Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Emerging trends in pediatric candidemia: mapping the rise in Candida parapsilosis incidence and antifungal resistance in Turkey.

Candidemia is emerging as a significant concern in children, particularly among those with underlying conditions like malignancies or prematurity. The interpretation of epidemiological data on candidemias and their antifungal resistance plays a vital role in aiding diagnosis and guiding clinicians in treatment decisions. From 2014 to 2021, a retrospective analysis was conducted in Istanbul, Turkey; comparing Candida albicans and non-albicans (NAC) spp in both surviving and deceased groups. Furthermore, an examination of Candida parapsilosis and other species was performed, assessing various clinical and laboratory parameters. Among 93 patients, with a median age of 17 months, C. parapsilosis emerged as the predominant isolated species (44%), followed by C. albicans (34.4%). Resistance to fluconazole, voricanozole, and echinocandins, along with a history of broad-spectrum antibiotic use were found to be significantly higher in the non-albicans Candida group compared to C. albicans group. In the C. parapsilosis group, statistically lower age was identified in comparison to the other groups (P = .018). In addition, high fluconazole and voriconazole resistance was detected in Candida parapsilosis spp. Our study highlights a notable prevalence of C. parapsilosis, particularly in younger children, which is different from similar studies in childhood. This trend may be attributed to the common use of total parenteral nutrition and central venous catheter in gastrointestinal disorders and metabolic diseases. Furthermore, as anticipated, high azole resistance is noted in C. parapsilosis and other non-albicans Candida species. Interestingly, resistance to both amphotericin B and echinocandins within this group has been notably high. It is crucial to emphasize the considerable antifungal resistance seen in C. parapsilosis isolates.

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.

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.

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 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.

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.

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.

Altered immune response in organic acidemia.

BACKGROUND: Most patients with organic acidemia suffer from recurrent infections. Although neutropenia has been reported in multiple studies, other components of the immune system have not been evaluated thoroughly. This study was conducted to assess the immune status of patients with organic acidemia (OA). METHODS: Thirty-three patients with OA who were followed up in Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine, Nutrition and Metabolism Department and a total of 32 age- and sex-matched healthy controls were enrolled to the study. The demographic and clinical data were recorded retrospectively from patient files. Complete blood counts, immunoglobulins, and lymphocyte immunophenotyping were recorded prospectively in a symptom- (infection-) free period. RESULTS: Of the 33 patients enrolled to the study, 21 (88%) were diagnosed with methylmalonic acidemia, 10 (33%) with propionic acidemia, and two (6.6%) with isovaleric acidemia. The mean age of the patients with OA and healthy subjects were 5.89 ± 4.11 years and 5.34 ± 4.36, respectively (P = 0.602). Twenty-nine (88%) of the patients had experienced frequent hospital admission, 13 (39%) were admitted to pediatric intensive care unit, and 18 (55%) suffered from sepsis. Naïve helper T cells and recent thymic emigrants were significantly lower in OAs (P < 0.001). Various defects in humoral immunity have also been documented including memory B cells and immunoglobulins. CONCLUSIONS: Patients with OAs may show adaptive immune defects rendering them susceptible to infections. Metabolic reprogramming based on nutritional modifications may be a promising therapeutic option in the future.

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.

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.

Evaluation of QuantiFERON tuberculosis Gold In-Tube assay for diagnosis of active tuberculosis in children.

AIM: Tuberculin skin test (TST) is still used in diagnostic algorithms of childhood tuberculosis (TB). QuantiFERON TB Gold In-Tube assay (QFT-GIT) is an alternative test to TST based on the detection of interferon-gamma release upon in vitro induction of peripheral mononuclear cells by TB antigens. In this study, we aimed to determine the diagnostic value and performance of QFT-GIT for active childhood TB. METHODS: This retrospective study was conducted between January 2005 and December 2011 in three referral hospitals in Turkey with 124 children who were diagnosed with definite active TB. Sensitivity values of TST and QFT-GIT were determined by accepting the microbiological confirmation as the gold standard of diagnosis of TB. RESULTS: In our study, sensitivity of QFT-GIT and TST was found to be 65 and 66% respectively. However, combined usage of QFT-GIT and TST was found to be more sensitive (85%) than TST or QFT-GIT alone (P < 0.0001). Although negative results of QFT-GIT or TST did not exclude the diagnosis of active TB in children, their positivity supported the diagnosis. Specificity could not be measured as only microbiologically confirmed cases of Mycobacterium tuberculosis disease were enrolled in the study. CONCLUSION: Although sensitivities of TST and QFT-GIT are too low to exclude active TB, their positivity supports diagnosis of active TB in children concomitant with signs and symptoms. QFT-GIT and TST should be used together to enhance diagnostic sensitivity and could help exclude a diagnosis of TB if the pretest probability is low.

Oxidative stress among L-2-hydroxyglutaric aciduria disease patients: evaluation of dynamic thiol/disulfide homeostasis.

L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive disorder that is caused by deficiency of 2-hydroxyglutarate dehydrogenase. Pathophysiology of brain damage is poorly understood. In recent years, it was proposed that oxidative stress was elevated and led to brain injury. Aim of this study is to evaluate thiol/disulphide homeostasis as an indicator of oxidative stress in L2HGA patients who have been receiving antioxidant treatment. Sixteen L2HGA patients and 16 healthy individuals were included in the study. All the L2HGA patients were regularly followed up and presented neurological dysfunction at different grades. Fourteen patients had been receiving antioxidant treatment. Serum native thiol (-SH), total thiol (-SH + -S-S-) and disulphide (-S-S) levels were measured. Disulphide/native thiol, disulphide/total thiol and native thiol/total thiol ratios were calculated from these values. No significant difference was observed in -SH, -SH + -S-S-, -S-S levels between two groups. In addition to that, no increase of disulphide/native thiol and disulphide/total thiol ratios was detected. Thiol/disulphide homeostasis parameters were also compared between patients who had been receiving and not receiving antioxidant therapy; and between different types of antioxidant therapy and the results did not point to any significant difference. This is the first study that evaluates dynamic thiol/disulphide homeostasis as an indicator of oxidative stress in L2HGA and it has one of the largest sample sizes among previous studies. In our study we suggest that antioxidant therapy should be effective in preventing oxidative stress in L2HGA patients, which has been reported in previous studies and should be a part of standard therapy.

Coagulation Disturbances in Patients with Argininemia.

BACKGROUND: Argininemia is an autosomal recessive urea cycle disorder (UCD). Unlike other UCD, hyperammonemia is rarely seen. Patients usually present in childhood with neurological symptoms. Uncommon presentations like neonatal cholestasis or cirrhosis have been reported. Although transient elevations of liver transaminases and coagulopathy have been reported during hyperammonemia episodes, a permanent coagulopathy has never been reported. METHODS: In this retrospective study, coagulation disturbances are examined in 6 argininemia patients. All of the patients were routinely followed up for hepatic involvement due to argininemia. Laboratory results, including liver transaminases, albumin, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and clotting factor levels, were assessed in all of the patients. RESULTS: All of the patients had a prolonged PT and an increased INR, while none of the patients had a prolonged aPTT. Five patients had slightly elevated liver transaminases. A liver biopsy was performed in 1 patient but neither cirrhosis nor cholestasis was documented. Five of the 6 patients had low factor VII and factor IX levels, while other clotting factors were normal. CONCLUSIONS: Argininemia patients should be investigated for coagulation disorders even if there is no apparent liver dysfunction or major bleeding symptoms.

Evaluation of dynamic thiol/disulphide homeostasis as a novel indicator of oxidative stress in maple syrup urine disease patients under treatment.

Maple syrup urine disease (MSUD) is a metabolic disorder that is caused by deficiency of branched-chain α-keto acid dehydrogenase complex. Although accumulation of toxic metabolites is associated with neurotoxicity, mechanisms underlying brain damage remain unclear. Aim of this study is to evaluate thiol/disulphide homeostasis as a novel indicator of oxidative stress in MSUD patients under treatment. Twenty patients with MSUD and 20 healthy individuals were included in study. All patients were under regular follow-up and had a good metabolic control. Serum native thiol (-SH), total thiol (-SH + -S-S-), disulphide (-S-S) levels were measured in all subjects. Disulphide/native thiol, disulphide/total thiol and native thiol/total thiol ratios were calculated from these values. Simultaneous blood sampling for plasma quantitative amino acid analysis was performed in both groups. Any significant difference was not observed in -SH, -SH + -S-S-, -S-S levels between two groups. In addition no increase of disulphide/native thiol and disulphide/total thiol ratios was detected in patient group. This study is the first study that evaluates dynamic thiol/disulphide homeostasis as an indicator of oxidative stress in MSUD patients. Among previous studies that were made to determine oxidative stress in treated MSUD patients, this study had the largest sample size also. In recent studies, it was claimed that oxidative stress could be responsible from neurotoxicity even in treated patients. Here, dynamic thiol/disulfide homeostasis status showed that providing good metabolic control in MSUD patients prevent oxidative stress. Under regular follow-up and good compliance with diet, additional antioxidant therapies would possibly not be necessary.

Hereditary tyrosinemia type 1 in Turkey: twenty year single-center experience.

BACKGROUND: Hereditary tyrosinemia type 1(HT1) is a chronic disorder leading to severe hepatic, renal and peripheral nerve damage if left untreated. Despite nitisinone treatment HT1 still carries the risks of hepatocellular carcinoma (HCC) and neuropsychological outcome. METHODS: A retrospective single center study was carried out based on the phenotype, therapy and outcome in 38 Turkish patients with HT1 diagnosed during the last 20 years. RESULTS: None of the patients was diagnosed on newborn screening. The patients were grouped according to acute, subacute and chronic forms of the disorder. The main clinical manifestations were hepatosplenomegaly, liver and renal tubular dysfunction. Thirty-six patients were treated with nitisinone. The mean duration of nitisinone treatment was 64 months and the mean dosage was 1.2 mg/kg/day. Dietary compliance problems were frequent. Eleven patients had cognitive evaluation (mean total IQ, 84 points). Six patients had living donor liver transplantation despite nitisinone treatment: three due to suspected HCC, two for non-compliance to diet, and one for both, at a median age of 90 months. CONCLUSION: Nitisinone treatment is effective and improves both short- and long-term prognosis of HT1. Early diagnosis on newborn screening is needed because delay in treatment increases the risk of the persistence of hepatic disease and HCC. Interruption of the drug can lead to re-occurrence of hepatocellular damage and neurological crisis. Increased α-fetoprotein and new hypoechoic nodule formation are the warning signs for HCC.

Comparison of Cost Analysis in Patients with Tetrahydrobiopterin-Responsive and Non-Responsive Phenylketonuria in Turkey.

Phenylketonuria is an inherited metabolic disorder that leads to neurobehavioral dysfunction. The main treatment is a low-phenylalanine diet and/or the cofactor tetrahydrobiopterin. Regular outpatient follow-up care and measurement of the phenylalanine levels in the blood are required. We aimed to analyze the economic burden of phenylketonuria on families and the state. The patients with phenylketonuria were divided into three groups according to their treatment: a low-phenylalanine diet group (n = 50), a tetrahydrobiopterin group (n = 44), and a group taking tetrahydrobiopterin together with the diet (n = 25). A comparative cost analysis was carried out. The annual economic burden to the state was calculated to average EUR 18,801 ± 15,345 and was lowest in the diet group, then in the tetrahydrobiopterin group, and highest in the tetrahydrobiopterin + diet group (p < 0.001). Out-of-pocket costs amounted to EUR 1531 ± 1173 per year, and indirect losses averaged EUR 2125 ± 1930 per year for all families. The economic loss was significantly lower in the families taking tetrahydrobiopterin than in the other groups (p = 0.001). The combined use of medical nutrition and BH4 treatments has been shown to increase the economic burden on the state. Reimbursing low-protein products and increasing the number of patients eligible for financial allowances may reduce the economic burden on families.

A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature.

Introduction: Acyl-CoA binding domain containing 5 (ACBD5) deficiency is a newly defined inborn peroxisomal disorder with only 7 patients reported to date. Herein, we report a patient with ACBD5 deficiency who was diagnosed after a complicated diagnostic process. Case Presentation: A 6-year-old male patient was admitted with complaints of neuromotor regression and visual disturbances. He had spastic paraparesis dominated with axial hypotonic posturing and horizontal nystagmus. His very-long-chain fatty acid levels were within normal ranges with a slightly elevated C26:0/C22:0 ratio. Brain magnetic resonance imaging revealed white matter involvement. Clinical exome sequencing displayed a novel homozygous intronic splice site variant (c.936 + 2T>G) in the ACBD5 (NM_145698.5) gene. Conclusion: With this report, a novel variant in ACBD5 deficiency was described. Macular dystrophy was demonstrated with optical coherence tomography imaging for the first time in the literature in ACBD5 deficiency. In order to contribute to the knowledge about the clinical, biochemical, and genetic spectrum of ACBD5 deficiency, new patients need to be defined.

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.

A New Perspective On Arterioectatic Spinal Angiopathy with a Reversible Pattern: Cause or Consequence?

OBJECTIVE: In 2022, arterioectatic spinal angiopathy (AESA) of childhood was reported as a fatal, progressive, multi-segment myelopathy associated with a unique form of non-inflammatory spinal angiopathy involving diffuse dilatation of the anterior spinal artery and cord congestion in children. In this study, we present four more cases of AESA, using early and long-term conventional imaging and flat detector computed tomography angiography (FDCTA) imaging to assess the probability of disease regression and prevent unnecessary interventions. METHODS: We retrospectively reviewed the clinical and radiological findings of four patients with AESA seen in two neuroradiology departments between 2014 and 2023. RESULTS: The study included three boys and one girl. Two of the boys were siblings. Although the clinical and radiological presentation in the early stages of the clinical course overlapped the definition of AESA, the clinical course was more benign in three of the cases. The clinical courses of the two siblings with monosegmental cord involvement and largely reversible radiological findings suggest that some of the features in the initial definition of the disease cannot be standardized for all patients. The siblings had a mutation of the NDUFS gene, which is involved in mitochondrial function and clinical-radiological reversibility in these patients. CONCLUSION: Many mitochondrial diseases, such as this NDUFS mutation, present with myelopathy, and mitochondrial diseases can sometimes show spontaneous recovery. It is crucial to identify other genetic mutations or environmental factors that trigger the accompanying vascular ectatic findings in AESA in larger multicenter studies to prevent its potential lethal course and possible unnecessary surgical-endovascular interventions.