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Clinical Case Reports Jan 2024This case report describes the clinical course of a juvenile female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. Our study demonstrates the...
KEY CLINICAL MESSAGE
This case report describes the clinical course of a juvenile female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. Our study demonstrates the possibility of hypophosphatemic rickets as an early symptom of SLE.
ABSTRACT
Fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets is observed in both genetic and acquired disorders. Various reports describe FGF23-related hypophosphatemia with systemic lupus erythematosus (SLE), although FGF23-related hypophosphatemia preceding the onset of SLE has never been described. Here, we report the case of a 9-year-old female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. The patient presented to us with arthralgia in the lower extremities and abnormality of gait lasting for 8 months. She was diagnosed with FGF23 hypophosphatemic rickets due to the presence of hypophosphatemic rickets symptoms and high serum levels of FGF23. Additional examination excluded hereditary diseases and tumor-induced osteomalacia. Three months after diagnosis of FGF23-related hypophosphatemic rickets, she developed nephritis and was diagnosed with SLE. She was treated with prednisolone, hemodialysis, and disease-modifying drugs, as well as oral sodium phosphate to improve hypophosphatemia. Serum anti-double-stranded DNA antibody (dsDNAab) and plasma tumor necrosis factor-α (TNF-α) were elevated at FGF23-related hypophosphatemic rickets diagnosis. During the clinical course, serum FGF23 correlated with dsDNAab and TNF-α serum levels, which are involved in SLE disease activity. In this case, FGF23-related hypophosphatemic rickets without hereditary diseases or tumor-induced osteomalacia occurred before the appearance of juvenile SLE symptoms, and serum FGF23 represented disease activity in SLE.
PubMed: 38223518
DOI: 10.1002/ccr3.8420 -
Frontiers in Medicine 2023Alport syndrome is a rare genetic condition characterized by kidney disease, hearing impairment, and ocular abnormalities. It exhibits various inheritance patterns...
Alport syndrome is a rare genetic condition characterized by kidney disease, hearing impairment, and ocular abnormalities. It exhibits various inheritance patterns involving pathogenic variants in , , and genes. The phenotypes can range from isolated hematuria with a non-progressive or very slowly progressive course to progressive kidney disease with extrarenal abnormalities. Timely diagnosis of Alport syndrome facilitates the early and effective implementation of treatment, as well as genetic counseling. Here, we report the c.765G > A, p.((=)) mutation in three ethnically Azerbaijani, apparently unrelated, consanguineous families from the village of Algeti in the Marneuli region of Georgia. We speculate that this variant could represent a founder mutation within this population and recommend offering genetic testing to Algeti village residents with persistent hematuria.
PubMed: 38188341
DOI: 10.3389/fmed.2023.1281049 -
Case Reports in Nephrology and Dialysis 2024Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS...
INTRODUCTION
Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS is classified as X-linked, autosomal, and digenic. The number of cases of digenic AS has increased, but the genotype-phenotype correlation of patient with digenic AS is still unclear. Here, we present a case of digenic AS with novel digenic missense variants in (c.827G>C, p.Gly276Ala) and (c.4369G>C, p.Gly1457Arg).
CASE PRESENTATION
The patient was a 29-year-old Japanese man suffering from persistent microscopic hematuria and proteinuria without kidney function impairment. Kidney biopsy showed focal interstitial foam cell infiltration, global and segmental glomerulosclerosis. Immunofluorescence staining for collagen IV α5 was almost negative in the GBM and Bowman's capsule. Electron microscopy revealed irregular thickening with lamellation and segmental thinning of the GBM. Clinical and pathological findings were consistent with AS. Comprehensive next-generation sequencing revealed a heterozygous missense variant in (c.827G>C, p.Gly276Ala) in exon 1 and a hemizygous missense variant in (c.4369G>C, p.Gly1457Arg) in exon 49 on the patient's paternal and maternal alleles, respectively. The same digenic variants were detected in his sister, and she also showed a similar phenotype. After treatment with angiotensin-converting enzyme inhibitors, proteinuria decreased from 2.3 to 1.1 g/g creatinine, but occult blood persisted. During follow-up, kidney function has been preserved.
CONCLUSION
The novel genotype of our case provides more information on the genotype-phenotype correlation of digenic XLAS, although long-term follow-up is required. The findings in the present case also indicate the importance of genetic tests for family members of a patient diagnosed with digenic AS.
PubMed: 38179179
DOI: 10.1159/000535493 -
Kidney International Reports Dec 2023Alport syndrome (AS) is a hereditary type IV collagen disease. It starts shortly after birth, without clinical symptoms, and progresses to end-stage kidney disease early...
INTRODUCTION
Alport syndrome (AS) is a hereditary type IV collagen disease. It starts shortly after birth, without clinical symptoms, and progresses to end-stage kidney disease early in life. The earlier therapy starts, the more effectively end-stage kidney disease can be delayed. Clearly then, to ensure preemptive therapy, early diagnosis is an essential prerequisite.
METHODS
To provide early diagnosis, we searched for protein biomarkers (BMs) by mass spectrometry in dogs with AS stage 0. At this very early stage, we identified 74 candidate BMs. Of these, using commercial enzyme-linked immunosorbent assays (ELISAs), we evaluated 27 in dogs and 28 in children, 50 with AS and 104 healthy controls.
RESULTS
Most BMs from blood appeared as fractions of multiple variants of the same protein, as shown by their chromatographic distribution before mass spectrometry. Blood samples showed only minor differences because ELISAs rarely detect disease-specific variants. However, in urine , several proteins, individually or in combination, were promising indicators of very early and preclinical kidney injury. The BMs with the highest sensitivity and specificity were collagen type XIII, hyaluronan binding protein 2 (HABP2), and complement C4 binding protein (C4BP).
CONCLUSION
We generated very strong candidate BMs by our approach of first examining preclinical AS in dogs and then validating these BMs in children at early stages of disease. These BMs might serve for screening purposes for AS before the onset of kidney damage and therefore allow preemptive therapy.
PubMed: 38106579
DOI: 10.1016/j.ekir.2023.09.028 -
Cureus Oct 2023We report two cases of Alport syndrome and compare the clinical presentations and imaging findings in these cases. The clinical examination consisted of best-corrected...
We report two cases of Alport syndrome and compare the clinical presentations and imaging findings in these cases. The clinical examination consisted of best-corrected visual acuity (BCVA), direct ophthalmoscopy, and slit-lamp examination. Macular optical coherence tomography (OCT) and anterior segment OCT (AS-OCT) and were utilized to document the details of the anterior and posterior segment pathologies. In order to evaluate systemic presentations of Alport syndrome, nephrology, and otolaryngology were consulted for each patient. In this study, the first case was a 27-year-old female with progressive myopia, anterior lenticonus, and temporal retinal thinning found in the ocular examination that led to the diagnosis of Alport syndrome. She underwent clear lens extraction and intraocular lens implantation, restoring acceptable visual acuity. The second case was a 20-year-old male patient with low visual acuity, severe bilateral anterior lenticonus, bilateral cataract, and temporal retinal thinning. The patient later developed renal failure and is a candidate for kidney transplantation. In this case report, progressive renal failure, hearing loss, and ocular abnormalities were all observed. This is consistent with previously reported cases given the typical characteristics of Alport syndrome, a rare inherited disease. The severity of those characteristics was higher in the male subject, a finding also consistent with prior reports indicating that males are usually affected more frequently and more severely than females, given that Alport syndrome is generally inherited as an X-linked disorder. Additionally, anterior segment and macular OCTs seemed to be of considerable significance in the early diagnosis of Alport syndrome given the typical ocular manifestations e.g. anterior lenticonus or temporal retinal atrophy.
PubMed: 38022159
DOI: 10.7759/cureus.47373 -
Cureus Oct 2023Alport syndrome is an genetic disorder that distresses the basement membrane of the kidneys and can also impact other organs, such as the cochlea of the inner ear and... (Review)
Review
Alport syndrome is an genetic disorder that distresses the basement membrane of the kidneys and can also impact other organs, such as the cochlea of the inner ear and eyes. It is characterized by mutation causing abnormalities in the collagen within the basement membrane, which has a crucial role in the filtration process of the kidneys. These abnormalities lead to progressive kidney damage and often result in chronic kidney disease. In some cases of Alport syndrome, the abnormal collagen can also affect the cochlea in the inner ear, leading to sensorineural hearing loss. Additionally, changes in the ocular lens, named anterior lenticonus, can occur, causing vision problems. Alport syndrome can manifest differently among individuals, and its severity can vary. Some people may experience mild symptoms, while others may develop more severe kidney problems, including end-stage renal disease, which may need dialysis or kidney transplant. Treatment for Alport syndrome primarily focuses on managing its symptoms and complications. Regular monitoring of kidney function and blood pressure, along with medications to control hypertension, are crucial aspects of the management plan. In cases of severe kidney damage, kidney transplantation may be necessary. As with any medical condition, early detection and intervention can improve results and quality of life for persons with Alport syndrome. Therefore, if there is a family history of the disorder or any concerning symptoms, it is essential to seek medical attention promptly. Genetic testing can help confirm the diagnosis and identify affected family members, allowing for appropriate monitoring and management.
PubMed: 38021591
DOI: 10.7759/cureus.47129 -
Medicine Nov 2023Autosomal recessive Alport syndrome (ARAS) is an hereditary heterogeneous disease that poses a serious risk to pregnant women.
RATIONALE
Autosomal recessive Alport syndrome (ARAS) is an hereditary heterogeneous disease that poses a serious risk to pregnant women.
PATIENT CONCERNS
We reported 2 cases of pregnancy with progressive proteinuria. The case 1 was a 21-year-old woman with 24-h proteinuria increased from 2.03 to 11.72 g at 13 to 35 weeks of gestation, and the case 2 was a 28-year-old woman with 24-h proteinuria increased from 2.10 to 9.32 g at 8 to 36 weeks of gestation. In advanced stage of pregnancy, the fetal development was smaller than the gestational age.
DIAGNOSES
Sanger sequencing showed that novel compound heterozygous mutations [c.1315 G>T (p.G439C) and c.4847 G>A (p.C1616Y)] of the collagen type IV alpha 3 chain (COL4A3) gene were found in the 2 cases. Renal puncture pathology confirmed the diagnosis of ARAS.
INTERVENTIONS
The 2 cases were treated with albumin, compounded amino acids, calcium, vitamin D, and low molecular weight heparin in addition to conventional treatment during pregnancy. Pregnancy was terminated by cesarean section at 36 to 37 weeks of gestation. After delivery, the patients were treated with Losartan for anti-proteinuric therapy for 1 year.
OUTCOMES
The neonatal weights and Apgar scores were normal. The patients recovered well and 24-h proteinuria decreased to pre-pregnancy level.
LESSONS
When pregnant women present with a persistent increasing proteinuria, ARAS needs to be considered. Sanger sequencing is useful to assist in the diagnosis of ARAS. Multidisciplinary treatments from nephrologists and gynecologists are needed to ensure the safety of pregnancy and the fetus.
Topics: Adult; Female; Humans; Infant, Newborn; Pregnancy; Young Adult; Cesarean Section; Collagen Type IV; Kidney; Mutation; Nephritis, Hereditary; Proteinuria
PubMed: 37986374
DOI: 10.1097/MD.0000000000036057 -
The Journal of Biological Chemistry Dec 2023The collagen IV (Col-IV) scaffold, the major constituent of the glomerular basement membrane (GBM), is a critical component of the kidney glomerular filtration barrier.... (Comparative Study)
Comparative Study
The collagen IV (Col-IV) scaffold, the major constituent of the glomerular basement membrane (GBM), is a critical component of the kidney glomerular filtration barrier. In Alport syndrome, affecting millions of people worldwide, over two thousand genetic variants occur in the COL4A3, COL4A4, and COL4A5 genes that encode the Col-IV scaffold. Variants cause loss of scaffold, a suprastructure that tethers macromolecules, from the GBM or assembly of a defective scaffold, causing hematuria in nearly all cases, proteinuria, and often progressive kidney failure. How these variants cause proteinuria remains an enigma. In a companion paper, we found that the evolutionary emergence of the COL4A3, COL4A4, COL4A5, and COL4A6 genes coincided with kidney emergence in hagfish and shark and that the COL4A3 and COL4A4 were lost in amphibians. These findings opened an experimental window to gain insights into functionality of the Col-IV scaffold. Here, using tissue staining, biochemical analysis and TEM, we characterized the scaffold chain arrangements and the morphology of the GBM of hagfish, shark, frog, and salamander. We found that α4 and α5 chains in shark GBM and α1 and α5 chains in amphibian GBM are spatially separated. Scaffolds are distinct from one another and from the mammalian Col-IV scaffold, and the GBM morphologies are distinct. Our findings revealed that the evolutionary emergence of the Col-IV scaffold enabled the genesis of a compact GBM that functions as an ultrafilter. Findings shed light on the conundrum, defined decades ago, whether the GBM or slit diaphragm is the primary filter.
Topics: Animals; Anura; Collagen Type IV; Glomerular Basement Membrane; Hagfishes; Mammals; Sharks; Species Specificity; Urodela
PubMed: 37977222
DOI: 10.1016/j.jbc.2023.105459 -
Frontiers in Medicine 2023Most male X-linked Alport syndrome patients with nonsense mutations experience end-stage kidney failure by 30 years old. Although there is no definition of high-flow...
Most male X-linked Alport syndrome patients with nonsense mutations experience end-stage kidney failure by 30 years old. Although there is no definition of high-flow arteriovenous fistula, access blood flows greater than 2000 mL/min might predict the occurrence of high-output heart failure. A 50-year-old Japanese man had suffered from proteinuria at 4 years old and sensorineural hearing loss and a lenticular lens at 20 years old. He had started to receive hemodialysis treatment due to end-stage kidney disease at 22 years old. A genetic test confirmed a novel hemizygous nonsense variant c.2980G > T (p.Gly994Ter), and he was diagnosed with X-linked Alport syndrome. c.2980G > T was considered "pathogenic" according to the American College of Medical Genetics and Genomics guidelines and experiments. Shortness of breath on exertion was exaggerated, his brachial artery blood flow was over 4,236-4,353 mL/min, his cardiac output was 5,874 mL/min, and he needed radial artery banding at 51 years old. After radial artery banding surgery, the brachial artery blood flow decreased to 987-1,236 mL/min, and echocardiography showed a cardiac output at 5100 mL/min with improved E' and E/E'. His shortness of breath on exertion improved gradually. Although rare, high-output heart failure due to high-flow arteriovenous fistula should be kept in mind as a complication in X-linked Alport syndrome patients, and our patient was successfully treated with radial artery banding surgery.
PubMed: 37928459
DOI: 10.3389/fmed.2023.1227283 -
BioRxiv : the Preprint Server For... Oct 2023Collagen IV is a primordial component of basement membranes, a specialized form of extracellular matrix that enabled multi-cellular epithelial tissues. In mammals,...
Collagen IV is a primordial component of basement membranes, a specialized form of extracellular matrix that enabled multi-cellular epithelial tissues. In mammals, collagen IV assembles from a family of six α-chains (α1 to α6), encoded by six genes (COL4A1 to COL4A6), into three distinct scaffolds: the α121, the α345 and a mixed scaffold containing both α121 and α565. The six mammalian COL4A genes occur in pairs that occur in a head-to-head arrangement on three distinct chromosomes. In Alport syndrome, variants in the COL4A3, 4 or 5 genes cause either loss or defective assembly of the collagen IV scaffold which results in a dysfunctional glomerular basement membrane, proteinuria and progression to renal failure in millions of people worldwide. Here, we determine the evolutionary emergence and diversification of the COL4A genes using comparative genomics and biochemical analyses. Using syntenic relationships to genes closely linked to the COL4A genes, we determine that the COL4A3 and COL4A4 gene pair appeared in cyclostomes (hagfish and lampreys) while the COL4A5 and COL4A6 gene pair emerged in gnathostomes, jawed vertebrates. The more basal chordate species, lancelets and tunicates, do not have discrete kidneys and have a single COL4A gene pair, though often with single isolated COL4 genes similar to those found in . Remarkably, while the six COL4A genes are conserved in vertebrates, amphibians have lost the COL4A3 and COL4A4 genes. Our findings of the evolutionary emergence of these genes, together with the amphibian double-knockout, opens an experimental window to gain insights into functionality of the Col IV scaffold.
PubMed: 37905027
DOI: 10.1101/2023.10.18.563013