Pteridine and tryptophan pathways in children with type 1 diabetes: Isoxanthopterin as an indicator of endothelial dysfunction.

AIM: Type 1 diabetes (T1D) and its complications are known to be associated with oxidative stress. Pteridine derivatives and indoleamine 2,3-dioxygenase (IDO) activity can be used as biomarkers in the evaluation of oxidative stress. In this study, our aim is to compare the concentrations of serum and urinary pteridine derivatives, as well as serum IDO activity, in children and adolescents diagnosed with T1D and those in a healthy control group. METHOD: A cross-sectional study was performed and included 93 patients with T1D and 71 healthy children. Serum and urine biopterin, neopterin, monapterin, pterin, isoxanthopterin, and pterin-6-carboxylic acid (6PTC) and serum tryptophan and kynurenine levels were analyzed and compared with healthy controls. High-performance liquid chromatography was used for the analysis of pteridine derivatives, tryptophan, and kynurenine. Xanthine oxidase (XO) activity, a marker of oxidative stress, was defined by measurement of serum and urine isoxanthopterin. As an indicator of indolamine 2,3-dioxygenase (IDO) activity, the ratio of serum kynurenine/tryptophan was used. RESULTS: Serum isoxanthopterin and tryptophan concentrations were increased, and serum 6PTC concentration was decreased in children with T1D (p=0.01, p=0.021, p<0.001, respectively). In children with T1D, IDO activity was not different from healthy controls (p>0.05). Serum neopterin level and duration of diabetes were weakly correlated (p=0.045, r=0.209); urine neopterin/creatinine and isoxanthopterin/creatinine levels were weakly correlated with HbA1c levels (p=0.005, r=0.305; p=0.021, r=0.249, respectively). Urine pterin/creatinine level negatively correlated with body mass index-SDS. (p=0.015, r=-0.208). CONCLUSION: We found for the first time that isoxanthopterin levels increased and 6PTC levels decreased in children and adolescents with T1D. Elevated isoxanthopterin levels suggest that the XO activity is increased in TID. Increased XO activity may be an indicator of vascular complications reflecting T1D-related endothelial dysfunction.

Serum Neopterin, Biopterin, Tryptophan, and Kynurenine Levels in Patients with Fabry Disease

Background: Fabry disease is characterized by the accumulation of globotriaosylceramide. Substrate accumulation in lysosomes is thought to trigger an inflammatory response and is responsible for progressive organ damage through the induction of autoimmunity. The levels of pteridine and kynurenine pathway metabolites increase when immune activation is observed and are employed to monitor several diseases and determine prognosis. Aims: To elucidate the effects of immune activation on the pathophysiology of Fabry disease and to investigate the potential utility of pteridine and kynurenine metabolites. Study Design: A prospective case-control study. Methods: In this study, 33 patients with Fabry disease and 33 age-and sex-matched healthy controls were included. Blood pteridine and kynurenine metabolites were studied in both groups. Organ involvement in Fabry disease and its correlation with the pteridine and kynurenine pathways were also investigated. Results: The patients' neopterin and biopterin levels and the tryptophan/kynurenine ratio were statistically higher than those of the healthy control group (p < 0.05). A statistically significant association was found between neopterin levels and hypertrophic cardiomyopathy, cardiac arrhythmias, and GFR values (p = 0.044, p = 0.021, and p = 0.030, respectively), tryptophan and corneal verticillate, hearing loss and tinnitus (p = 0.010, p = 0.009 and p = 0.046, respectively), and kynurenine levels and valvular heart disease (p = 0.020). Conclusion: From the onset of the disease, patients with Fabry disease exhibited elevated levels of inflammation and immune activation. Furthermore, inflammation and immune activation markers can be used as early disease biomarkers.

Analysis of Biotinidase Activity in Serum by Digital Imaging Colorimetry Detection.

Biotinidase deficiency (BD) is an autosomal recessive inherited disorder of biotin recycling that leads to neurological and cutaneous consequences if left untreated. The clinical features of BD can be ameliorated or prevented by the administration of pharmacological doses of the vitamin biotin. Since it is a treatable disorder, BD is included in the newborn screening program in Türkiye as in many other countries. Therefore, monitoring of biotinidase enzyme activity (BEA) is of vital importance, especially for patients. The aim of this study was to develop a simple and reliable colorimetric method based on digital imaging for the analysis of BEA in serum samples. To determine the optimum distance and LED light source in the analyzer box that we fabricated in the laboratory, images of the solutions in a 96-well microplate were taken with a mobile phone camera, and each color space was examined. The most reliable relationship was between blank subtracted intensities of green channel and analyte concentrations, which was in the range of 35-400 ng/mL p-aminobenzoic acid (r2 = 0.999). The limit of detection and limit of quantification were 11 and 35 ng/mL, respectively. The proposed method was successfully applied to serum samples of 60 patients with BD and 60 healthy controls. We claim that the method can be easily performed for determination of BEA anywhere without needing expensive instruments.

Autism Spectrum Disorder in Two Unrelated Patients with Homozygous Variants in Either ALG8 or ALG11.

Background: Autism spectrum disorder (ASD) is used to describe individuals with a specific combination of disorders in social communication and repetitive behaviors, highly restricted interests, and/or sensory behavior that begin early in life. The prevalence of ASD has been increasing rapidly in recent years. Pathophysiology of ASDs remains still unclear; however, genetic defects and multifactorial causes have been reported to play an important role in genetic disorders. The prevalence of inborn errors of metabolism (IEM) reported among patients with ASD is 2-5%. The clinical presentation of congenital disorders of glycosylation (CDG) may be in the form of psychiatric disorder only. Case Study: Case 1: a 5-year-old female patient was admitted for investigation of ASD. She had a dysmorphic facial appearance, inverted nipples, abnormal fat distribution, ataxic gait, and autistic features. Her transferrin isoelectric focusing test was compatible with a type 1 CDG pattern. A homozygous variant in ALG8 gene revealed the diagnosis of ALG8-CDG (CDG Type 1H). Case 2: a 2-year-old male patient was admitted with complaints of ASD for investigation of an underlying IEM due to speech delay. Physical examination revealed hypertelorism, small hands, and autistic behavior. Transferrin isoelectric focusing test was also found normal. As a result of the WES, a homozygous variant was detected in ALG11 confirming the diagnosis of CDG type 1p. Conclusion: CDG should also be considered in the differential diagnosis of autistic patients with dysmorphic findings. The aim of our study was to emphasize that autism should be listed among the neurological findings of CDG.

Urinary neopterin and biopterin indicate that inflammation has a role in autism spectrum disorder.

Inflammation is thought to be involved in the pathogenesis of autism spectrum disorder (ASD). Pteridine metabolites are biomarkers of inflammation that increase on immune system activation. In this study, we investigated the urinary pteridine metabolites in ASD patients as a possible biomarker for immune activation and inflammation. This observational, cross-sectional, prospective study collected urine samples from 212 patients with ASD and 68 age- and sex-matched healthy individuals. Urine neopterin (NE) and biopterin (BIO) levels were measured. Patients who had chronic disorders, active infection at the time of sampling, or high C-reactive protein levels were excluded. The urine NE and BIO concentrations were determined by high-performance liquid chromatography. The ratios of both NE and BIO to creatinine (CRE) were used to standardise the measurements. The NE/CRE and NE/BIO levels were significantly higher in ASD patients than controls. Univariate and multivariate models revealed a significant increase in NE/CRE and NE/BIO in ASD patients. There was a significant relationship between the NE/BIO [average area under the curve (AUC) = 0.717; range: 0.637-0.797] and NE/CRE (average AUC = 0.756; range: 0.684-0.828) ratios, which distinguished individuals with ASD from controls. The elevated NE/CRE and NE/BIO ratios suggest that inflammation and T cell-mediated immunity are involved in the pathophysiology of autism. NE/BIO could serve as a diagnostic inflammatory marker in the pathogenesis of ASD.

A Methionine-Portioning-Based Medical Nutrition Therapy with Relaxed Fruit and Vegetable Consumption in Patients with Pyridoxine-Nonresponsive Cystathionine-ß-Synthase Deficiency.

The main treatment for pyridoxine-nonresponsive cystathionine-ß-synthase deficiency is a strict diet. Most centers prescribe low-protein diets based on gram-protein exchanges, and all protein sources are weighed. The purpose of this study is to investigate the effects of a more liberal methionine (Met)-based diet with relaxed consumption of fruits and vegetables on metabolic outcomes and dietary adherence. Ten patients previously on a low-protein diet based on a gram-protein exchange list were enrolled. The natural protein exchange lists were switched to a "Met portion exchange list". Foods containing less than 0.005 g methionine per 100 g of the food were accepted as exchange-free foods. The switch to Met portioning had no adverse effects on the control of plasma homocysteine levels in terms of metabolic outcomes. It resulted in a significant reduction in patients' daily betaine dose. All patients preferred to continue with this modality. In conclusion, methionine-portion-based medical nutrition therapy with relaxed consumption of fruits and vegetables seems to be a good and safe option to achieve good metabolic outcomes and high treatment adherence.

Expert opinion on patient journey, diagnosis and clinical monitoring in acid sphingomyelinase deficiency in Turkey: a pediatric metabolic disease specialist's perspective.

This review by a panel of pediatric metabolic disease specialists aimed to provide a practical and implementable guidance document to assist clinicians in best clinical practice in terms of recognition, diagnosis and management of patients with acid sphingomyelinase deficiency (ASMD). The participating experts consider the clinical suspicion of ASMD by the physician to be of utmost importance in the prevention of diagnostic delay and strongly suggest the use of a diagnostic algorithm including/starting with dried blood spots assay in the timely diagnosis of ASMD in patients presenting with hepatosplenomegaly and a need for increased awareness among physicians in this regard to consider ASMD in the differential diagnosis. In anticipation of the introduction of enzyme replacement therapy, raising awareness of the disease among physicians to prevent diagnostic delay and further investigation addressing natural history of ASMD across the disease spectrum, potential presenting characteristics with a high index of suspicion, as well as biomarkers and genotype-phenotype correlations suggestive of poor prognosis seem important in terms of implementation of best practice patterns.

Separation and quantification of the urinary enantiomers of 2-hydroxyglutaric acid by capillary electrophoresis with capacitively coupled contactless conductivity detection: Application to the diagnosis of D- and L-2-hydroxyglutaric aciduria.

2-hydroxyglutaric aciduria is an inherited neurometabolic disorder with two major types: D-2-hydroxyglutaric aciduria and L-2-hydroxyglutaric aciduria. An easy and fast capillary electrophoresis system combined with a capacitively coupled contactless conductivity detection method was developed for the enantioseparation and determination of D- and L-2-hydroxyglutaric acid in urine. D- and L-2-hydroxyglutaric acids were separated using vancomycin as the chiral selector. The optimal separation conditions for enantiomers were achieved by the use of a buffer containing 50 mM 4-(N-morpholino) butane sulfonic acid solution (pH 6.5), an electroosmotic flow modifier (0.001% [w/v] polybrene), and 30 mM vancomycin as chiral selector. The analysis time was 6 min under optimal conditions. The optimized and validated method was successfully implemented for quantifying D- and L-2-hydroxyglutaric aciduria in patients' urine, without any pretreatment step. The linearity of the method was determined to be in the range of 2-100 mg/L for D- and L-2-hydroxyglutaric acid in urine. The precision (relative standard deviation%) was obtained at about 7%. For D- and L-2-hydroxyglutaric acids, the limits of detection were 0.567 and 0.497 mg/L, respectively.

Maternal Inborn Errors of Metabolism Detected in Expanded Newborn Metabolic Screening.

OBJECTIVE: Pathologic results in expanded metabolic screening tests may be due to the medications, inappropriate sampling methods, or the maternal originated inborn errors of metabolism. The aim of this study is to identify mothers with inborn errors of metabolism through the pathologic expanded metabolic screening results of their babies. MATERIALS AND METHODS: Babies who were under 1 year of age and had a pathologic result of an expanded newborn screening for inborn errors of metabolism and their mothers were included in this retrospective single-centered study. Data of expanded metabolic screening results of both babies and their mothers were recorded. Clinical and laboratory findings relevant to suspected inborn errors of metabolism due to the pathologic screening results analysis were also noted for the mothers. RESULTS: Seventeen babies and their mothers were enrolled. Expanded metabolic screening results were found compatible with inborn errors of metabolism in 4 (23.5%) of 17 mothers. Two of these mothers were diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency and 2 mothers were diagnosed with glutaric aciduria type 1. CONCLUSION: Inborn errors of metabolism can present in any period of life, and this is the first study to address the importance of metabolic screening via tandem mass spectrometry in terms of early diagnosis of inborn errors of metabolism not only in pediatric aged patients but also in adulthood in Turkey. The performance of expanded metabolic screening tests may be an important step in terms of detecting maternal inborn errors of metabolism that are not diagnosed until adulthood.

Auto brewery syndrome from the perspective of the neurologist.

BACKGROUND AND PURPOSE: Auto-brewery syndrome (ABS) is a rare condition that causes the digestive system to produce intoxicating amounts of alcohol due to abnormal growth of the gut microbiota. Medicolegal inferences of ABS have two distinct edges. First, malingering in drunk-driving and abusing the syndrome as a factitious disorder may occur. Second, patients suffering from the syndrome may face medicolegal and social problems. Moreover, chronic exposure to alcohol due to undiagnosed ABS might result in cognitive and behavioral disturbances. Here, we present a patient with recurrent encephalopathy episodes and chronic cognitive disturbances, who was diagnosed with the auto-brewery syndrome, to emphasize the neurocognitive consequences of the syndrome. CASE PRESENTATION: A 58 years old female presented with mild cognitive impairment, behavioral disturbances, and recurrent encephalopathy episodes. The history of hemicolectomy, an odd smell on her breath, and cravings for high carbohydrate meals during the paroxysmal episodes raised the suspicion of ABS. Her blood ethanol concentration reached 315 mg/dL following an oral glucose tolerance test (OGTT), and stool analysis revealed increased colonization with C. krusei and C. parapsilosis. She was free of the acute episodes, cognitive and behavioral disturbances improved, and C. krusei and C. parapsilosis were eliminated from the intestinal flora with dietary recommendations and nystatin treatment. CONCLUSION: The auto brewery syndrome is a rare disorder of dysbiosis leading to a disturbed gut-brain axis. Being a treatable and relatively benign diagnosis, presentation of the ABS with neurocognitive disturbances necessitates highlighting.

An Overview of Acute Hepatic Porphyrias: Clinical Implications, Diagnostic Approaches, and Management Strategies.

Porphyrias are inborn errors of heme biosynthesis pathway that result in neurovisceral and/ or cutaneous manifestations which occur with episodic attacks, usually accompanied by a multisystemic involvement. Acute hepatic porphyrias include acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficiency porphyria. Acute hepatic porphyrias may present with symptoms of an affected central, peripheral, and autonomic nervous system and are generally diagnosed in time of an acute neurovisceral attack. In children, clinical picture is more complicated and presents with neurological findings predominantly. First-line investigation should be the urinary porphobilinogen and aminolevulinic acid performance when acute hepatic porphyria is clinically suspected. Comprehensive testing including urine porphyrin separation, fluorescence scanning of diluted plasma at neutral pH, evaluation of fecal porphyrins, and measurement of erythrocyte porphobilinogen deaminase activity is indicated for confirmation or exclusion of the porphyria and define the type of acute hepatic porphyrias. The main aim of the treatment is to decrease aminolevulinic acid, porphobilinogen, and porphyrins by reducing hepatic ALAS1 activity. The first measure should always be the avoidance of any porphyrinogenic drugs. Hemin therapy should not be delayed in the treatment of a severe acute attack. Gonadotropin-releasing hormone analogs and prophylactic hemin protocols can be used for selected cases with more than 4 attacks per year. Givosiran is a promising treatment option for severe cases.

Safety of COVID-19 vaccines in children with inborn errors of metabolism in terms of developing metabolic decompensation.

AIM: There are no recommended guidelines or clinical studies on safety of COVID-19 vaccines in patients with inborn errors of metabolism (IEMs). Here, we aimed to examine the relationship between COVID-19 vaccination and metabolic outcome in paediatric IEM patients. METHODS: Patients with IEM between the ages of 12 and 18 were enrolled. Term metabolic decompensation was defined as acute disruption in metabolic homeostasis due to vaccination. Clinical and biochemical markers were compared between pre- and post-vaccination periods. RESULTS: Data from a total of 36 vaccination episodes in 18 patients were included. Thirteen patients had intoxication-type metabolic disorders including organic acidemia (OA), urea cycle disorders (UCDs), maple syrup urine disease (MSUD) and phenylketonuria (PKU); 4 patients had energy metabolism disorders including fatty acid metabolism disorders and LIPIN 1 deficiency; and 1 patient had glycogen storage disorder (GSD) type 5. Seventeen patients received BNT162b2, and 1 received CoronaVac because of an underlying long QT syndrome. Fatty acid metabolism disorders, LIPIN 1 deficiency and GSD type 5 were included in the same group named 'metabolic myopathies'. In two PKU patients, plasma phenylalanine level increased significantly within 24 h following the second dose of vaccination. None of the OA, UCD, MSUD and metabolic myopathy patients experienced acute metabolic attack and had emergency department admission due to metabolic decompensation within 1 month after vaccination. CONCLUSIONS: COVID-19 vaccines did not cause acute metabolic decompensation in a cohort of 18 children with IEM.

Evaluation of plasma carnitine status in patients diagnosed with juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and manifests mainly as autoinflammation of the joints and other tissues. Several treatment options such as nonsteroidal antiinflammatory drugs, methotrexate, and intra-articular steroids are widely used to relieve and improve this inflammation. Secondary carnitine deficiency can be detected in chronic diseases by either renal loss or increased demand. While carnitine status can be associated with several conditions, in the present study our aim is to determine the levels of free carnitine and acyl-carnitine in Turkish JIA patients. METHODS: One hundred and fourteen patients diagnosed with juvenile idiopathic arthritis and 50 healthy individuals who served as the control group were included in the study. A fasting blood sample was collected from the children in both groups to determine free carnitine and acylcarnitine ester by quadripole electrospray tandem mass spectrometry (ESI-MS/ MS). RESULTS: Screening of acyl-carnitine profile revealed free carnitine, C14, C14:2, C16, C16-OH, and C18 carnitine levels were higher (p < 0.0001, p < 0.0001, p < 0.001, p < 0.001, and p = 0.011, respectively), while C2, C3, C4, C6, C8, C10, C10:1, C10:2, C3DC, C4DC, C5DC, C4-OH, and C18:1-OH carnitine levels were lower (p < 0.0001) in JIA patients in comparison to the control group. Total acyl-carnitine levels (p < 0.001) and acyl-carnitine to free carnitine ratio (p < 0.001) were also lower in JIA patients than the control group. Free carnitine levels were significantly higher (48.05 ± 13.36 µmol/L) in patients under antiinflammatory drug therapy than those who did not receive any treatment (43.18 ± 7.96 µmol/L) (p = 0.004). DISCUSSION: In the present study we were not able to define secondary carnitine deficiency in JIA patients, although free carnitine and acyl-carnitine variations were detected in JIA patients. In conclusion, routine carnitine supplementation is not recommended in all patients with JIA.

The impact of the COVID-19 pandemic on Fabry Disease Patients: an examination of Mood Status, Therapy Adherence, and COVID-19 infection.

BACKGROUND: Fabry disease (FD) is a rare metabolic disorder, in which a lifelong enzyme replacement therapy (ERT) constitutes the cornerstone of disease-specific therapy. In this study, we examined the effects of the COVID-19 pandemic and lockdown measures on the management of FD patients. METHODS: We collected data in three main domains; mood status, adherence to ERT, and COVID-19 infection. We used the Hospital Anxiety and Depression Scale (HADS) to evaluate the mood statuses of FD patients and the Morisky Medication Adherence Scale (MMAS) and the Medication Adherence Report Scale (MARS) to assess patients' adherence to non-disease specific therapy. We also examined a control group to compare the mood status data. RESULTS: A total of 67 FD patients (males: 47.8%, mean age: 37.0 years) were recruited to the study, of which 58 were receiving ERT. Both the HADS depression and anxiety scores were higher in the control group compared to FD patients. During the first wave of the pandemic, 25 patients reported to have missed an infusion for a mean of 2.3 ± 1.7 doses and half of the patients had adopted a home-based infusion treatment regimen. COVID-19 infection developed in 25 patients, of which one died. The majority of our patients (71.6%) have had at least one shot of the vaccine. CONCLUSION: We found that FD patients were more resilient to the negative psychological effects of lockdown. Traumatic growth may be an important factor in explaining this finding. Government-supported home therapy programs might be beneficial for FD patients to increase the therapy adherence.

Identifying and elucidating the roles of Y198N and Y204F mutations in the PAH enzyme through molecular dynamic simulations.

Phenylketonuria is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase gene. In phenylketonuria causes various symptoms including severe mental retardation. PAH gene of a classical Phenylketonuria patient was sequenced, and two novel heterozygous mutations, p.Y198N and p.Y204F, were found. This study aimed to reveal the impacts of these variants on the structural stability of the PAH enzyme. In-silico analyses using prediction tools and molecular dynamics simulations were performed. Mutations were introduced to the wild type catalytic monomer and full length tetramer crystal structures. Variant pathogenicity analyses predicted p.Y198N to be damaging, and p.Y204F to be benign by some prediction tools and damaging by others. Simulations suggested p.Y198N mutation cause significant fluctuations in the spatial organization of two catalytic residues in the temperature accelerated MD simulations with the monomer and increased root-mean-square deviations in the tetramer structure. p.Y204F causes noticeable changes in the spatial positioning of T278 suggesting a possible segregation from the catalytic site in temperature accelerated MD simulations with the monomer. This mutation also leads to increased root-mean-square fluctuations in the regulatory domain which may lead to conformational change resulting in inhibition of dimerization and enzyme activation. Our study reports two novel mutations in the PAH gene and gives insight to their effects on the PAH activity. MD simulations did not yield conclusive results that explains the phenotype but gave plausible insight to possible effects which should be investigated further with in-silico and in-vitro studies to assess the roles of these mutations in etiology of PKU. Communicated by Ramaswamy H. Sarma.

Postural tremor in L-2-hydroxyglutaric aciduria is associated with cerebellar atrophy.

OBJECTIVE: In this study, we performed analysis of brainstem reflexes and movement disorders using surface polymyogram in L-2-hydroxyglutaric aciduria (L2HGA). We also reviewed all cases in the literature with detailed clinical and radiological description to analyze the anatomical correlates of involuntary movements. PATIENTS AND METHOD: We performed surface electromyography of appropriate muscles, long-loop reflexes, and somatosensory evoked potentials and analyzed the neuroimaging findings in patients with L2HGA and recorded blink reflex (BR), auditory startle response (ASR), and startle response after somatosensory stimuli (SSS) in patients and healthy subjects. We also performed a systematic literature search to identify the association of neuroimaging findings and movements disorders in previous patients with L2HGA. RESULTS: Thirteen patients were enrolled in the study. Among them, ten had low-amplitude postural tremor with a frequency between 4 and 7 Hz. The tremor was predominant on distal parts of the upper extremities. Postural tremor was accompanied by negative myoclonus in one-third. The BR, ASR, and SSS, all, were hypoactive. There was a close association of postural tremor with cerebellar atrophy in patients who participated in this study and by the analysis of the previously reported patients. CONCLUSIONS: Low-amplitude postural tremor is common in L2HGA. It is related with cerebellar atrophy. Although the neuroimaging shows no overt lesions at the brainstem, there is a functional inhibition at this level.

Evaluation of dynamic thiol/disulfide homeostasis in hereditary tyrosinemia type 1 patients.

BACKGROUND: Despite successful treatment with nitisinone, the pathophysiology of long-term complications, including hepatocellular carcinoma and mental decline in tyrosinemia type 1 patients, is still obscure. Oxidative stress may play a role in these complications. While increased fumarylacetoacetate and maleylacetoacetate cause oxidative stress in the liver, increased tyrosine causes oxidative stress in the brain. The aim of this study is to evaluate dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed tyrosinemia type 1 patients. METHODS: Twenty-four late-diagnosed (age of diagnosis; 14.43 ± 26.35 months) tyrosinemia type 1 patients (19 under nitisinone treatment and 5 with liver transplantation) and 25 healthy subjects were enrolled in the study. Serum native thiol, total thiol, and disulfide levels were measured, and disulfide/native, disulfide/total, and native thiol/total thiol ratios were calculated from these values. RESULTS: No significant difference was observed in native, total, and disulfide thiol levels between the groups and no increase in disulfide/native, disulfide/total, and native/total thiol ratios was detected, despite significantly higher plasma tyrosine levels in the nitisinone-treated group. CONCLUSIONS: We suggest that providing sufficient metabolic control with good compliance to nitisinone treatment can help to prevent oxidative stress in late-diagnosed tyrosinemia type 1 patients. IMPACT: Despite successful nitisinone (NTBC) treatment, the underlying mechanisms of long-term complications in hereditary tyrosinemia type 1 (HT1), including hepatocellular carcinoma and mental decline, are still obscure. Oxidative stress may play a role in these complications. Thiol/disulfide homeostasis, which is an indicator of oxidative stress, is not disturbed in hereditary tyrosinemia patients under NTBC treatment, despite higher plasma tyrosine levels and patients who had liver transplantation. This is the first study evaluating dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed HT1 patients.

Inborn errors of metabolism and coronavirus disease 2019: Evaluation of the metabolic outcome.

BACKGROUND: Infectious diseases can result in a catabolic state and possibly trigger an acute metabolic decompensation in inborn errors of metabolism (IEM), which could be life threatening. Studies regarding the course of severe acute respiratory syndrome coronavirus 2 infections in patients with IEM are generally limited to case reports. Here, we aimed to evaluate the clinical findings of coronavirus disease 2019 (COVID-19) and describe the impact of severe acute respiratory syndrome coronavirus 2 infections on metabolic outcomes in IEM patients. METHODS: Patients who were diagnosed with different types of IEM and developed microbiologically confirmed COVID-19 infection were included. Clinical findings and laboratory results were recorded retrospectively in terms of both IEM and COVID-19. RESULTS: Eleven patients with diagnosis of intoxication type metabolic disorders, five patients with energy metabolism disorders, and six patients with complex molecular disorders were enrolled. The most frequent clinical finding was fever (52.1%) followed by fatigue/myalgia (47.8%). None of the patients was younger than 1 year. None of the patients presented severe or critical disease. In terms of metabolic decompensation, two patients diagnosed with propionic acidemia, one patient with methylmalonic acidemia and one patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency presented clinical and biochemical findings of an acute metabolic attack. CONCLUSIONS: Based on our results, IEM are not found to be an additional risk factor for severe COVID-19 infection. However, patients with intoxication type and energy metabolism disorders should be considered as a vulnerable population for COVID-19 and have a major risk of developing acute metabolic decompensation that can lead to life-threatening complications.

The Impact of Telemedicine for Monitoring and Treatment of Phenylketonuria Patients on Metabolic Outcome During Coronavirus Disease-19 Outbreak.

Introduction: The prognosis of phenylketonuria (PKU) in terms of neurocognitive outcome is directly related to lifelong phenylalanine (Phe) levels and adherence to treatment. Monitoring and treatment of PKU patients can be complicated in challenging circumstances as pandemics. This study aims to evaluate the impact of telemedicine for monitoring and treatment of PKU patients on metabolic outcome during coronavirus disease-19 (COVID-19) outbreak. Materials and Methods: Patients who were diagnosed as PKU and treated with low Phe diet, tetrahydrobiopterin (BH4), or BH4 adjunct with low Phe diet were enrolled. Study period was divided into two periods: prepandemic period wherein patients were followed up in outpatients' clinic and during pandemic wherein telemedicine was used. Demographic findings, laboratory results, and therapy responses were reviewed retrospectively and compared between the two periods. All procedures were in accordance with the ethical standards of the local ethical committee of Cerrahpasa Medical Faculty (17/11/2020-151640) and with the Helsinki Declaration of 1975, as revised in 2013. Results: Ninety-three (n = 93) patients were enrolled to this study. The ratio of the samples with Phe levels in the recommended ranges was found to be statistically higher during the pandemic wherein an online monitoring system was used in all treatment modalities (p< 0.05). The decrease in Phe washout frequency was statistically significant during the pandemic in the low Phe diet group (p < 0.05). Considering the relationship between Phe tolerance before and during the pandemic, a significant increase in Phe tolerance was noted during the pandemic in the low Phe diet group (p< 0.05). Conclusions: Telemedicine can be an appropriate and effective monitoring option for PKU patients during the COVID-19 pandemic.

Blood Pressure Variability in Fabry Disease Patients.

INTRODUCTION: Fabry disease is a rare metabolic, multisystemic, and X-linked lysosomal storage disorder. The involvement of the autonomic nervous system is well defined; however, data on the variability of the blood pressure (BP) and heart rate in Fabry disease are largely missing. In this study, we aimed to examine the circadian variations of BP and heart rate variability in Fabry disease patients. METHODS: We recruited 31 consecutive adult (age >18 years) Fabry disease patients (16 males and 15 females) who were regularly followed up in our outpatient clinic between July 2019 and March 2020. We performed ambulatory blood pressure monitoring and echocardiography in all patients. We used standard deviation (SD), coefficient of variation (CV), and average real variability as the measures of variability. We constructed 2 control groups for propensity score matching using age, sex, and eGFR parameters in the first group and adding antihypertensive drug use to the above parameters in the second group. RESULTS: All BP measurements were significantly lower in the FD group compared to that of the control groups, except the nighttime systolic BP. Regarding nondipping and reverse dipping statuses, FD patients and controls were similar. We found that none of the BP variability measures were higher in FD patients. Regarding heart rate variability data, both the nighttime SD and CV were significantly lower in FD patients compared to those of the controls. CONCLUSION: A decrease in heart rate variability, rather than an increase in BP variability, might be an early marker of autonomic involvement in FD.