Abstract Phenylketonuria (PKU) is an autosomal recessive defect affecting the metabolic pathway of phenylalanine (Phe), causing hyperphenylalaninemia and neurotoxicity. Diagnosis must occur in the neonatal period and treatment should begin as early as possible. Evidence implies that treatment adherence declines as age advances. The aim was to describe the diet of a subgroup of Chilean adults with PKU currently in follow-up. Fifty-three subjects (49% women) followed up between January 2021 to April 2023 were considered. The concentration of Phe (PheC) in dried blood spots measured by fluorometry and 24-hour dietary recalls were analyzed. The median PheC of the sample was 438µmol/L (interquartile range(IQR):351-585µmol/L). A protein intake of 1.35±0.3 gr/Kg/d was observed of which 87% came from the protein substitute without Phe. Participants had a median Phe intake of 459mg/d (IQR:327-976) and 13.1g/d of fiber intake. Most participants, 51% and 92% reported consuming fruits and vegetables, respectively, and 32% consumed Low-Protein foods. Regarding micronutrients, all participants exceeded 90% adequacy according to recommendations. For vitamin-D and vitamin-B12, 100% is provided by the protein substitute. According to our results, it is mandatory to establish transition programs toward adulthood, to constantly maintain good metabolic control, and to adapt diet therapy to their new lifestyle. (PKU Phe, , (Phe) neurotoxicity possible advances followup. followup follow up. follow-up Fiftythree Fifty three 49% 49 (49 women 202 considered (PheC 24hour hour 24 analyzed 438µmolL µmolL 438µmol L µmol interquartile rangeIQR351585µmol/L. rangeIQR351585µmolL rangeIQRµmolL range IQR 351 585µmol/L . 585µmol range(IQR):351-585µmol/L) 13503 1 35 0 3 1.35±0. grKgd gr Kg d 87 459mgd mgd 459mg mg IQR327976 327 976 (IQR:327-976 131gd gd 13 1g g 51 92 vegetables respectively 32 LowProtein Low Protein foods micronutrients 90 recommendations vitaminD vitamin D vitaminB12, vitaminB12 vitaminB B12, B12 B vitamin-B12 100 results adulthood control lifestyle (Phe 4 (4 20 2 rangeIQR351585µmol rangeIQR rangeIQR351585µmol/L 585µmolL range(IQR):351-585µmol/L 1350 1.35±0 8 IQR32797 97 (IQR:327-97 5 9 vitaminB1 B1 vitamin-B1 10 ( rangeIQRµmol 135 1.35± IQR3279 (IQR:327-9 vitamin-B 1.35 IQR327 (IQR:327- 1.3 IQR32 (IQR:327 1. IQR3 (IQR:32 (IQR:3 (IQR: (IQR

Abstract Hepatic glycogen storage diseases (GSD) are characterized by recurrent episodes of hypoglycemia, and anemia has been recognized as a frequent complication of these disorders.This was a convenience cross-sectional study to evaluate hepcidin and IL-6 concentrations in patients with hepatic GSD and their association with anemia and other parameters of iron metabolism.Levels of hepcidin, IL-6, and markers of iron metabolism were measured in 32 patients receiving uncooked cornstarch therapy for GSD (GSD Ia= 18; Ib= 7; III= 3; IXa= 3; IXb= 1; median age 9.5 years). IL-6 concentrations were compared to those of 8 individuals heterozygous for GSD. Nine patients were anemic and five patients had hepatic adenomas. IL-6 levels were higher in patients than in heterozygotes. Eight patients had hyperferritinemia, and one had elevated transferrin saturation as well. Hepcidin correlated positively with ferritin levels. IL-6 correlated with hemoglobin, iron, transferrin, and transferrin saturation. There was no correlation between hepcidin and IL-6 levels. Patients with GSD Ib had the highest IL-6 levels.Anemia is a common finding in hepatic GSD, especially in GSD Ib, the type of GSD associated with the highest IL-6 levels. These findings suggest that inflammation is strongly associated with development of anemia in GSD Ib. hypoglycemia disordersThis disorders This crosssectional cross sectional IL6 IL 6 IL- metabolismLevels Levels IL6, 6, 3 Ia 18 7 III IXa IXb 1 95 9 5 9. years. years . years) adenomas heterozygotes hyperferritinemia well hemoglobin levelsAnemia Anemia

Abstract Mucopolysaccharidosis type IH (MPS IH) is caused by homozygous IDUA gene pathogenic variants. This results in deficiency of the enzyme α-L-iduronidase (IDUA), which is necessary for the degradation of glycosaminoglycans (GAGs). This study outlines the long-term outcomes in adult Irish patients affected with MPS IH, who were followed up for mean 28 years post Haematopoietic Stem Cell Transplantation. Nineteen adult MPS IH patients underwent HSCT in childhood. The participant cohort represents 6 families. Among the 13 patients with Irish Traveller ethnicity, 6 patients were either siblings or first cousins. All these related patients were homozygous for p. Trp402Ter (W402X). Mean age at the first transplantation was 8 months (range 3-21). Five patients had undergone a second transplantation (n=5, 26%) in childhood, due to graft failure. None of the patients had a cardiac valve surgery at the time of the study. 14/19 patients had mild to moderate aortic or mitral valve insufficiency or stenosis. 3/19 patients used non-invasive ventilation at night. Two patients had tracheostomy in situ. Both sensorineural as well as conductive hearing defects. No corneal clouding post corneal transplantation (n=8) was observed. Six patients attended regular secondary school. Multidisciplinary follow-up is needed to address the disease specific complications in adulthood. variants αLiduronidase α L iduronidase IDUA, , (IDUA) GAGs. GAGs . (GAGs) longterm long term 2 Transplantation childhood families 1 ethnicity cousins p TrpTer Trp Ter W402X. W402X WX W X (W402X) range 321. 321 3 21 3-21) n=5, n5 n 5 (n=5 26% 26 failure 1419 14 19 14/1 stenosis 319 3/1 noninvasive non invasive night situ defects n=8 n8 (n=8 observed school followup follow adulthood (IDUA (GAGs (W402X 32 3-21 n=5 (n= 141 14/ 31 3/ n= 3-2 (n 3-

Abstract Medium chain acyl-coA dehydrogenase deficiency (MCADD), the most common fatty acid oxidation disorder, has been regarded as a relatively benign condition with low risk of mortality in patients with a known diagnosis, if adequate caloric intake is met. However, inadequate energy provision, as occurs in eating disorders, significantly amplifies the risk of metabolic decompensation. This case series describes four patients with MCADD and a concomitant eating disorder and aims to raise awareness of the potentially under-recognised coexistence of these conditions. All patients were female with signs of disordered eating in adolescence and young adulthood though latency in diagnosis was apparent. Three of the patients had low body mass index (BMI) and the other was overweight. Metabolic decompensation and hospitalisation occurred in three of four patients secondary to extreme risk-taking behaviour with caloric restriction. The coexistence of MCADD and eating disorders is of significant concern, placing the patient at substantial risk of decompensation in an otherwise relatively stable metabolic condition. Awareness of disordered eating in this population is paramount, as early recognition of signs and symptoms of eating disorders in the MCADD population may facilitate prompt intervention and avoidance of morbidity and potential mortality. acylcoA acyl coA MCADD, , (MCADD) met However provision underrecognised under recognised conditions apparent BMI (BMI overweight risktaking taking restriction concern paramount (MCADD

Abstract Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder, characterized by alterations in the catabolism of chylomicrons and by increased levels of plasma triglycerides. It has been shown that about 60-90% of FCS patients have biallelic mutations in the LPL gene and the remaining patients have mutations in genes encoding proteins closely related to LPL function. The objective of this manuscript is to illustrate the different clinical scenarios of FCS presentation, and to guide practitioners on the usefulness of genetic tests in each of them. To this end, several published papers about recommendations for the diagnosis of FCS are discussed briefly, in addition to the presentation of several hypothetical cases, highlighting different clinical presentations and possible associated genetic findings. These cases illustrate the multiplicity of potential aspects of family history, clinical manifestations, biochemical parameters, and patterns of genetic variants found in genomic analyses of FCS. (FCS disorder triglycerides 6090% 6090 60 90% 90 60-90 function them end briefly findings history manifestations parameters 609 6 9 60-9 60-

Abstract Fabry disease is a rare X-linked lysosomal storage disorder that causes progressive cellular accumulation of glycosphingolipids, leading to various end-organ manifestations such as chronic kidney disease and cardiomyopathy. Currently, troponin is the preferred biomarker to identify acute coronary syndromes and cardiac inflammation/myocarditis, as well as monitor myocardial damage. Macrotroponin is an immunoglobulin G-troponin bound complex with reduced clearance due to its higher molecular weight. This can cause false elevations in troponin, in the absence of myocardial damage, which has been reported in up to 5% of patients presenting to emergency departments in Australia. In this case series, we report on ten Fabry patients in whom macrotroponin was demonstrated after precipitation with polyethylene glycol (PEG). Of the 47 routine clinical samples of Fabry patients that were analysed, troponin was demonstrated to be elevated in 15 samples (32%), and ten of these demonstrated macrotroponin (21% of total, 67% of elevated troponin). This case series highlights the need to consider the possibility of macrotroponin in Fabry patients with elevated troponin. This relatively high prevalence raises the questions of whether Fabry patients are intrinsically more predisposed to macrotroponin and how this influences clinical management, which warrants further research. Xlinked X linked glycosphingolipids endorgan end organ cardiomyopathy Currently inflammationmyocarditis inflammation myocarditis inflammation/myocarditis damage Gtroponin G weight 5 Australia PEG. PEG . (PEG) 4 analysed 1 32%, 32 32% , (32%) 21% 21 (21 total 67 troponin) management research (PEG 3 (32% 2 (2 6 (32 ( (3

Abstract Introduction: The advent of newborn screening across India has led to an increase in the early diagnosis of inborn errors of metabolisms (IEMs). Aminoacidopathies, the group of inherited disorders of amino acid metabolisms are of particular important because of the ease of early diagnosis and the availability of effective treatment options. Unfortunately, the biological reference intervals for amino acids vary widely between different ethnic groups and geographical locations, thereby necessitating the need to establish a population specific reference interval for optimal diagnosis. Aims and objectives: Establishment of the biological reference interval for all amino acids in the Dried Blood Spots (DBS) of term neonates belonging to coastal Karnataka using High Performance Liquid Chromatography. Methods: Heel prick blood samples were collected from 175 healthy, term neonates on a filter paper. After safe transport to the laboratory, the amino acids were extracted using an appropriate solution, derivatized, and analyzed using high performance liquid chromatography. Mean, standard deviation, and 95% confidence interval of the mean were used to establish the reference interval. Students T-test was used to compare the differences in amino acids levels among different groups. Conclusions: The biological reference intervals obtained in this study was found to have significant variations from studies conducted elsewhere in the world. This puts into perspective the need to establish a population specific reference interval for these parameters to avoid potential misdiagnosis. This reference interval may also be adopted by other labs catering to new-born screening in the same geographical area. Introduction IEMs. IEMs . (IEMs) Aminoacidopathies options Unfortunately locations objectives DBS (DBS Chromatography Methods 17 healthy paper laboratory solution derivatized chromatography Mean deviation 95 Ttest T test Conclusions world misdiagnosis new born area (IEMs 1 9

Abstract Fabry disease (FD) is a rare, x-linked lysosomal storage disease caused by mutations in the GLA gene that leads to total or partial alfa galactosidase A deficiency. Its prevalence ranges between 1:117,000 and 1:8,454. Mutations in the GLA gene result in alpha galactosidase A deficiency leading to the progressive accumulation of globotriaosylceramide (Gb3) in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The cardiac manifestation most frequently found in FD is the presence of left ventricular hypertrophy (LVH) in a concentric pattern, although asymmetric forms are also reported. In clinical practice, it is often difficult to differentiate between FD and other diseases associated with LVH. In adults with LVH, a prevalence of FD of 3-5% has been reported. Therefore, diagnosing these patients is of fundamental importance, as specific treatment for FD has the potential to change the prognosis, especially if instituted early. The purpose of this article is to describe an algorithm developed through a thorough literature review to assist in the identification of FD in patients with cardiomyopathies. (FD rare xlinked x linked 1117,000 1117000 1 117,000 117 000 1:117,00 18,454. 18454 8,454. 8 454 1:8,454 Gb3 Gb (Gb3 heart kidneys skin eyes system scenarios LVH (LVH pattern reported practice 35% 35 3 5% 5 3-5 Therefore importance prognosis early cardiomyopathies 1117 1117,00 111700 117000 117,00 11 00 1:117,0 18 18,454 1845 8454 8,454 45 1:8,45 (Gb 3- 111 1117,0 11170 11700 117,0 0 1:117, 18,45 184 845 8,45 4 1:8,4 1117, 1170 117, 1:117 18,4 84 8,4 1:8, 1:11 18, 8, 1:8 1:1 1:

Abstract COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, first identified in China, which later gave rise to a global pandemic. Little is known about the impact of COVID-19 on patients with rare diseases. More than 8,000 rare diseases have been identified, which makes this quite a significant contingent of patients. This study aims to characterize SARS-CoV-2 infection in unvaccinated patients with rare diseases. Data were collected by means of a specific form distributed to medical teams involved in the care of rare diseases and disseminated to communities of patients with rare diseases via social networks in Brazil and Argentina. COVID-19 infection was characterized in 75 patients (82.7% with confirmatory tests), both pediatric and adult (age 6 months to 64 years), representing 40 different genetic and non-genetic rare diseases. Inborn errors of metabolism (IEM) accounted for most genetic cases. Fifty-nine patients (78.7%) required medical care, of which 17 (22.6%) required hospitalization. Three patients (4%) died due to complications from COVID-19 (Glycogenosis type II, 50 years old; Mitochondrial Myopathy, 11 years and Trisomy 18, 0.5 years). Extreme patient ages and diseases characterized by muscle involvement were associated with worse COVID-19 outcomes. COVID19 COVID 19 COVID-1 SARSCoV2 SARSCoV SARS CoV 2 SARS-CoV- virus China pandemic 8000 8 000 8,00 Argentina 7 82.7% 827 82 (82.7 tests, tests , tests) age years, years) 4 nongenetic non IEM (IEM cases Fiftynine Fifty nine 78.7% 787 78 (78.7% 1 22.6% 226 22 (22.6% hospitalization 4% (4% Glycogenosis II 5 old Myopathy 18 05 0 0. years. . outcomes COVID1 COVID- SARS-CoV 800 00 8,0 82.7 (82. 78.7 (78.7 22.6 (22.6 (4 80 8, 82. (82 78. (78. 22. (22. ( (8 (78 (22 (7 (2

Abstract Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) caused by deficiency of lysosomal N-sulphoglucosamine sulphohydrolase, which is one of four enzymes involved in heparan sulfate degradation. Traditional methods used for MPS IIIA diagnostics usually constitute of selective screening, based on the analysis of urinary glycosaminoglycans, further enzymatic assays in leukocytes, and mutation analysis. Nowadays, some LSDs, including mucopolysaccharidoses, can be precisely diagnosed by mass spectrometry-based techniques. Up to this date, there are no comprehensive studies of MPS IIIA diagnostics by MALDI-TOF analysis of free oligosaccharides in urine published. In the presented work, MALDI-TOF/TOF analysis of permethylated oligosaccharides was performed to obtain the set of glyco-biomarkers that together form the specific fingerprint of this disease. Early and accurate diagnostics of MPS IIIA is crucial to stabilize the progressive cellular damage and improve the overall well-being of patients. LSD (LSD Nsulphoglucosamine N sulphoglucosamine sulphohydrolase degradation screening glycosaminoglycans leukocytes Nowadays LSDs mucopolysaccharidoses spectrometrybased spectrometry techniques date MALDITOF MALDI TOF published work MALDITOF/TOF MALDITOFTOF TOF/TOF glycobiomarkers glyco biomarkers disease wellbeing well being patients TOFTOF

ABSTRACT In Cuba, newborn screening (NBS) for cystic fibrosis (CF) was introduced in January 2019. The results from the first three years of the CF NBS program are presented. An IRT/IRT protocol was followed using a cut-off value of 50 ng/mL. In this period 281,717 neonates were screened, 2,197 samples had increased IRT values, and a second sample was necessary (recall rate=0.78%). In 686 (0.24%) neonates, IRT was still elevated, and they were referred for clinical evaluation. Twenty-one children were confirmed by sweat test and molecular biology. Eighteen newborns presented variant F508del. A false negative case was reported. Demographic data of 32,764 neonates were collected. The average age of sampling was six days with results available at 11 days of life, but 1.7% of the samples were collected 20 days after birth. The mean IRT value was 12.7±11.7 ng/mL (ranging 0-283 ng/mL) with a calculated 98.5 percentile value of 42.4 ng/mL. On average, the samples were processed five days after collection and two days after they were received at the laboratory. Although CF NBS program in Cuba is just beginning, it can be predicted that CF will be one of the most frequent inherited-metabolic diseases in the Cuban population. (NBS (CF 2019 IRTIRT cutoff cut off 5 ngmL ng mL 281717 281 717 281,71 screened 2197 2 197 2,19 values recall rate=0.78%. rate078 rate rate=0.78% . 0 78 rate=0.78%) 68 0.24% 024 24 (0.24% elevated evaluation Twentyone Twenty biology F508del Fdel F del reported 32764 32 764 32,76 1 life 17 7 1.7 birth 127117 12 12.7±11. ranging 0283 283 0-28 985 98 98. 424 42 4 42. laboratory beginning inheritedmetabolic inherited metabolic population 201 28171 28 71 281,7 219 19 2,1 rate07 rate=0.78 6 0.24 02 (0.24 3276 3 76 32,7 1. 12711 12.7±11 028 0-2 9 2817 281, 21 2, rate0 rate=0.7 0.2 (0.2 327 32, 1271 12.7±1 0- rate=0. 0. (0. 127 12.7± rate=0 (0 12.7 rate= ( 12.

Abstract Congenital muscular dystrophies (CMDs) are inherited, progressive and heterogeneous muscle disorders. A group of CMDs are dystroglycanopathies, also called α-dystroglycanopathies, where there is an abnormal glycosylation of protein α-dystroglycan. Hypoglycosylation of α-DG results in different severities of congenital muscular dystrophies and they present with progressive muscle weakness and loss of motor functions. This article first focuses on the CMDs, their classification according to the observed symptoms or the protein involved in the resulting phenotype. We then focus on dystroglycanopathies, the importance of its correct O-glycosylation of the α-dystroglycan given its important structural function, considering the enzymes involved in said glycosylation and the phenotypes that can result, to finally address current therapeutics for these diseases with the aim of increasing current knowledge. (CMDs inherited disorders dystroglycanopathies αdystroglycanopathies, αdystroglycanopathies α α-dystroglycanopathies αdystroglycan. αdystroglycan dystroglycan. dystroglycan αDG DG functions phenotype Oglycosylation O function result knowledge

Abstract Screening newborns for genetic and other diseases is one of the most effective ways to improve health and reduce disease in a population. In developed countries, newborn screening has been a cornerstone of public health for decades. In many developing countries, however, newborn screening is still in its infancy. Many countries still lack screening programs. When a program is available, it generally lacks well-defined criteria on which decision-makers can justify the choice of diseases screened for and the methods used. One of the reasons put forward to understand this observation is the fact that little consideration is given by decision-makers to economic evaluations as a pillar of decision-making, as is the case in industrialized countries. This article provides a brief description of the challenges of using economic evaluation of newborn screening in developing countries. This will be illustrated by the example of the national newborn screening program in Vietnam. population decades however infancy programs available welldefined well defined decisionmakers decision makers used decisionmaking, decisionmaking making, making decision-making Vietnam

Abstract Cystic fibrosis (CF) is an autosomal recessive disorder and is caused by variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. We aimed to study the frequency of the F508del variant, the most common variant worldwide, in patients with CF from Paraguay. The frequency of the F508del variant in Paraguayan patients with a clinical diagnosis of CF was assessed using a polymerase chain reaction followed by the sequencing of the PCR products. 43 of the 86 patients (50%) were homozygous for the F508del variant, 28 were heterozygous (32.56%), and the remaining 15 (17.44%) were non-carriers. In terms of alleles, there were 114 mutated (114/172 or 66.28%) and 58 did not correspond to this variant (58/172 or 33.72%). This is the first study of the frequency of the F508del variant in patients with CF in Paraguay. This information is of utmost relevance when planning and offering treatments from health services. (CF CFTR (CFTR gene Fdel F del worldwide Paraguay products 4 8 50% 50 (50% 2 32.56%, 3256 32.56% , 32 56 (32.56%) 1 17.44% 1744 17 44 (17.44% noncarriers. noncarriers non carriers. carriers non-carriers alleles 11 114/172 114172 172 (114/17 66.28% 6628 66 5 58/172 58172 (58/17 33.72%. 3372 33.72% . 33 72 33.72%) services (50 325 32.56 3 (32.56% 17.44 174 (17.44 114/17 11417 (114/1 66.28 662 6 58/17 5817 (58/1 337 33.72 7 (5 32.5 (32.56 17.4 (17.4 114/1 1141 (114/ 66.2 58/1 581 (58/ 33.7 ( 32. (32.5 17. (17. 114/ (114 66. 58/ (58 33. (32. (17 (11 (32 (1 (3