatine is the main source of energy for the brain. Primary creatine deficiency syndromes (PCDSs) are inborn error of metabolism of creatine synthesis. Symptoms of central nervous system involvement are the most common clinical manifestations in these disorders. We reviewed medical records of all genetically confirmed patients diagnosed by whole exome sequencing who were referred to Myelin and Neurodegenerative Disorders Clinic, Children's Medical Center, Tehran, Iran, from May 2016 to Dec 2018. A literature review was conducted on clinical and genomic variability of PCDS to compare our patients with previously reported cases. We report two patients with creatine deficiency among a cohort of 550 registered cases out of which 200 patients had a genetically confirmed neurodegenerative disorder diagnosis. The main complain in the first patient with creatine transporter (CRTR) deficiency was seizure and genetic study in this patient identified a novel hemizygote variant of "c.92 > T; p.Pro31Leu" in the first exon of SLC6A8 gene. The second patient with guanidinoacetate methyltransferase (GAMT) deficiency had an unknown motor and speech delay as the striking manifestation and molecular assay revealed a novel homozygote variant of "c.134G > A; p.Trp45*" in the first exon of GAMT gene. PCDSs usually are associated with nonspecific neurologic symptoms. The first presented case had a mean delayed diagnosis of 5 years. Therefore, in children with unexplained neurologic features including developmental delay and/or regression, mental disability and repeated seizures without any significant findings in metabolic studies, PCDSs can be considered as a differential diagnosis and molecular analysis can be helpful for the precise diagnosis and treatment.
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Outcome of twin pregnancy in a patient with Gitelman syndrome: a case report and literature review.
Yu, H, Liao, H, Wang, X, Tong, Y
Annals of palliative medicine. 2020;(4):2361-2366
Abstract
Gitelman syndrome (GS) is a rare autosomal-recessive disease characterized by hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria. The impact of GS to pregnant and fetus is not wellknown, with few reports until now and no report about twin pregnancy and GS. We report the successful outcome of monochorionic twin pregnancy in a patient with GS. Oral or intravenously potassium chloride and magnesium citrate were prescribed. The course of the pregnancy was uneventful and the patient remained asymptomatic despite persistent hypokalemia. At 36+4 weeks of gestation, two female babies were delivered, weighing 2,380 and 2,210 g respectively. SLC12A3 gene analysis in mother and two babies revealed heterozygous mutations at 988 ATA codon in exon 26, which convert isoleucine to threonine (I988T). The mother and the twins are all in good health condition during three years follow-up. Close fetal serial surveillance, frequent electrolyte evaluation and adequately supplement with potassium and magnesium should be required to prevent obstetrical and fetal complications in a patient with GS. Management by multidisciplinary team is critical to optimizing outcomes for mother and fetus.
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Hyperkalemia in type 4 renal tubular acidosis associated with systemic lupus erythematosus.
Üsküdar Cansu, D, Cansu, GB, Güvenir, S, Korkmaz, C
Rheumatology international. 2020;(11):1895-1901
Abstract
Renal tubular acidosis (RTA) is a normal anion gap metabolic acidosis that manifests with insufficiency of hydrogen ion excretion or bicarbonate (HCO3) reuptake as a result of renal tubular dysfunction independent of glomerular filtration rate. Hypokalemic RTA subtypes co-existing with autoimmune diseases particularly appear in Sjogren's syndrome, but rarely in systemic lupus erythematosus (SLE). Type 4 RTA associated with hyperkalemia is very rare during the course of SLE and hence has been scarcely reported in the literature. Here, we report a 42-year-old patient for whom regular follow-up was ongoing due to class IV lupus nephritis when she developed hyperkalemia. The patient had normal anion gap hyperkalemic metabolic acidosis and her urine pH was 5.5. Type 4 RTA was considered and, therefore, tests for renin and aldosterone levels were requested, which revealed that renin was suppressed and aldosterone was decreased. Upon diagnosis of SLE-associated type 4 RTA, short-term oral HCO3 and fludrocortisone were initiated. Potassium (K) and HCO3 levels improved at day 15 of therapy. In this review, we analyzed our case along with five other reports (a total of seven cases) of SLE-associated type 4 RTA we identified through a literature search. We wanted to highlight RTA for differential diagnosis of hyperkalemia emerging during SLE/lupus nephritis and we also discussed possible underlying mechanisms.
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A novel mutation in gene of PRPS1 in a young Chinese woman with X-linked gout: a case report and review of the literature.
Yang, BY, Yu, HX, Min, J, Song, XX
Clinical rheumatology. 2020;(3):949-956
Abstract
Pyrophosphate synthetase-1(PRS-1) is a crucial enzyme that catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) with substrate: adenosine triphosphate (ATP) and ribose-5-phophate(R5P) in the de novo pathways of purine and pyrimidine nucleotide synthesis. Mutation in PRPS1 can result in a series of diseases of purine metabolism, which includes PRS-1 superactivity. The common clinical phenotypes are hyperuricemia and hyperuricosuria. We identified a novel missense mutation in X-chromosomal gene PRPS1 in a young Chinese woman while her mother has heterogeneous genotype and phenotype. A 24-year-old Chinese female patient suffered hyperuricemia, gout, and recurrent hyperpyrexia for more than 6 years, and then was diagnosed with hyperandrogenism, insulin resistance (IR), and polycystic ovary syndrome (PCOS). A novel missense mutation, c.521(exon)G>T, p.(Gly174Val) was detected by next-generation sequencing (NGS) and confirmed by Sanger sequencing in the patient and her parents. Interestingly, her mother has the same heterozygous missense mutation but without uric acid overproduction which can be explained by the phenomenon of the skewed X-chromosome inactivation. The substituted amino acid Val for Gly174 is positioned in the pyrophosphate (PPi) binding loop, and this mutation impacts the binding rate of Mg2+-ATP complex to PRS-1, thus the assembling of homodimer is affected by changed Val174 leading to the instability of the allosteric site. Our report highlights the X-linked inheritance of gout in females caused by mutation in PRPS1 accompanied with severe metabolic disorders and recurrent hyperpyrexia.
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Pediatric Acute-onset Neuropsychiatric Syndrome and Mycoplasma Pneumoniae Infection: A Case Report Analysis with a Metabolomics Approach.
Piras, C, Pintus, R, Pruna, D, Dessì, A, Atzori, L, Fanos, V
Current pediatric reviews. 2020;(3):183-193
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Abstract
Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinical condition characterized by a sudden and dramatic obsessive-compulsive disorder with a suggested post-infectious immune-mediated etiology. This condition is accompanied by an extensive series of relatively serious neuropsychiatric symptoms. The diagnosis of PANS is made by "exclusion", as the individual PANS symptoms overlap with a multiplicity of psychiatric disorders with the onset in childhood. A number of researchers accumulated evidence to support the hypothesis that PANS was closely associated with a number of infections. In the last decade, metabolomics played an essential role in improving the knowledge of complex biological systems and identifying potential new biomarkers as indicators of pathological progressions or pharmacologic responses to therapy. The metabolome is considered the most predictive phenotype, capable of recognizing epigenetic differences, reflecting more closely the clinical reality at any given moment and thus providing extremely dynamic data. In the present work, the most recent hypothesis and suggested mechanisms of this condition are reviewed and the case of a 10 - year-old girl with PANS is described, before and after clarithromycin treatment. The main results of this case report are discussed from a metabolomics point of view. The alteration of several metabolic pathways concerning the microbial activity highlights the possible role of the microbiome in the development of PANS. Furthermore, different metabolic perturbations at the level of protein biosynthesis, energy and amino acid metabolisms are observed and discussed. Based on our observations, it is believed that metabolomics is a promising technology to unravel the mysteries of PANS in the near future.
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Late-Onset Bartter Syndrome Type II Due to a Homozygous Mutation in KCNJ1 Gene: A Case Report and Literature Review.
Elfert, KA, Geller, DS, Nelson-Williams, C, Lifton, RP, Al-Malki, H, Nauman, A
The American journal of case reports. 2020;:e924527
Abstract
BACKGROUND Bartter syndrome is a rare genetic disease characterized by hypokalemia, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Five different subtypes have been described based on the genetic defect identified. Bartter syndrome type II is caused by homozygous or compound heterozygous loss-of-function mutations in the KCNJ1 gene encoding ROMK. This subtype is typically described as a severe antenatal form of the disease, often presenting with polyhydramnios before childbirth. CASE REPORT Here, we describe the case of a 26-year-old man who presented with generalized body weakness and hypokalemia and was ultimately diagnosed with Bartter syndrome type II based on his clinical features coupled with the identification of a homozygous missense mutation in KCNJ1. CONCLUSIONS To the best of our knowledge, this is the fifth case of late-onset Bartter syndrome type II. Interestingly, the mutation identified in our patient has been previously described in patients with antenatal Bartter's Syndrome. The late presentation in our patient suggests a surprising degree of phenotypic variability, even in patients carrying the identical disease-causing mutation.