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Journal of Inherited Metabolic Disease Mar 2024Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol....
Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.
Topics: Humans; Mitochondria, Liver; HEK293 Cells; Transaminases; Oxalates; Liver; Glyoxylates; Alcohol Oxidoreductases
PubMed: 38200664
DOI: 10.1002/jimd.12711 -
Clinical Case Reports Jan 2024Cutaneous oxalosis is a rare manifestation of systemic oxalosis, typically associated with primary or secondary hyperoxaluria. We present a rare case of a 23-year-old...
Cutaneous oxalosis is a rare manifestation of systemic oxalosis, typically associated with primary or secondary hyperoxaluria. We present a rare case of a 23-year-old female diagnosed with primary hyperoxaluria and end-stage renal disease, who presented with papules on the palms without any vascular complications. The skin can be affected by oxalate deposition, resulting in various manifestations such as vascular complications or calcified nodules. In our case, the patient had primary hyperoxaluria and end-stage renal disease but exhibited atypical features of cutaneous oxalosis. Histopathology confirmed the presence of oxalate crystals in the dermis, subcutis, and medium-sized arteries. The mechanism of oxalate deposition in this case remains unclear. This case underscores the importance of considering cutaneous oxalosis in the differential diagnosis of patients with renal failure and skin lesions, and highlights the variability of clinical presentations in primary hyperoxaluria.
PubMed: 38188849
DOI: 10.1002/ccr3.8423 -
EMBO Molecular Medicine Jan 2024The therapeutic use of adeno-associated viral vector (AAV)-mediated gene disruption using CRISPR-Cas9 is limited by potential off-target modifications and the risk of...
The therapeutic use of adeno-associated viral vector (AAV)-mediated gene disruption using CRISPR-Cas9 is limited by potential off-target modifications and the risk of uncontrolled integration of vector genomes into CRISPR-mediated double-strand breaks. To address these concerns, we explored the use of AAV-delivered paired Staphylococcus aureus nickases (D10ASaCas9) to target the Hao1 gene for the treatment of primary hyperoxaluria type 1 (PH1). Our study demonstrated effective Hao1 gene disruption, a significant decrease in glycolate oxidase expression, and a therapeutic effect in PH1 mice. The assessment of undesired genetic modifications through CIRCLE-seq and CAST-Seq analyses revealed neither off-target activity nor chromosomal translocations. Importantly, the use of paired-D10ASaCas9 resulted in a significant reduction in AAV integration at the target site compared to SaCas9 nuclease. In addition, our study highlights the limitations of current analytical tools in characterizing modifications introduced by paired D10ASaCas9, necessitating the development of a custom pipeline for more accurate characterization. These results describe a positive advance towards a safe and effective potential long-term treatment for PH1 patients.
Topics: Humans; Animals; Mice; CRISPR-Cas Systems; Deoxyribonuclease I; Gene Editing; Hyperoxaluria, Primary
PubMed: 38182795
DOI: 10.1038/s44321-023-00008-8 -
Dermatologie (Heidelberg, Germany) Apr 2024Livedo racemosa is characterized by a bizarrely configurated lightning figure-like appearance with striated to reticulated, livid erythematous macules and results from...
Livedo racemosa is characterized by a bizarrely configurated lightning figure-like appearance with striated to reticulated, livid erythematous macules and results from a reduced perfusion of the respective skin area, which can have different underlying pathophysiologies. A rare but relevant cause, especially in young patients with end-stage kidney failure, is primary hyperoxaluria type 1 (PH1), a hereditary metabolic disorder in which oxalate accumulates in the body.
Topics: Humans; Livedo Reticularis; Hyperoxaluria, Primary; Kidney Failure, Chronic; Oxalates
PubMed: 38167780
DOI: 10.1007/s00105-023-05276-6 -
BMC Medical Genomics Jan 2024People with autosomal recessive disorders often were born without awareness of the carrier status of their parents. The American College of Medical Genetics and Genomics...
BACKGROUND
People with autosomal recessive disorders often were born without awareness of the carrier status of their parents. The American College of Medical Genetics and Genomics (ACMG) recommends screening 113 genes known to cause autosomal recessive and X-linked conditions in couples seeking to learn about their risk of having children with these disorders to have an appropriate reproductive plan.
METHODS
We analyzed the exome sequencing data of 1,642 unrelated Thai individuals to identify the pathogenic variant (PV) frequencies in genes recommended by ACMG.
RESULTS
In the 113 ACMG-recommended genes, 165 PV and likely PVs in 60 genes of 559 exomes (34%, 559/1642) were identified. The carrier rate was increased to 39% when glucose-6-phosphate dehydrogenase (G6PD) was added. The carrier rate was still as high as 14.7% when thalassemia and hemoglobinopathies were excluded. In addition to thalassemia, hemoglobinopathies, and G6PD deficiency, carrier frequencies of > 1% were found for Gaucher disease, primary hyperoxaluria, Pendred syndrome, and Wilson disease. Nearly 2% of the couples were at risk of having offsprings with the tested autosomal recessive conditions.
CONCLUSIONS
Based on the study samples, the expanded carrier screening, which specifically targeted common autosomal recessive conditions in Thai individuals, will benefit clinical outcomes, regarding preconception/prenatal genetic carrier screening.
Topics: Child; Pregnancy; Female; Humans; Thailand; Exome Sequencing; Exome; Hemoglobinopathies; Thalassemia
PubMed: 38167091
DOI: 10.1186/s12920-023-01771-w -
Frontiers in Pediatrics 2023Incidence and prevalence of urolithiasis is apparently increasing worldwide, also among children and adolescents. Nevertheless, robust data have only been obtained in a...
Incidence and prevalence of urolithiasis is apparently increasing worldwide, also among children and adolescents. Nevertheless, robust data have only been obtained in a few countries. In Spain, a voluntary Registry for Pediatric Renal Lithiasis has been active since 2015. Irregular participation limits its applicability, as well as its limitation to patients with a stone available for morphocompositional study, to obtain data about incidence and prevalence. On the other hand, findings about typology of stones and clinical and analytical characteristics of these subjects have been communicated in several meetings. Other valuable efforts in this field are the elaboration of guidelines for the collection and processing of urine samples for the study of urolithiasis in pediatric patients with the consensus of the Spanish Society for Pediatric Nephrology (AENP) as well as the Spanish Society for Laboratory Medicine (SEQC), the collaborative network RenalTube for the diagnosis of primary tubulopathies and the registry of patients with Primary Hyperoxaluria (OxalSpain). In many hospitals from the public healthcare system, pediatric nephrologists are the specialists in charge of the management of children with kidney stones, but there is no formal regulation on this competence. Other specialists, such as urologists, pediatric surgeons or pediatric urologists, in many cases do not offer a complete insight into the etiopathogenic mechanisms and the consequent medical treatment. Access to medication according to standards of treatment is warranted, provided a correct diagnosis is achieved, but criteria for the reimbursement of certain therapies, such as RNAi drugs for primary hyperoxaluria, are arguable.
PubMed: 38143536
DOI: 10.3389/fped.2023.1294319 -
Kidney International Mar 2024Primary hyperoxaluria type 1 (PH1) is a childhood-onset autosomal recessive disease, characterized by nephrocalcinosis, multiple recurrent urinary calcium oxalate...
Primary hyperoxaluria type 1 (PH1) is a childhood-onset autosomal recessive disease, characterized by nephrocalcinosis, multiple recurrent urinary calcium oxalate stones, and a high risk of progressive kidney damage. PH1 is caused by inherent genetic defects of the alanine glyoxylate aminotransferase (AGXT) gene. The in vivo repair of disease-causing genes was exceedingly inefficient before the invention of base editors which can efficiently introduce precisely targeted base alterations without double-strand DNA breaks. Adenine base editor (ABE) can precisely convert A·T to G·C with the assistance of specific guide RNA. Here, we demonstrated that systemic delivery of dual adeno-associated virus encoding a split-ABE8e could artificially repair 13% of the pathogenic allele in Agxt rats, a model of PH1, alleviating the disease phenotype. Specifically, ABE treatment partially restored the expression of alanine-glyoxylate-aminotransferase (AGT), reduced endogenous oxalate synthesis and alleviated calcium oxalate crystal deposition. Western blot and immunohistochemistry confirmed that ABE8e treatment restored AGT protein expression in hepatocytes. Moreover, the precise editing efficiency in the liver remained stable six months after treatment. Thus, our findings provided a prospect of in vivo base editing as a personalized and precise medicine for PH1 by directly correcting the mutant Agxt gene.
Topics: Humans; Rats; Animals; Child; Calcium Oxalate; Gene Editing; RNA, Guide, CRISPR-Cas Systems; Hyperoxaluria, Primary; Transaminases; Alanine; Hyperoxaluria; Mutation
PubMed: 38142039
DOI: 10.1016/j.kint.2023.11.029 -
Ophthalmology Dec 2023
PubMed: 38099910
DOI: 10.1016/j.ophtha.2023.11.012 -
Kidney360 Jan 2024Oxalate nephropathy is an underrecognized cause of CKD and ESKD. We present one of the largest native oxalate nephropathy cohorts to date from a tertiary care...
KEY POINTS
Oxalate nephropathy is an underrecognized cause of CKD and ESKD. We present one of the largest native oxalate nephropathy cohorts to date from a tertiary care institution in the United States. Oxalate nephropathy has multiple etiologies and given its clinical course and poor prognosis, attention must be paid to screening for risk factors to guide prompt diagnosis and management.
BACKGROUND
Oxalate nephropathy (ON) is characterized by deposition of calcium oxalate crystals in the kidney and is commonly under-recognized. Causes of ON include primary hyperoxaluria, enteric hyperoxaluria, and ingestion of excess oxalate or its precursors.
METHODS
We report the clinical and pathological characteristics of one of the largest series of native kidney ON to date, from January 2015 to March 2023 at the Cleveland Clinic.
RESULTS
We identified 60 native biopsies with oxalate deposits and excluded patients with clinically insignificant biopsies (=12) or lack of data (=17). Thirty-one patients with native ON were described. The mean age at diagnosis was 66.2 years (±12.1), and 58.1% were female. 87.1% had hypertension, 58.1% had diabetes, 42% had nephrolithiasis, and 77.4% had underlying CKD, with a mean baseline creatinine of 1.8 mg/dl ±1.3. The mean creatinine at biopsy was 5.2 mg/dl ±1.7. Kidney biopsies showed abundant calcium oxalate crystal deposits, and 27 of 31 biopsies had additional diagnoses, the most common of which were acute tubular injury =17 (54.8%) and diabetic glomerulosclerosis =7 (22.6%). Severe and moderate interstitial fibrosis was present in 38.7% (=12) and 51.6% (=16) of biopsies, respectively. Ten had a single etiology of ON, ten had a multifactorial etiology (both enteric hyperoxaluria and high precursor intake), and 11 had an unclear etiology. Notably, only seven patients had a history of gastric bypass. The mean duration of follow-up was 26.8 months, and 26 patients had follow-up data >1 year. Of these, 21 required dialysis, and five were dialysis-free at presentation. Five of the 26 were deceased at 1 year, with 12 patients (38.7%) deceased at last follow-up. Seventeen patients received targeted management, while nine patients did not receive targeted treatment, and all nine required hemodialysis. More patients (31.6%) had vitamin C intake after the coronavirus disease 2019 pandemic (2020–2023) versus 16.7% before 2020.
CONCLUSIONS
ON presents as AKI or acute on CKD. The prognosis is poor with most patients requiring dialysis at presentation with high morbidity and mortality. Clinicians need to be aware of the risk factors associated with ON to aid prompt diagnosis and management.
PODCAST
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/K360/2024_01_26_KID0000000000000340.mp3
Topics: Humans; Hyperoxaluria; Renal Insufficiency; Oxalates
PubMed: 38095544
DOI: 10.34067/KID.0000000000000340 -
Nutrients Nov 2023Nephrolithiasis affects around 10% of the population and is frequently associated with impaired dietary factors. The first one is insufficient fluid intake inducing... (Review)
Review
Nephrolithiasis affects around 10% of the population and is frequently associated with impaired dietary factors. The first one is insufficient fluid intake inducing reduced urine volume, urine supersaturation, and subsequently urinary lithiasis. Kidneys regulate 24 h urine volume, which, under physiological conditions, approximately reflects daily fluid intake. The aim of this study is to synthesize and highlight the role of hydration in the treatment of nephrolithiasis. Increasing fluid intake has a preventive effect on the risk of developing a first kidney stone (primary prevention) and also decreases the risk of stone recurrence (secondary prevention). Current guidelines recommend increasing fluid intake to at least at 2.5 L/day to prevent stone formation, and even to 3.5-4 L in some severe forms of nephrolithiasis (primary or enteric hyperoxaluria or cystinuria). Fluid intake must also be balanced between day and night, to avoid urinary supersaturation during the night. Patients should be informed and supported in this difficult process of increasing urine dilution, with practical ways and daily routines to increase their fluid intake. The liquid of choice is water, which should be chosen depending on its composition (such as calcium, bicarbonate, or magnesium content). Finally, some additional advice has to be given to avoid certain beverages such as those containing fructose or phosphoric acid, which are susceptible to increase the risk of nephrolithiasis.
Topics: Adult; Humans; Kidney Calculi; Kidney; Calcium, Dietary; Cystinuria; Hyperoxaluria
PubMed: 38068743
DOI: 10.3390/nu15234885