Purine inborn errors of metabolism (IEM) are serious hereditary disorders, which should be suspected in any case of neonatal fitting, failure to thrive, recurrent infections, neurological deficit, ...renal disease, self-mutilation and other manifestations. Investigation usually starts with uric acid (UA) determination in urine and plasma. UA, the final product of purine metabolism in humans, may be altered not only in purine IEM, but also in other related pathologies and clinical conditions. However, data and information about abnormal UA levels are scattered in the literature, often being controversial and confusing. A comprehensive overview has been elaborated, according to abnormal UA levels in urine and plasma, which associates these alterations with purine IEM. Other possible diseases, clinical conditions, diet and drug intake, related to the metabolism of uric acid, are also presented. The article includes tables that classify the disorders according to different patterns of UA alterations, with pertinent enzymes, clinical symptoms, inheritance and comments. Additionally, summarized pathophysiological mechanisms of important disorders are described. The overview is intended to assist in the interpretation of the results of UA analyses. It demonstrates that variation of UA concentrations in urine and plasma may constitute an effective tool in screening for purine IEM and other related pathological conditions.
Abstract
Background: The standard first-line therapy for clinically nonfunctioning adenomas (NFPA) is transsphenoidal surgery, however there is no consensus of the optimal postsurgical treatment for ...residual adenoma. Medical therapy, such as cabergoline (CAB), may be an alternative for preventing growth of postoperative pituitary tumor remnants. The moment of introduction dopamine agonist (DA) is still uncertain. Objective: To assess tumor behavior in patients who used CAB in the postoperative period. Design and methods: A retrospective cross-sectional study was performed with twenty one patients with NFPA treated surgically. All patients stayed with residual tumor and were divided in two groups: patients who received CAB early in postoperative period (Group A, n=6) and when tumor growth were detected during follow-up (Group B, n=15). CAB dosage was 1.5mg or 3.5mg per week. A change in tumor size was considered significant and recorded as such if a difference of at least 5 mm in major diameter was observed. MRI was performed four months after surgery and yearly thereafter in all patients. Subjects in treatment groups also underwent MRI 6 months following medical therapy. No patients were treated by irradiation before or during the follow-up. Statistical analysis was performed using the Fisher’s exact test. Results: From 21 patients, 11 were men and 10 women with similar mean age in two groups (p=0.651). MRI in group A showed stabilization of residual tumor in 50% (3/6) and tumor reduction in 50% (3/6) in group A. In group B, tumor shrinkage was observed in 47% (7/15), stabilization in 27% (4/15) and enlarged in 27% (4/15). No statistical difference between groups was obtained regarding tumor shrinkage and stabilization with the treatment (Group A n=6 versus Group B n=11, p=0.281). In contraste Batista et al., 2016, have already shown that CAB was effective alternative in residual tumor reduction in a study with 74 patients. Conclusion: A multicenter study is necessary to define the role of CAB in the treatment of residual tumor in postsurgical patients with NFPA.
Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ...ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.
Pompe disease (PD) is an inborn error of metabolism caused by α-glucosidase acid enzyme deficiency. It significantly impacts patients' health and life quality and may lead to death in the first few ...years of life. Among the well-established diagnostic methods, urinary glucose tetrasaccharide (Glc
4
) screening by high performance-liquid chromatography has been helpful in monitoring Glc
4
levels in patients on enzyme replacement therapy, demonstrating therapy efficacy. However, the specimen shipping process from a sample collecting location to a specialized laboratory for monitoring the Glc
4
is costly and presents preanalytical challenges. In this work, we developed a filter paper based-urine collection kit to facilitate specimen shipment, and liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) analysis to determine Glc
4
and creatinine in dried urine on filter paper. The LC-HRMS was based on a combination of targeted and untargeted screening on the same specimen injection and was successfully developed and validated. Bland-Altman statistics revealed a good relationship between dried and liquid urine samples and Glc
4
and creatinine. Glc
4
and other metabolites in dried urine showed stability for at least 7 days at 4 and 22 °C, and 3 days at 50 °C. The stability of the analytes and the efficiency of the kit were tested simulating real conditions by sending it by post. After two days in transit without refrigeration, the stability of compounds was maintained, showing the reliability of the urine collection kit and analysis method to determine the PD biomarker Glc
4
.
This work reports the validation and application of a method for determination of glucose tetrasaccharide (Glc
4
) in urine collected on filter paper for monitoring Pompe disease patients.
Abstract
Introduction
Neuroendocrine Neoplasms are rare, with an incidence of 5 to 100,000 inhabitants, constituting 1% of all malignancies, presenting high survival rates in general, even in ...metastatic diseases. However, in those poorly differentiated, as in the following case, survival is around 4% in 5 years. We will describe a case of primary neuroendocrine tumor in the brain, of which is uncommon in the literature.
Clinical case
A 26 years women was referred to the ER of Santa Casa de São Paulo, in January 2019, to be evaluated by neurosurgery, due to progressive left hemiparesis and headache for 3 months, which got worse in 4 days. On CT scan, there was a 6 x 6 cm solid-cystic, expansive, lesion in the right frontal lobe, with perilesional edema and contralateral midline 1.3cm deviation and subfalcine herniation.
Thus, the tumor was resected soon, with anatomopathological analysis showing poorly differentiated tumor of cells with scarce cytoplasm, hyperchromatic nuclei and high mitotic activity.
Immunohistochemical analysis finds 50% Ki67, with focal p53, TTF1, CD99, CD 56 and synaptophysin positivity. The main hypotheses, then, consisted of Neuroendocrine Carcinoma.
Four months after surgery, the patient reported worsening deficit, headache, pain, weight loss, being referred to the Emergency Room, once more. In RM an expansive lesion was found 6.6 x 4.4 cm, in the right frontoparietal surgical cavity, edema, compression and 0,4 cm midline deviation.
The patient was once again submitted to emergency neurosurgery, with microsurgical resection. The pathology was identical to the previous one.
We proceed with hormonal evaluation, regarding to Medular Thyroid carcinoma, Gastrinoma, Insulinoma, Pheochromocytoma, Carcinoid tumor and others.
Imaging exams were also performed to investigate other primary sites: no changes in CT scan of the chest and abdomen and PET CT FDG. However, this one showed recurrence of the intracranial lesion, with three sites of involvement, all hypermetabolic: one of 4.1 x 2.9 cm (SUV 4.9) and another of 3.9 x 3.3 cm (SUV 8, 4) in the right frontoparietal region and medial nodule to the right thalamus of 1.2 cm (SUV 6.1).
Patient currently maintain left hemiparesis, frequent pain, taking carbamazepine due to epileptic seizures, and considerable weight loss. She has an important limitation of daily activities and basic self-care, with 50% Karnofsky scale. Due to relapse, palliative radiotherapy was initiated in the region of the tumors.
Conclusion
The patient had a poor outcome in relation to cancer, with little possibility of treatment due to poor tumor differentiation and poor performance status.
Metabolic profiling of complex biological matrices based on liquid chromatography-mass spectrometry (LC-MS) allows detecting a wide range of metabolites with distinct concentrations and ...physicochemical properties. Given the complexity of samples and the necessity of a comprehensive approach in untargeted metabolomics, quality control strategies are mandatory to obtain high-quality data. The LC-MS performance must be monitored and evaluated to guarantee data reliability. In this study, a test mixture (TM) was developed, systematically evaluated, and applied to untargeted metabolomics of urine samples from individuals suspected of inborn errors of metabolism. The TM was composed of fifteen analytes that eluted across the entire gradient in reversed-phase columns and ionized in positive/negative electrospray modes. It helped set the LC-MS conditions for urine analysis, from sample reconstitution solvent to selecting the MS ion source parameters. The TM quickly indicated column stationary phase degradation during the batch analysis when employed to monitor and evaluate the LC-MS system in an untargeted metabolomic analysis. Thus, in addition to pooled QC samples, a TM can be employed in untargeted metabolomics to rapidly assess the system performance avoiding unnecessary efforts for further data treatment and multivariate analysis of poor-quality data
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder due to an inborn error of cholesterol metabolism, characterized by congenital malformations, dysmorphism of multiple organs, ...mental retardation and delayed neuropsychomotor development resulting from cholesterol biosynthesis deficiency. A defect in 3 -hydroxysteroid-delta7-reductase (delta7-sterol-reductase), responsible for the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, causes an increase in 7-DHC and frequently reduces plasma cholesterol levels. The clinical diagnosis of SLOS cannot always be conclusive because of the remarkable variability of clinical expression of the disorder. Thus, confirmation by the measurement of plasma 7-DHC levels is needed. In the present study, we used a simple, fast, and selective method based on ultraviolet spectrophotometry to measure 7-DHC in order to diagnose SLOS. 7-DHC was extracted serially from 200 l plasma with ethanol and n-hexane and the absorbance at 234 and 282 nm was determined. The method was applied to negative control plasma samples from 23 normal individuals and from 6 cases of suspected SLOS. The method was adequate and reliable and 2 SLOS cases were diagnosed.
Abstract
Introduction: Multiple endocrine neoplasia type 2A (MEN 2A) is a autosomal dominant transmission inherited syndrome which oncogenesis is based on germline mutations with RET proto-oncogene ...function gain. Patients have medullary thyroid carcinoma (CMT) and some develop unilateral or bilateral pheochromocytoma and/or primary hyperparathyroidism, its frequency depends on the inherited RET mutation. We present a case of a mother and daughter with marfanoid habitus and MEN 2A syndrome confirmed by genetic analysis that identified mutation in the RET gene, codon 634.Clinical cases: 35-year-old woman with weight loss, sweating, nausea, hypertensive peaks, syncope episodes and marfanoid habitus, with plasma metanephrines 9.1nmol/L (RV<0.5), bilateral adrenal tumors on MRI (4.7x4.5x3.3 cm left adrenal and 7.4x7.3x6.3 cm) and MIBG scintigraphy high uptake bilateral, with diagnosis of bilateral pheochromocytoma. She also had calcitonin 49.40pg/mL (RV<6.4), calcium 11.9mg/dL (RV 8.6-10.2), PTH 372.7pg/mL (RV15-65) and cervical ultrasound (USG) with solid and hypoechogenic thyroid nodule, diagnosed with CMT and primary hyperparathyroidism with 6 possible parathyroid glands by SPECT CT scintigraphy. Genetic panel by NGS identify germline mutation in RET códon 634 - minsense mutation: c.1900T>C. The patient denied prior family history. In the familiar screening, her 18-year-old daughter has a marfanoid habitus, serum calcitonin 48.8pg /mL (RV<9.8), CEA 3.8ng/mL(RV<3.0), cervical USG shows a thyroid nodule of 0.7x0.5x0.5cm, solid, hypoechoic, with microcalcifications and a central compartiment lymph node, whose puncture calcitonin > 2000pg/mL and 118pg/mL, respectively. She features plasma metanephrines 0.5mmol/L (RV<0.5), normal plasma normetanephrines, MIBG scintigraphy and adrenal MRI without alterations and absence of primary hyperparathyroidism. She has the same mutation as her mother.Conclusion: Although rare, it is essential to know the clinical and laboratory changes in MEN 2A in order to enable early diagnosis and treatment. Also, investigate every first-degree relative is important so complications and mortality of this syndrome can be reduced.
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