scholarly journals Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort

2020 ◽  
Vol 61 (12) ◽  
pp. 1784-1788
Author(s):  
Chiara Pavanello ◽  
Alice Ossoli ◽  
Marcello Arca ◽  
Laura D’Erasmo ◽  
Giuliano Boscutti ◽  
...  
Keyword(s):  
Renal Disease ◽  
Kidney Function ◽  
Genetic Disorder ◽  
High Plasma ◽  
Loss Of Function ◽  
Lcat Deficiency ◽  
Predicting Factor ◽  
Hdl Metabolism ◽  
Italian Cohort

Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient to patient. In this article, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years. We show that renal failure occurs at the median age of 46 years, with a median time to a second recurrence of 10 years. Additionally, we identify high plasma unesterified cholesterol level as a predicting factor for rapid deterioration of kidney function. In conclusion, this study highlights the severe consequences of FLD, underlines the need of correct early diagnosis and referral of patients to specialized centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency.

Abstract 234: Reduction of LpX and Improvement in Kidney Function in LCAT-KO Mice by Enzyme Replacement Therapy

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Boris L Vaisman ◽  
Edward B Neufeld ◽  
Lita A Freeman ◽  
Maureen L Sampson ◽  
Milton Pryor ◽  
...  
Keyword(s):  
Mouse Model ◽  
Renal Disease ◽  
Kidney Function ◽  
Chow Diet ◽  
Creatinine Ratio ◽  
Kidney Dysfunction ◽  
Albumin Creatinine Ratio ◽  
Normal Chow ◽  
Lcat Deficiency ◽  
Normal Chow Diet

Familial LCAT Deficiency (FLD) is associated with the gradual development of severe kidney dysfunction from the renal deposition of LpX, an abnormal lipoprotein that accumulates in this disorder. The aim of our study was to develop an efficient mouse model of FLD in which elevated plasma LpX and kidney dysfunction can be rapidly induced in order to test whether recombinant human LCAT (rhLCAT) injections can prevent renal disease. We used the previously described LCAT-Ko x SREBP1a transgenic mouse model (Zhu et al., 2004) with the transgene placed under control of PEPCK promoter, which can be induced by high protein diets. We demonstrate that high levels of LpX plasma particles appeared within 5-7 days after 2-3 month old mice were switched to a protein rich carbohydrate low diet (PRCL). Kidney dysfunction measured by albumin/creatinine ratio after 9 days on PRCL diet increased by 32±12 fold. On the PRCL diet, plasma VLDL-C and LDL-C fractions of LCAT-Ko x SREBP1a mice increased 2-4 fold compared to mice on a normal chow diet. Transmission electron microscopy clearly demonstrated the presence of multilamellar LpX particles in plasma and renal glomeruli, as well as robust accumulation lipid droplets in hepatocytes of mice kept on the PRCL diet for 7 days. All these changes were reversible; when mice were returned to the normal chow diet their plasma lipid characteristics and kidney function quickly returned within days to the level observed before the diet was initiated. When LCAT-Ko x SREBP1a mice were placed on PRCL diet and simultaneously treated with rhLCAT (x 3 per week IV injection 30 mg/kg for 2 weeks) plasma LpX was eliminated and a normal mouse lipoprotein profile was observed and most notably HDL-C increased from 5.6 g/dL to 54.1 mg/dL. Treatment with rhLCAT decreased the albumin/creatinine ratio 5±1 fold. Conclusions: LCAT-Ko and SREBP1a mice on a PRCL diet can be used as efficient model for investigating potential therapies for LCAT deficiency. Results show the feasibility of rhLCAT treatment for preventing renal disease in patients with FLD.

scholarly journals Favorable response to carbamazepine therapy in genetically proven myoclonus-dystonia child

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Mohammed F. Aljabri ◽  
Naglaa M. Kamal ◽  
Abdulrhman Alghamdi ◽  
Hamdan Alghamdi ◽  
Naif Alomairi
Keyword(s):  
Genetic Disorder ◽  
Pathogenic Mutation ◽  
The Other ◽  
Loss Of Function ◽  
Case Presentation ◽  
Carbamazepine Therapy ◽  
Myoclonus Dystonia ◽  
Back Ward

Abstract Background Myoclonus dystonia (MDS) is a dominantly inherited genetic disorder caused by loss-of-function mutations in the epsilon sarcoglycan gene (SGCE). Case presentation We here in report a twenty months old Saudi boy who presented to us with a concern that the child is unable to walk properly. On assessment, he was flexing his left arm and left leg that usually followed by a back-ward fall. Diagnosis of dystonia induced with initiation of movement was suggested that later on proven genetically to be pathogenic mutation of sarcoglycan gene. Carbamazepine therapy was initiated with dramatic response. Response was maintained at 4 years follow up. Conclusions Our patient and the other previously reported cases might highlight the response of SGCE mutations to carbamazepine therapy.

scholarly journals Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study

2021 ◽  
Vol 22 (4) ◽  
pp. 1681
Author(s):  
Raffaella Brunetti-Pierri ◽  
Marianthi Karali ◽  
Paolo Melillo ◽  
Valentina Di Iorio ◽  
Antonella De Benedictis ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Structural Integrity ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Gene Replacement ◽  
Novel Variants ◽  
Reduced Light ◽  
Italian Cohort

Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (−0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies.

Serum Free Light Chains Identify Patients With Monoclonal Gammopathy At Increased Risk Of Developing Renal Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1876-1876 ◽  
Author(s):  
Lawrence R. Johnson ◽  
Gerald C. Miller ◽  
Spencer R. Stout
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Renal Impairment ◽  
Renal Disease ◽  
Kidney Function ◽  
Monoclonal Gammopathy ◽  
Normal Kidney ◽  
Serum Free ◽  
Increased Risk

Abstract Background Monoclonal gammopathy (MG) is frequently associated with kidney disease (monoclonal gammopathy of renal significance; MGRS). International guidelines recommend the use of the serum free light chain (FLC) assay when screening for monoclonal gammopathies; an abnormal FLC ratio and an elevation of at least one FLC isotype indicates an Ig LC clone. However it is not known if, in patients with normal kidney function, the presence of a FLC clone predisposes to the future development of kidney disease. Patients and Methods A 22485 patient database with multiple laboratory tests and up to 15-year follow up (Regional Medical Laboratory, Tulsa, OK, USA) was analysed. There were 425 confirmed MG patients with no progression to multiple myeloma. Median age was 72 years (22-97 years) and M/F ratio was 177/248. FLC kappa and lambda were measured nephelometrically with Freelite® (The Binding Site Ltd, Birmingham, UK). Baseline was defined on the first available FLC measurement; this was available at inception in 258 (61%) patients and during follow-up in 167 (39%) patients. 128 patients with MG and an eGFR <60ml/min/1.75m2 and/or a clinical diagnosis of renal disease (ICD9 code) prior to and up to 100 days after baseline were excluded from the analysis. Statistical analyses, including Receiver Operating Characteristics (ROC) to identify monoclonal FLC (iFLC) cut-off were carried out using SPSS v21. Results 297 (of 425) patients had a MG with normal renal function at baseline; 118 (40%) patients had an abnormal FLC ratio (88 kappa, median: 35.5 (7.7-2675) mg/L; 30 lambda, median: 83.6 (0.9-3552) mg/L). 21/297 (7%) patients developed renal impairment during the course of follow up (median: 852 (114-2388) days); 15/21 (71%) had monoclonal FLC production. In these patients there was no association between iFLC (median: 47.8 (0.9-3552) mg/L) and creatinine (median: 0.9 (0.5-1.5) mg/dL) levels (p=0.3966). Time to renal impairment (TTRI) was significantly shorter for patients with an abnormal v normal FLC ratio (75% TTRI: 1261 days v not reached (NR), hazard ratio (HR): 5.31; p<0.001). Age between groups was similar (median: 68 (22-97) v 72 (39-92) years; p=0.0544). In 118 patients withan abnormal FLC ratio, Cox regression analysis identified iFLC concentrations as being associated with the development of impaired renal function (p=0001). Furthermore, patients with iFLC>100mg/L (n=25) were at a significantly increased risk of developing renal impairment compared with patients with iFLC<100mg/L (n=93) (75% TTRI: 874 days v NR, respectively; HR: 6.10; p<0.001). Conclusions These results indicate that the presence of an Ig LC clone is associated with an increased risk of people with MG and normal kidney function progressing to renal disease. Disclosures: No relevant conflicts of interest to declare.

Effects of background substraction on differential kidney function measured by static scintigraphy with DMSA and dynamic scintigraphy with MAG 3

2008 ◽  
Vol 47 (01) ◽  
pp. 43-47 ◽  
Author(s):  
A. Smokvina ◽  
S. Grbac Ivanković ◽  
V. Licul ◽  
N. Girotto
Keyword(s):  
Kidney Function ◽  
Background Subtraction ◽  
Background Activity ◽  
Ratio Method ◽  
Uptake Ratio ◽  
Kidney Size ◽  
Significant Difference ◽  
Laboratory Changes ◽  
Dynamic Scintigraphy

SummaryThe aim of this study was to assess the influence of background subtraction (BS) on estimation of differential kidney function (DF) on the static scintigraphy with 99mTc dimercaptosuccinic acid (DMSA) and dynamic scintigraphy with 99mTc mercaptoacetyltriglicine (MAG3) and to establish possible differences between DF values estimated with these methods. Patients, methods: Patients (n = 106) were selected among those scheduled to static and dynamic scintigraphies within 3 months, with no interim clinical and laboratory changes, regardless the kidney pathology. DF was estimated according to the uptake ratio method. Four background regions of interest (ROIs) were applied, identical for both studies, and DF values were recalculated after BS. The corrected values were compared to the values before correction, separately for DMSA and MAG3, and between the studies. The results showed that ROIs used introduce variable results for the same patients, predominantly when noncorrected DF values were <45%. There were no significant differences between DF values (corrected and noncorrected) obtained from static and dynamic scintigraphy in all groups of patients. Since numerous reasons can bring to the errors in DF estimation when BS is used, the conclusions are that it would probably be more accurate to avoid BS, particularly when DF values are compared in a patient follow-up, and when kidney function is normal. BS should be used, but always in the same way, only when there is a significant difference in kidney size, or when DF is <25%, since background activity is then considerable. MAG3 and DMSA can be equally used for DF estimation and their results compared in patient follow-up.

scholarly journals SAT0172 UTILIZATION OF HYDROXYCHLOROQUINE AND CORTICOSTEROIDS AMONG LUPUS PATIENTS WITH INCIDENT END-STAGE RENAL DISEASE (ESRD) ONSET: A LONGITUDINAL STUDY USING USRDS REGISTRY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1027.2-1027
Author(s):  
A. R. Broder ◽  
W. Mowrey ◽  
A. Valle ◽  
B. Goilav ◽  
K. Yoshida ◽  
...  
Keyword(s):  
United States ◽  
Lupus Nephritis ◽  
Renal Disease ◽  
International Classification Of Diseases ◽  
The United States ◽  
Diagnostic Code ◽  
Prescribing Practices ◽  
Part D ◽  
Stage Renal Disease

Background:The development of ESRD due to lupus nephritis is one of the most common and serious complications of SLE. Mortality among SLE ESRD patients is 4-fold higher compared to lupus nephritis patients with preserved renal function1Mortality in SLE ESRD is also twice as high compared with non-SLE ESRD, even though SLE patients develop ESRD at a significantly younger age. In the absence of ESRD specific guidelines, medication utilization in SLE ESRD is unknown.Objectives:The objective of this study was to investigate the real-world current US-wide patterns of medication prescribing among lupus nephritis patients with new onset ESRD enrolled in the United States Renal Disease Systems (USRDS) registry. We specifically focused on HCQ and corticosteroids (CS) as the most used medications to treat SLE.Methods:Inclusion: USRDS patients 18 years and above with SLE as a primary cause of ESRD (International Classification of Diseases, 9thRevision (ICD9) diagnostic code 710.0, previously validated2). who developed ESRD between January 1st, 2006 and July 31, 2011 (to ensure at least 6 months of follow-up in the USRDS). Patients had to be enrolled in Medicare Part D (to capture pharmacy claims). The last follow-up date was defined as either the last date of continuous part D coverage or the end of the study period, Dec 31, 2013.Results:Of the 2579 patients included, 1708 (66%) were HCQ- at baseline, and 871 (34%) were HCQ+ at baseline. HCQ+ patients at baseline had a slightly lower duration of follow-up compared to HCQ- patients at baseline, median (IQR) of 2.32 (1.33, 3.97) years and 2.55 (1.44, 4.25) years, respectively, p= 0.02. During follow-up period, only 778 (30%) continued HCQ either intermittently or continuously to the last follow-up date, 1306 (51%) were never prescribed HCQ after baseline, and 495 (19%) discontinued HCQ before the last follow-up date. Of the 1801 patients who were either never prescribed or discontinued HCQ early after ESRD onset, 713 (40%) were prescribed CS to the end of the follow-up period: 55% were receiving a low dose <10mg/daily, and 43 were receiving moderate dose (10-20mg daily)Conclusion:HCQ may be underprescribed and CS may be overprescribed in SLE ESRD. Changing the current prescribing practices may improve outcomes in SLE ESRDReferences:[1]Yap DY et al., NDT 2012.[2]Broder A et al., AC&R 2016.Acknowledgments :The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government.Funding: :NIH/NIAMS K23 AR068441 (A Broder), NIH/NIAMS R01 AR 057327 and K24 AR 066109 (KH Costenbader)Disclosure of Interests: :Anna R. Broder: None declared, Wenzhu Mowrey: None declared, Anna Valle: None declared, Beatrice Goilav: None declared, Kazuki Yoshida: None declared, Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca

scholarly journals Outcomes of infants born to pregnant women with syphilis: a nationwide study in Korea

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Joohee Lim ◽  
So Jin Yoon ◽  
Jeong Eun Shin ◽  
Jung Ho Han ◽  
Soon Min Lee ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Renal Disease ◽  
Hearing Impairment ◽  
Congenital Syphilis ◽  
Day Treatment ◽  
National Level ◽  
International Classification Of Diseases ◽  
Nationwide Study ◽  
Screening Programs

Abstract Background Despite the expansion of antenatal syphilis screening programs, congenital syphilis (CS) remains a concern. Purpose This study aimed to analyze the manifestation and progress of CS, including treatment and follow-up, based on a nationwide study. Methods From the Korean National Health Insurance Service database, a total of 548 infants were examined for CS during their first year of life from 2013 to 2018. Neurosyphilis and complications were investigated using the International Classification of Diseases-10 codes. Results The birth rate of infants from mothers with syphilis was 2.8 per 10,000 live births for 5 years, which is not indicative of a decreasing trend. Overall, 148 infants were proven or highly probable or possible of having CS with treatment for 10 days; 66 infants were possible or less likely of having CS with only 1-day treatment. Jaundice (56 %) was common, followed by hearing impairment (14 %), renal disease (8 %), and mental retardation (8 %). Fourteen cases of neurosyphilis occurred. Infants with complications, including mental retardation, eye involvement, hearing impairment, or renal disease, were significantly associated with neurosyphilis (OR 8.49, P < 0.0001). Of 250 patients who received treatment, 92.8 % were treated with one medication: benzathine penicillin was used in 73 % of patients. Only four patients were re-treated due to treatment failure. In addition to the treponemal test, fluorescent treponemal antibody-absorption was the most utilized tool for diagnosis and follow-up. Conclusions Establishing standardized guidelines for the evaluation of CS, as well as the establishment of treatment regimens and follow up-plans for the disease, at a national level would help improve maternal and neonatal care and facilitate the eradication of CS in Korea.

scholarly journals Inborn errors of immunity—recent advances in research on the pathogenesis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Motoi Yamashita ◽  
Kento Inoue ◽  
Tsubasa Okano ◽  
Tomohiro Morio
Keyword(s):  
Immune System ◽  
Hematopoietic Cell Transplantation ◽  
Epigenetic Modification ◽  
Genetic Disorder ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Whole Genome Analysis ◽  
Curative Therapy ◽  
Inborn Errors Of Immunity ◽  
Recent Advances

AbstractPrimary immunodeficiency (PID) is a genetic disorder with a defect of one of the important components of our immune system. Classical PID has been recognized as a disorder with loss of function of the immune system. Recent studies have unveiled disorders with immune dysfunction with autoimmunity, autoinflammation, allergy, or predisposition to malignancy. Some of them were caused by an augmented immune function or a defect in immune regulation. With this background, the term inborn errors of immunity (IEI) is now used to refer to PID in the International Union of Immunological Societies (IUIS) classification. More than 400 responsible genes have been identified in patients with IEI so far, and importantly, many of them identified lately were caused by a heterologous mutation. Moreover, the onset is not necessarily in childhood, and we started seeing more and more IEI patients diagnosed in adulthood in the clinical settings. Recent advances in genetic analysis, including whole-exome analysis, whole-genome analysis, and RNA-seq have contributed to the identification of the disease-causing gene mutation. We also started to find heterogeneity of phenotype even in the patients with the same mutation in the same family, leading us to wonder if modifier gene or epigenetic modification is involved in the pathogenesis. In contrast, we accumulated many cases suggesting genetic heterogeneity is associated with phenotypic homogeneity. It has thus become difficult to deduce a responsible gene only from the phenotype in a certain type of IEI. Current curative therapy for IEI includes hematopoietic cell transplantation and gene therapy. Other curative therapeutic modalities have been long waited and are to be introduced in the future. These include a small molecule that inhibits the gain-of-function of the molecule- and genome-editing technology. Research on IEI will surely lead to a better understanding of other immune-related disorders including rheumatic diseases and atopic disorders.

Principles of pediatric lupus nephritis in a prospective contemporary multi-center cohort

Lupus ◽  
2021 ◽  
pp. 096120332110286
Author(s):  
Kathleen M Vazzana ◽  
Ankana Daga ◽  
Beatrice Goilav ◽  
Ekemini A Ogbu ◽  
Daryl M Okamura ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Kidney Function ◽  
Lupus Erythematosus ◽  
Extensive Literature ◽  
Short Term ◽  
Renal Outcomes ◽  
Childhood Arthritis ◽  
Black Patients ◽  
End Stage

Lupus nephritis (LN) is a life-threatening manifestation of systemic lupus erythematosus (SLE) and is more common in children than adults. The epidemiology and management of childhood-onset SLE (cSLE) have changed over time, prompting the need to reassess expected outcomes. The purpose of this study is to use the Childhood Arthritis and Rheumatology Research Alliance (CARRA) prospective registry to validate historical principles of LN in a contemporary, real-world cohort. After an extensive literature review, six principles of LN in cSLE were identified. The CARRA registry was queried to evaluate these principles in determining the rate of LN in cSLE, median time from cSLE diagnosis to LN, short-term renal outcomes, and frequency of rituximab as an induction therapy. Of the 677 cSLE patients in the CARRA registry, 32% had documented LN. Decline in kidney function was more common in Black cSLE patients than non-Black patients ( p = 0.04). Black race was associated with worse short-term renal outcomes. In short-term follow up, most children with LN had unchanged or improved kidney function, and end stage kidney disease (ESKD) was rare. Ongoing follow-up of cSLE patients in the CARRA registry will be necessary to evaluate long-term outcomes to inform risk, management, and prognosis of LN in cSLE.

scholarly journals Heterogeneity of the Clinical Presentation of the MEN1 LRG_509 c.781C>T (p.Leu261Phe) Variant Within a Three-Generation Family

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 512
Author(s):  
Aleksandra Gilis-Januszewska ◽  
Anna Bogusławska ◽  
Kornelia Hasse-Lazar ◽  
Beata Jurecka-Lubieniecka ◽  
Barbara Jarząb ◽  
...  
Keyword(s):  
Neuroendocrine Tumor ◽  
Clinical Presentation ◽  
Age Of Onset ◽  
Malignant Tumors ◽  
Genetic Disorder ◽  
Family Members ◽  
Pancreatic Neuroendocrine Tumor ◽  
Index Patient ◽  
Generation Family

Multiple neuroendocrine neoplasia type 1 (MEN1) is a rare genetic disorder with an autosomal dominant inheritance, predisposing carriers to benign and malignant tumors. The phenotype of MEN1 syndrome varies between patients in terms of tumor localization, age of onset, and clinical aggressiveness, even between affected members within the same family. We describe a heterogenic phenotype of the MEN1 variant c.781C>T (LRG_509t1), which was previously reported only once in a family with isolated hyperparathyroidism. A heterozygous missense variant in exon 4 of the gene was identified in the sequence of the MEN1 gene, i.e., c.781C>T, leading to the amino acid change p.Leu261Phe in a three-generation family. In the screened family, 5/6 affected members had already developed hyperparathyroidism. In the index patient and two other family members, an aggressive course of pancreatic neuroendocrine tumor (insulinoma and non-functioning neuroendocrine tumors) with dissemination was diagnosed. In the index patient, late diagnosis and slow progression of the disseminated neuroendocrine tumor have been observed (24 years of follow-up). The very rare variant of MEN1, LRG_509t1 c.781C>T /p.Leu261Phe (LRG_509p1), diagnosed within a three-generation family has a heterogenic clinical presentation. Further follow-up of the family members should be carried out to confirm the spectrum and exact time of clinical presentation.

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