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Molecular Genetics & Genomic Medicine Jan 2024Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial neurometabolic disorder of energy deficit, with incidence of about 1 in 42,000 live births annually... (Review)
Review
BACKGROUND
Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial neurometabolic disorder of energy deficit, with incidence of about 1 in 42,000 live births annually in the USA. The median and mean ages of diagnosis of PDCD are about 12 and 31 months, respectively. PDCD is a major cause of primary lactic acidosis with concomitant elevation in blood alanine (Ala) and proline (Pro) concentrations depending on phenotypic severity. Alanine/Leucine (Ala/Leu) ≥4.0 and Proline/Leucine (Pro/Leu) ≥3.0 combination cutoff from dried blood spot specimens was used as a biomarker for early identification of neonates/infants with PDCD. Further investigations were needed to evaluate the sensitivity (SN), specificity (SP), and clinical utility of such amino acid (AA) ratio combination cutoffs in discriminating PDCD from other inborn errors of metabolism (IEM) for early identification of such patients.
METHODS
We reviewed medical records of patients seen at UPMC in the past 11 years with molecularly or enzymatically confirmed diagnosis. We collected plasma AA analysis data from samples prior to initiation of therapeutic interventions such as total parenteral nutrition and/or ketogenic diet. Conditions evaluated included organic acidemias, primary mitochondrial disorders (MtDs), fatty acid oxidation disorders (FAOD), other IEMs on current newborn screening panels, congenital cardiac great vessel anomalies, renal tubular acidosis, and non-IEMs. The utility of specific AA ratio combinations as biomarkers were evaluated using receiver operating characteristic curves, correlation analysis, principal component analysis, and cutoff SN, SP, and positive predictive value determined from 201 subjects with broad age range.
RESULTS
Alanine/Lysine (Ala/Lys) and Ala/Leu as well as (Ala + Pro)/(Leu + Lys) and Ala/Leu ratio combinations effectively discriminated subjects with PDCD from those with other MtDs and IEMs on current newborn screening panels. Specific AA ratio combinations were significantly more sensitive in identifying PDCD than Ala alone or combinations of Ala and/or Pro in the evaluated cohort of subjects. Ala/Lys ≥3.0 and Ala/Leu ≥5.0 as well as (Ala + Pro)/(Leu + Lys) ≥2.5 and Ala/Leu ≥5.0 combination cutoffs identified patients with PDCD with 100% SN and ~85% SP.
CONCLUSIONS
With the best predictor of survival and positive cognitive outcome in PDCD being age of diagnosis, PDCD patients would benefit from use of such highly SN and SP AA ratio combination cutoffs as biomarkers for early identification of at-risk newborns, infants, and children, for early intervention(s) with known and/or novel therapeutics for this disorder.
Topics: Child; Humans; Infant, Newborn; Infant; Child, Preschool; Amino Acids; Leucine; Pyruvate Dehydrogenase Complex Deficiency Disease; Metabolism, Inborn Errors; Alanine; Proline; Biomarkers
PubMed: 37688338
DOI: 10.1002/mgg3.2283 -
World Journal of Clinical Cases Sep 2023Renal tubular acidosis (RTA) is a renal cause of non-anion-gap metabolic acidosis characterized by low urinary ammonia excretion. This condition has a low prevalence,...
BACKGROUND
Renal tubular acidosis (RTA) is a renal cause of non-anion-gap metabolic acidosis characterized by low urinary ammonia excretion. This condition has a low prevalence, and various congenital and acquired etiologies. To date, only a few cases of idiopathic RTA uncovered during pregnancy have been reported.
CASE SUMMARY
A previously healthy 32-year-old Korean woman at 30 wk of gestation was admitted to Pusan National University Hospital with preterm labor. At admission, the patient presented with hypokalemia, non-anion-gap metabolic acidosis, and nephrocalcinosis. Distal RTA was diagnosed based on laboratory blood and urine findings and imaging examinations. Various tests, including next-generation gene sequencing panels for nephropathy, were performed to determine the etiology of the disease, which indicated that it was idiopathic. The patient received sodium bicarbonate and potassium chloride supplementation. After 3 wk, she delivered a baby who was subsequently diagnosed with corpus callosum agenesis and colpocephaly. During regular follow-ups for 6 mo postpartum, her hypokalemia and metabolic acidosis were gradually resolved, and medications eventually discontinued.
CONCLUSION
Herein we describe a case of idiopathic distal RTA discovered during pregnancy. Hypokalemia and metabolic acidosis resolved spontaneously after delivery.
PubMed: 37727491
DOI: 10.12998/wjcc.v11.i25.5988 -
Kidney & Blood Pressure Research 2024This study was designed to determine the mineral composition of calculi in nephrocalcinosis with nephrolithiasis, diagnose the underlying disease, and monitor the course...
INTRODUCTION
This study was designed to determine the mineral composition of calculi in nephrocalcinosis with nephrolithiasis, diagnose the underlying disease, and monitor the course of renal function in patients with nephrocalcinosis-nephrolithiasis.
METHODS
Renal calculi extruded in a series of 8 patients with nephrocalcinosis were analysed using Fourier transmission infrared spectrometry. In 4 patients, next-generation sequencing using a nephrocalcinosis-nephrolithiasis panel was performed to determine the nature of the underlying disease. In addition, longitudinal analysis of renal function was performed in all patients.
RESULTS
Seven patients revealed carbonate apatite as the sole constituent of renal calculi. One patient showed a mixed composition of dicalcium phosphate dihydrate/carbonate apatite at first analysis yet in subsequent episodes also had calculi composed of pure carbonate apatite. Further molecular analysis displayed distal renal tubular acidosis in 2 of 4 patients who consented to sequencing. No known genetic defect could be found in the other two cases. In line with prior reports, decline of renal function was dependent on underlying disease. Distal renal tubular acidosis revealed a progressive course of renal failure, whereas other causes showed stable renal function in long term analysis.
CONCLUSION
Nephrocalcinosis with nephrolithiasis is a rare condition with heterogeneous aetiology. Yet mineral composition of renal calculi predominantly consisted of pure carbonate apatite. This uniform finding is similar to subcutaneous calcifications of various origins and might propose a general principle of tissue calcification. Progressive decline of renal function was found in distal renal tubular acidosis, whereas other conditions remained stable over time.
Topics: Humans; Apatites; Nephrocalcinosis; Male; Nephrolithiasis; Female; Adult; Middle Aged; Acidosis, Renal Tubular
PubMed: 38513628
DOI: 10.1159/000537699 -
Cureus Mar 2024The occurrence of hyperkalemic renal tubular acidosis (RTA) in the post-transplantation period is likely underestimated, and its identification remains important to...
INTRODUCTION
The occurrence of hyperkalemic renal tubular acidosis (RTA) in the post-transplantation period is likely underestimated, and its identification remains important to offer adequate medical management. Transplant recipients frequently present with clinical and biological characteristics that may be associated with the occurrence of this complication.
METHODS
This was a single-center retrospective study that compared transplanted patients with hyperkalemic RTA and a control group to identify variables associated with the occurrence of this complication. Fisher's exact test and the Mann-Whitney test, followed by multivariate logistic regression, were applied to test whether there was a significant association between hyperkalemic RTA and different variables.
RESULTS
Kidney and heart transplant recipients were at greater risk of developing RTA than lung transplant recipients (p = 0.016). There was also a significant association between the development of RTA and kalemia (p < 0.01), chloremia (p < 0.01), and bicarbonatemia (p < 0.01). The significant impact of these last three variables was confirmed by the results of the multivariate logistic regression. Residual serum tacrolimus levels (p = 0.13) and creatinine levels (p = 0.17) of renal transplant patients were not significantly associated with hyperkalemic RTA.
CONCLUSION
The type of transplanted organ, kalemia, chloremia, and bicarbonatemia were significantly associated with the occurrence of hyperkalemic RTA. This study calls into question certain approaches to managing this complication proposed in a number of case reports, such as reducing the target serum residual of tacrolimus or discontinuing trimethoprim-sulfamethoxazole (TMP-SMX) in favor of another antibiotic prophylactic agent, potentially exposing patients to graft rejection and opportunistic infections.
PubMed: 38434606
DOI: 10.7759/cureus.55379 -
Pediatric Nephrology (Berlin, Germany) Mar 2024Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the...
Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the most common clinical finding is recurrent enlargement of the salivary glands. In pediatric SS, extraglandular manifestations represent a significant feature and, among these, kidney manifestations are relevant. Kidney involvement is observed in 5-20.5% of children with SS, most frequently tubulointerstitial nephritis. This injury can lead to serious phenotypes, including distal kidney tubular acidosis with the development of severe hypokalemia, which can lead to ECG abnormalities, weakness, and hypokalemic periodic paralysis. Kidney implications in pediatric SS also include nephrolithiasis, nephrocalcinosis, and various types of glomerular damage, which often require immunosuppressive therapies. Laboratory findings are usually comparable to adults, including hyperglobulinemia and high rates of antinuclear antibodies (ANA, 63.6-96.2%), and anti-Ro/SSA (36.4-84.6%). The current classification criteria for SS are inaccurate for the pediatric population, and more specific criteria are needed to improve the diagnostic rate. Due to the rarity of the disease, strong recommendations for treatment are lacking, and several therapeutic strategies have been reported, mostly based on glucocorticoids and disease-modifying antirheumatic drugs, with different outcomes. The aim of this paper is to provide an overview of the kidney implications of pediatric SS based on the latest evidence of the medical literature.
Topics: Adult; Humans; Child; Sjogren's Syndrome; Kidney; Acidosis, Renal Tubular; Nephritis, Interstitial; Hypokalemia
PubMed: 37638982
DOI: 10.1007/s00467-023-06135-1 -
Journal of Medical Case Reports Oct 2023Metabolic bone disease causes significant morbidity and mortality, especially when misdiagnosed. With genetic testing, multiple disease pathologies can be analyzed.
BACKGROUND
Metabolic bone disease causes significant morbidity and mortality, especially when misdiagnosed. With genetic testing, multiple disease pathologies can be analyzed.
CASE PRESENTATION
A 5-year and 9-month-old otherwise healthy Yemeni girl presented to her Yemen physician for evaluation of inward bending of her right knee and short stature. After extensive medical testing, she was given a diagnosis of hypophosphatemic rickets and growth hormone deficiency and started on treatment. Despite appropriate treatment, however, her condition continued to progress, prompting her family to pursue additional workup including genetic testing outside of Yemen. Genetic testing ultimately revealed a variation of unknown significance associated with amelogenesis imperfecta.
CONCLUSIONS
Hypophosphatemic rickets secondary to renal tubular acidosis was the working diagnosis. However, the patient's condition did not improve. Further genetic testing revealed a variation of unknown significance associated with amelogenesis imperfecta. We aim to present this case, provide an overview of the causes, and diagnostic metabolic bone health evaluation.
Topics: Female; Humans; Infant; Amelogenesis Imperfecta; Rickets, Hypophosphatemic; Acidosis, Renal Tubular; Diagnostic Errors
PubMed: 37858137
DOI: 10.1186/s13256-023-04164-w -
CEN Case Reports Apr 2024Distal renal tubular acidosis (dRTA) is a clinical picture of hyperchloremic hypokalemic metabolic acidosis with a normal anion gap. It can be caused by a variety of...
Distal renal tubular acidosis (dRTA) is a clinical picture of hyperchloremic hypokalemic metabolic acidosis with a normal anion gap. It can be caused by a variety of conditions including obstructive uropathy such as vesicoureteral reflux (VUR). We report a rare case of dRTA secondary to VUR in a 4-year-old girl with a history of meningomyelocele, neurogenic bladder and recurrent urinary tract infections. She was admitted to the hospital with complaints of polydipsia, polyuria, and inability to gain weight for the last 1 year. She was on prophylactic antibiotic treatment with clean intermittent catheterization and anticholinergic drug. She had a history of subureteral injection of various agents and botulin toxin injection into the bladder. Her voiding cystourethrogram revealed grade 5 VUR in the left kidney, tortuosity in the left ureter, and the bladder had a dome-like appearance and was trabeculated. When all laboratory values of the patient since birth were examined, it was observed that urine pH was high despite hypokalemic hyperchloremic metabolic acidosis for the last year; these abnormalities became more severe in the last few months. In conclusion, the development of hypokalemia and nephrolithiasis/nephrocalcinosis along with metabolic acidosis in a patient diagnosed with VUR should be considered as an indicator of impaired tubular functions. Also, the possibility of an underlying VUR in the presence of recurrent urinary tract infection in a patient diagnosed with dRTA should not be ignored.
PubMed: 38637460
DOI: 10.1007/s13730-024-00873-3 -
Pediatric Nephrology (Berlin, Germany) Sep 2023Although hyperuricemia is a widely studied condition with well-known effects on the kidneys, hypouricemia is usually considered a biochemical abnormality of no clinical...
BACKGROUND
Although hyperuricemia is a widely studied condition with well-known effects on the kidneys, hypouricemia is usually considered a biochemical abnormality of no clinical significance despite the fact that it can be a sign or major finding of serious metabolic or genetic diseases affecting kidney health. In this study, we aimed to investigate and emphasize the clinical significance of hypouricemia.
METHODS
Patients were evaluated retrospectively for persistent hypouricemia defined as serum uric acid concentrations of < 2 mg/dL on at least 3 different occasions. According to the blood and urine uric acid (UA) levels, the patients were classified as having hypouricemia due to UA underproduction vs. overexcretion. Demographic, clinical, and genetic characteristics were noted for analysis.
RESULTS
Fourteen patients (n = 14; M/F 8/6) with persistent hypouricemia were identified. Hypouricemia due to underproduction was the cause of 42.8% of these cases. All of the patients with a uric acid level of 0 mg/dL (n = 4) had hypouricemia due to underproduction. The median serum uric acid level was 0.85 (0-1.6) mg/dL. Isolated hypouricemia and hypouricemia with metabolic acidosis were equally distributed. Among the patients with hypouricemia due to underproduction, the final diagnoses were xanthine dehydrogenase deficiency (n = 5) and alkaptonuria (n = 1). In the overexcretion group, the final diagnoses were nephropathic cystinosis (n = 6), distal renal tubular acidosis (n = 1), and hereditary renal hypouricemia (n = 1). The diagnostic lag was longer for patients with isolated hypouricemia compared to other patients (p = 0.001).
CONCLUSIONS
Hypouricemia may reflect underlying genetic or metabolic diseases, early diagnosis of which could help preserve kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Humans; Child; Adolescent; Uric Acid; Retrospective Studies; Renal Tubular Transport, Inborn Errors; Metabolism, Inborn Errors; Acidosis, Renal Tubular; Azotemia
PubMed: 37000195
DOI: 10.1007/s00467-023-05948-4 -
JIMD Reports Nov 2023Lysinuric protein intolerance (LPI), caused by pathogenic variants of is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent...
Lysinuric protein intolerance (LPI), caused by pathogenic variants of is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent studies have reported that LPI can cause multiple organ dysfunctions, including kidney disease, autoimmune deficiency, pulmonary alveolar proteinosis, and osteoporosis. We report the case of a 47-year-old Japanese woman who was initially diagnosed with renal tubular acidosis (RTA), Fanconi syndrome, and rickets. At the age of 3 years, she demonstrated a failure to thrive. Urinary amino acid analysis revealed elevated lysine and arginine levels, which were masked by pan-amino aciduria. She was subsequently diagnosed with rickets at 5 years of age and RTA/Fanconi syndrome at 15 years of age. She was continuously treated with supplementation of vitamin D3, phosphate, and bicarbonate. A renal biopsy at 18 years of age demonstrated diffuse proximal and distal tubular damage with endocytosis-lysosome pathway abnormalities. Distinctive symptoms of LPI, such as protein aversion and postprandial hyperammonemia were not observed throughout the patient's clinical course. The patient underwent a panel-based comprehensive genetic testing and was diagnosed with LPI. As the complications of LPI involve many organs, patients lacking distinctive symptoms may develop various diseases, including RTA/Fanconi syndrome. Our case indicates that proximal and distal tubular damages are notable findings in patients with LPI. The possibility of LPI should be carefully considered in the management of RTA/Fanconi syndrome and/or incomprehensible pathological tubular damage, even in the absence of distinctive symptoms; furthermore, a comprehensive genetic analysis is useful for diagnosing LPI.
PubMed: 37927490
DOI: 10.1002/jmd2.12392 -
Molecular Genetics and Metabolism... Mar 2024Carnitine palmitoyltransferase I (CPT I) deficiency is an autosomal recessive disorder causing long-chain fatty acid oxidation defect, characterized by metabolic...
Carnitine palmitoyltransferase I (CPT I) deficiency is an autosomal recessive disorder causing long-chain fatty acid oxidation defect, characterized by metabolic decompensation episodes accompanied by hypoketotic hypoglycemia, hepatomegaly, seizures, renal tubular acidosis, and hyperammonemia. The aim of this study was to investigate the neurological symptoms in CPT I deficiency and different outcomes with respect to predisposing factors for sequela and to draw attention to the neurological impairment that may develop during the course of the disease. The retrospective study reviewed clinical characteristics of 14 patients. Mean follow-up period was 10.3 ± 4.7 (range: 8 months-18.6 years; median: 10 years) years. Three patients were diagnosed with newborn screening. In the symptomatic group ( = 12) most common presenting symptoms were psychomotor retardation ( = 6), seizures ( = 5), encephalopathy (n = 5), dystonia ( = 1), Reye-like syndrome (n = 5), muscle weakness ( = 3), and autism (n = 1). Neurologic findings detected in the follow-up period included speech disorder ( = 9), abnormal cranial MRI findings ( = 5), neuropathy ( = 1), and attention deficit hyperactivity disorder (n = 1). Speech disorders collectively included delayed expressive language development, speech articulation disorder, speech delay, stuttering, and specific speech difficulties. After starting treatment for CPT I deficiency, speech disorders improved in 3 patients. Our findings confirmed that the clinical manifestations of CPT I deficiency is wider than previously thought, causing specific neurologic dysfunction, mainly speech disorders at a large scale, that were unexpected in a fatty acid oxidation disorder. We suggest that early diagnosis and treatment is the key factor to prevent neurologic sequelae while an extensive neurological evaluation is essential in patients with CPT I deficiency both at the time of diagnosis and during the follow-up period.
PubMed: 38090675
DOI: 10.1016/j.ymgmr.2023.101032