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 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 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 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

Abstract Mucopolysaccharidosis (MPS) is a group of metabolic disorders caused by the deficiency or complete absence of certain lysosomal enzymes responsible for the breakdown of mucopolysaccharides, causing an accumulation of glycosaminoglycans (GAGs) throughout the body. Mucopolysaccharidosis type I (MPS I), also called Hurler syndrome, is an autosomal recessive lysosomal storage disorder resulting from a deficiency of the enzyme α-L-iduronidase. This report aims to present the clinical findings and diagnosis of a 21-month-old female with no history of similar cases in their previous generations. The diagnosis was considered based on the clinical and radiological characteristics of Hurler syndrome (HS) and confirmed biochemically, becoming the first confirmed case in the Dominican Republic. MPS mucopolysaccharides GAGs (GAGs body I, , I) αLiduronidase. αLiduronidase α L iduronidase. iduronidase α-L-iduronidase 21monthold monthold 21 month old generations HS (HS biochemically Republic 2

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 We aimed to characterize the clinical spectrum of patients diagnosed with SRD5A3-CDG, a subtype of congenital disorders of glycosylation (CDG) due to variants in the steroid 5a-reductase type 3 (SRD5A3) gene. It presents with multi-systemic involvement including neurological disability, dermatologic abnormalities, and ophthalmological defects. We conducted a cross-sectional study of children (n=6, ages 4-16 years) with a confirmed diagnosis of SRD5A3-CDG (c.57G>A, p.W19X). Families completed a detailed medical history questionnaire, two quality of life measures, and an adaptive behavior scale. Prevalent clinical features in our cohort included visual impairment (6/6), developmental delay (6/6), nystagmus (5/6), retinal dystrophy (4/6), and hypotonia (3/6). The Vineland Adaptive Behavior Scales demonstrated deficits across all functional domains (Composite Mean 36.17 ± 26.88), although one child did not show significant deficits. The QI-Disability Form demonstrated a mean total score of 64.8 (±12.7), and the PedsQL-Family Impact Module demonstrated a mean total score of 56.5 (±31.5). Vineland composite scores did not correlate with levels of disability captured by the QI-Disability Form (Pearson Correlation range -0.63 to +0.69, p>0.05 on all subscales). Ultimately, despite genotypic homogeneity, there is notable variability in adaptive functioning and quality of life among affected children that does not correlate with age. SRD5A3CDG, SRD5A3CDG SRDACDG SRD5A3 CDG, CDG SRD A (CDG 5areductase areductase 5a reductase SRDA (SRD5A3 gene multisystemic multi systemic abnormalities defects crosssectional cross sectional n=6, n6 n 6 (n=6 416 4 16 4-1 years c.57G>A, c57GA cGA c 57G G (c.57G>A p.W19X. pW19X pWX p.W19X . p W19X W X p.W19X) questionnaire measures scale 6/6, 66 6/6 , (6/6) 5/6, 56 5/6 5 (5/6) 4/6, 46 4/6 (4/6) 3/6. 36 3/6 (3/6) Composite 3617 17 36.1 26.88, 2688 26.88 26 88 26.88) QIDisability QI Disability 648 64 8 64. ±12.7, 127 ±12.7 12 7 (±12.7) PedsQLFamily PedsQL Family 565 56. ±31.5. 315 ±31.5 31 (±31.5) Pearson 0.63 063 0 63 -0.6 069 69 +0.69 p005 05 p>0.0 subscales. subscales subscales) Ultimately homogeneity age SRD5A (SRD5A n=6 (n= 41 1 4- c.57G>A GA pW WX 6/ (6/6 5/ (5/6 4/ (4/6 3/ (3/6 361 36. 268 26.8 2 ±12. (±12.7 ±31. (±31.5 0.6 06 -0. +0.6 p00 p>0. n= (n (6/ (5/ (4/ (3/ 26. ±12 (±12. ±31 (±31. 0. -0 +0. p0 p>0 (6 (5 (4 (3 ±1 (±12 ±3 (±31 - +0 p> ( (±1 (±3 + (±

Abstract The familial chylomicronemia syndrome (FCS) is characterized by very high levels of circulating triglycerides. FCS is caused by lipoprotein lipase (LPL) deficiency resulting from homozygous or biallelic loss-of-function variants in the LPL or other related genes. Here, we report a case of severe hypertriglyceridemia refractory to conventional therapy in a male patient diagnosed at 33 years of age. LPL activity was below 20%. During the clinical course, the patient developed severe acute pancreatitis in addition to other complications. Two heterozygous variants (c.984G>A and c.1139+6T>C) which had not been previously reported in the major databases were identified in the LPL gene. Treatment with volanesorsen was proposed based on its approved indication as an adjunct to diet in adult patients with confirmed FCS and at high risk for pancreatitis. Volanesorsen was effective and well-tolerated, and the patient did not experience abdominal pain or any other manifestations. The assessment of genetic characterization is essential to guide treatment decisions during follow-up, in addition to the patient’s history, their comorbidities and clinical stigmas. (FCS triglycerides (LPL lossoffunction loss function genes Here 3 age 20 20% course complications c.984G>A c984GA cGA c 984G A G c.1139+6T>C c11396TC cTC 1139 6T C T gene welltolerated, welltolerated well tolerated, tolerated well-tolerated manifestations followup, followup follow up, up follow-up s history stigmas 2 GA TC 113 11 1

Abstract Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by reduced or absent activity of the enzyme α-galactosidase A. Due to systemic accumulation of glycolipids, FD phenotype is diverse, and diagnosis may be challenging. Clinical manifestations include small fiber neuropathy, renal dysfunction, cardiac involvement, cerebrovascular disease, among others. In the present study, we describe biopsy proven small fiber neuropathy and subclinical cardiac involvement in two cousins diagnosed with FD secondary to a recently described pathogenic variant, highlighting the importance of diagnostic tools to document organ damage and allow early treatment. (FD Xlinked X linked αgalactosidase α galactosidase A glycolipids diverse challenging dysfunction others study variant treatment

Abstract Mucopolysaccharidosis type II (MPS II) is a rare genetic, multiorgan disease. Little information about the Brazilian context is available to date; thus, this descriptive subgroup analysis was conducted on Brazilian data from the Hunter Outcome Survey (HOS), including clinical characteristics among MPS II patients from Brazil. HOS is a global, multi-center, long-term, observational registry of patients with MPS II (NCT03292887). Variables related to organ system involvement, signs and symptoms, surgical procedures and survival among Brazilian patients were extracted from HOS database. Data from 153 Brazilian patients with MPS II were analyzed. Musculoskeletal (96.6%), abdomen/gastrointestinal (95.2%), neurological (88.7%), pulmonary (86.2%), and ear (81.3%) were the most frequently observed organ/systems involved. Regarding signs and symptoms, the most prevalent symptom was coarse facial features consistent with the disease (94.6%), followed by joint stiffness and limited function (89.3%), hernia (84.2%) and hepatomegaly (82.2%). Median survival time was 22.0 years, and the major cause of death was respiratory failure (31.8%). These data may be helpful to understand disease characteristics and to help improve the quality of MPS II patient care in Brazil. genetic date thus HOS, , (HOS) Brazil global multicenter, multicenter multi center, center multi-center longterm, longterm long term, term long-term NCT03292887. NCT03292887 NCT . (NCT03292887) involvement symptoms database 15 analyzed 96.6%, 966 96.6% 96 6 (96.6%) abdomengastrointestinal abdomen gastrointestinal 95.2%, 952 95.2% 95 2 (95.2%) 88.7%, 887 88.7% 88 7 (88.7%) 86.2%, 862 86.2% 86 (86.2%) 81.3% 813 81 3 (81.3% organsystems systems involved 94.6%, 946 94.6% 94 (94.6%) 89.3%, 893 89.3% 89 (89.3%) 84.2% 842 84 (84.2% 82.2%. 822 82.2% 82 (82.2%) 220 22 0 22. years 31.8%. 318 31.8% 31 8 (31.8%) (HOS NCT0329288 (NCT03292887 1 96.6 9 (96.6% 95.2 (95.2% 88.7 (88.7% 86.2 (86.2% 81.3 (81.3 94.6 (94.6% 89.3 (89.3% 84.2 (84.2 82.2 (82.2% 31.8 (31.8% NCT032928 (NCT0329288 96. (96.6 95. (95.2 88. (88.7 86. (86.2 81. (81. 94. (94.6 89. (89.3 84. (84. 82. (82.2 31. (31.8 NCT03292 (NCT032928 (96. (95. (88. (86. (81 (94. (89. (84 (82. (31. NCT0329 (NCT03292 (96 (95 (88 (86 (8 (94 (89 (82 (31 NCT032 (NCT0329 (9 ( (3 NCT03 (NCT032 NCT0 (NCT03 (NCT0 (NCT

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 Data on Mucopolysaccharidosis type II (MPS II) in Latin America are scarce. This retrospective database study, using data from the Informatics Department of the Brazilian Health System (DATASUS), aimed to estimate the prevalence of MPSII in Brazil from 2008 to 2020 and to describe demographic and clinical profiles from patients under treatment. The study population was derived from DATASUS records of MPS II (ICD-10 E76.1) diagnosed in Brazil. Initially 455 patients were found, but only 181 patients who were receiving idursulfase treatment were included in this study. Among these cases, as expected in a X-linked disease, all were males and 40% of the cases were recorded in the Southeast region, and another 34% in the Northeast region. The biggest proportion of patients (39%) were diagnosed when they were 10-19 years old. There are 212 clinical conditions associated with MPS II, although the main comorbidities related to MPSII include: abdominal/inguinal hernia, respiratory complications, and carpal tunnel syndrome. Respiratory disorders were the fifth most frequent comorbidity recorded in these patients. The healthcare professionals in Brazil more involved in the diagnosis of MPS II were radiologists, followed by geneticists and cardiologists. Despite some limitations, DATASUS is a relevant database to provide information on rare diseases such as MPS II. Most cases were reported in southeast and northeast regions, respectively. This information is crucial to help design targeted public policies. scarce DATASUS, , (DATASUS) 200 202 ICD10 ICD 10 (ICD-1 E76.1 E761 E E76 1 45 found 18 Xlinked X linked disease 40 region 34 39% 39 (39% 1019 19 10-1 old 21 include abdominalinguinal abdominal inguinal hernia complications syndrome radiologists cardiologists limitations regions respectively policies (DATASUS 20 ICD1 (ICD- E76. E7 4 3 (39 101 10- 2 (ICD (3 (