INTRODUCTION:Mucopolysaccharidosis type IVA (MPS IVA) is an ultra-rare lysosomal storage disease treated with enzyme replacement therapy (ERT) using elosulfase alfa (ELA). However, ELA may induce immediate hypersensitivity reactions (I-HSRs), including anaphylaxis, and data on ELA-induced I-HSRs and rapid drug desensitization (RDD) are limited. This study aimed to evaluate the frequency, phenotypes, risk factors, and desensitization outcomes of ELA-induced I-HSRs in children with MPS IVA. METHODS:Medical records of patients with MPS IVA between April 2004 and July 2023 were analyzed. I-HSRs were classified as type I, cytokine release syndrome (CRS), or mixed-type. Diagnostic testing and RDD protocols were evaluated. Logistic regression and receiver operating characteristic analyses identified predictors of I-HSR occurrence. RESULTS:Thirty-one patients were included (48% male); the median age at diagnosis was 45 months (6-203) and follow-up was 109 months (1-234). ERT was given to 25 patients (81%) for a median of 66 months (1-98). I-HSRs occurred in 28%; 71% were type I (all consistent with anaphylaxis), 14% were mixed, and 14% were CRS; all were moderate to severe. Patients with I-HSRs had a significantly lower age at diagnosis (p = 0.021); diagnosis ≤30 months predicted I-HSR (area under the ROC curve = 0.80; sensitivity 71.4%, specificity 83.3%, odds ratio 12.5; p = 0.016). Four patients underwent 490 RDDs, with only one mild breakthrough reaction (0.2%). CONCLUSION:ELA-induced I-HSRs are relatively frequent in MPS IVA, occur predominantly as type I phenotypes, and are clinically significant. Younger age at diagnosis (≤30 months) markedly increases the risk of I-HSRs, and RDD is safe and effective in the long term.

Fabry disease (FD) is a rare inherited X-linked lysosomal disorder caused by the deficiency or dysfunction of the enzyme α-galactosidase. This leads to a detrimental accumulation of globotriaosylceramide (Gb3) within multiple cell types. Enzyme replacement therapies (ERTs), including agalsidase alfa and agalsidase beta, can diminish Gb3 levels. Published real-world data on the time, cost and burden associated with the administration of ERTs are limited. These evidence gaps were addressed by generating real-world data quantifying the burden of agalsidase alfa and beta infusions for FD treatment. The study (ClinicalTrials.gov number: NCT04281537) comprised a prospective time-and-motion and a cross-sectional evaluation of self-reported burden and outcomes associated with ERT administration (including work productivity and out-of-pocket costs) from multiple perspectives (healthcare professionals [HCPs], patients, and caregivers). To assess patient/caregiver experience and burden of ERT, the primary objective was to quantify the total time spent by HCPs in the preparation and administration of a single dose of ERT. Overall, 76 patients and 6 caregivers were included. Of the 76 patients, (Brazil [n = 23], Japan [n = 4], Taiwan [n = 30] and Turkey [n = 19]), 41

Glycogen storage disease type 1 (GSD1), which is categorized into GSD1a and GSD1b, is caused by disease-causing genetic variants in G6PC or SLC37A4 genes, respectively. The aim of this study was to present clinical characteristics, novel phenotypic and molecular features as well as long-term complications of the largest cohort of patients in Turkey and one of the largest cohorts in the world. The demographic, clinical, and molecular data of GSD1a or 1b patients who were followed up between 2000 and 2024 were collected retrospectively from patients’ medical records. A total of 39 GSD1a patients were enrolled, and four different variants in the G6PC gene, c.247C > T (p.R83C), c.809G > T (p.G270V), c.562G > C (p.G188R), c.480G > A (p.W160*) were revealed. The most common variant among Turkish GSD1a patients was the c.247C > T (p.R83C) variant with an allele frequency of about 90

Objectives Empagliflozin has been used for the treatment of over 100 glycogen storage disease type Ib (GSDIb) patients worldwide since 2019. We aimed to evaluate the effect of empagliflozin treatment on the laboratory and clinical findings of patients with GSDIb in T & uuml;rkiye.Methods Included in this multicenter study were 10 patients with GSDIb, and whose demographic, clinical and laboratory data were analyzed retrospectively. Further data for the study were garnered through a survey of patients and caregivers to evaluate the effects of empagliflozin treatment on quality of life (QoL).Results The mean age at which the empagliflozin treatment was started was 73.2 (4-239) months. The mean duration of empagliflozin treatment was 16.9 (8-39) months. Glucosuria was identified in eight (80 %) patients undergoing empagliflozin treatment, while urogenital infections were detected in six (60 %) and hypoglycemia in two (20 %). An analysis of neutrophil levels revealed increased absolute neutrophil counts following empagliflozin treatment. Skin and/or mucosal lesions were noted in nine (90 %) patients prior to the initiation of empagliflozin treatment, but persisted in only one patient following empagliflozin treatment (10 %) (p=0.008). Empagliflozin treatment resulted in a decrease in the frequency of hospitalizations due to infection (p=0.0015). Furthermore, 80 % of the patients reported positive impact on their well-being as a result of the empagliflozin treatment, and 70 % of parents reported improvement in physical performance and activities, in the sleep quality of both the patient and parents, and in mobility.Conclusions This study revealed empagliflozin to be effective in improving the neutrophil counts of patients with GSD Ib and in enhancing the QoL of both the patients and their caregivers.

A patient with scurvy presented with malnutrition and generalised myalgia, bone pain, petechial rash, ecchymosis, gingival hypertrophy and bleeding, and an inability to walk. Initially, the petechial rash, arthralgia and bone pain posed a diagnostic challenge, with differential diagnoses including IgA vasculitis (Henoch-Sch & ouml;nlein purpura, HSP) and leukaemia. However, the rash was not typical of HSP, and there were no pathological blood smear findings. Vitamin C levels in the plasma were prioritised before conducting further investigations, including bone marrow aspiration and skin biopsy. Laboratory and radiological findings confirmed undetectable vitamin C levels in the plasma, and other results were compatible with scurvy and malnutrition. Notably, the erythrocyte sedimentation rate was elevated. The cause of multivitamin deficiency and malnutrition was investigated, and coeliac disease was identified. Scurvy in patients with coeliac disease is very rarely reported. The aim of this article is to draw attention to the importance of assessing and managing the dietary habits of school-age children, and, if necessary, further investigation for coeliac disease, and to highlight that scurvy can mimic HSP.AbbreviationsESR: erythrocyte sedimentation rate; Hb: haemoglobin; HSP: Henoch-Sch & ouml;nlein purpura; WCC: white-cell count.

Background: Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the MAN2B1 gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly. This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics. Method: Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded. Results: Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 +/- 56.1 (16-208) months, and the mean diagnosis delay time was 57.9 +/- 51.9 (4-181) months. Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%). Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease. Homozygous c.2477C>A (p.Ser826Ter) and homozygous c.967G>A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C>A (p.Ser826Ter). Conclusion: The present study identified two novel MAN2B1 variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.

Background: One of the most common causes of carpal tunnel syndrome (CTS) in childhood is mucopolysaccharidosis (MPS). While ultrasonography (US) can aid in the diagnosis of CTS in adult patients, there is limited experience of this in the pediatric group. We aimed to investigate the results of wrist ultrasonography, which may be a candidate alternative to electrophysiological examination. Methods: The participants were evaluated for symptoms, physical examination findings, electrophysiological tests and grayscale US. CTS was diagnosed in accordance with the American Academy of Orthopedic Surgeons Management of Carpal Tunnel Syndrome: Evidence-Based Clinical Practice Guideline. Results: Included in the study were 27 MPS patients aged 4.5-32 years and 30 healthy control subjects aged 4.3-26 years. Of the 54 wrists in the MPS group, 30 were diagnosed with CTS. The median crosssectional area (CSA) at the proximal carpal tunnel, the CSA at the forearm, and the wrist-forearm ratio (WFR) were higher in the wrists of the MPS with CTS group than in those without CTS and the healthy control subjects. The WFR cutoff of >= 1.35, 56.6% (95% CI: 437.4-74.5) sensitivity, and 89.8% (95% CI: 81.0 -95.5) specificity were consistent with a diagnosis of CTS (receiver operating characteristics analysis, area under the curve = 0.775, 95% CI: 0.673-0.877). Conclusion: Although the US provides results with unsatisfactory specificity and sensitivity, it is a candidate for further investigation for the diagnosis of CTS because it is an innovative, noninvasive, and more accessible method. WFR value may produce more meaningful results than wrist or forearm nerve area measurements.

Inborn errors of metabolism (IEMs) are a group of genetic diseases that occur due to the either deficiency of an enzyme involved in a metabolic/biochemical pathway or other disturbances in the metabolic pathway including transport protein or activator protein deficiencies, cofactor deficiencies, organelle biogenesis, maturation or trafficking problems. These disorders are collectively significant due to their substantial impact on both the well-being and survival of affected individuals. In the quest for effective treatments, enzyme replacement therapy (ERT) has emerged as a viable strategy for patients with many of the lysosomal storage disorders (LSD) and enzyme substitution therapy in the rare form of the other inborn errors of metabolism including phenylketonuria and hypophosphatasia. However, a major challenge associated with enzyme infusion in patients with these disorders, mainly LSD, is the development of high antibody titres. Strategies focusing on immunomodulation have shown promise in inducing immune tolerance to ERT, leading to improved overall survival rates. The implementation of immunomodulation concurrent with ERT administration has also resulted in a decreased occurrence of IgG antibody development compared with cases treated solely with ERT. By incorporating the knowledge gained from current approaches and analysing the outcomes of immune tolerance induction (ITI) modalities from clinical and preclinical trials have demonstrated significant improvement in the efficacy of ERT. In this comprehensive review, the progress in ITI modalities is assessed, drawing insights from both clinical and preclinical trials. The focus is on evaluating the advancements in ITI within the context of IEM, specifically addressing LSDs managed through ERT.

Background:Hyperphenylalaninemia (HPA) is defined as blood phenylalanine (Phe) levels exceeding the normal values (>120 μmol/L or >2 mg/dL) and is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). The widespread screening of Phe levels in newborn screening programs has led to a very high number of patients with HPA.Methods:The samples were collected at various ages, not at the point of diagnosis. Nine pterin derivatives, including isoxanthopterin, sepiapterin, xanthopterin, primapterin, biopterin, neopterin, 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and tetrahydrobiopterin (BH4), were analyzed in different HPA classes in serum, dried blood spots (DBS), and urine samples. A total of 18 patients, including six classical phenylketonuria (PKU), eight BH4-responsive PKU, and four mild HPA patients, were included in the study.Results:Among the nine pterin derivatives measured, a significant increase was observed in the levels of isoxanthopterin, biopterin, and 7,8-dihydrobiopterin in serum, dried blood spots (DBS), and urine samples of patients with HPA compared to the control group. However, elevations in isoxanthopterin, biopterin, and 7,8-dihydrobiopterin were observed in all HPA groups, although the extent of elevation varied among the different disease groups. There were also significant differences between HPA subgroups among these high values.Conclusion:In this study, it might be suggested that pterin profiling shows promising potential for its effective utilization in the differential diagnosis of HPA. Pterin profiling demonstrated its efficacy in accurately categorizing patients into distinct subtypes. This approach offers several notable advantages, including the ability to simultaneously screen multiple HPA subtypes through a single test, establish disease decision limits for pterins, shorten the time required for HPA differential diagnosis, reduce the risk of misdiagnosis, and increase overall diagnostic accuracy. This study is the most comprehensive study examining the association between HPA pterin in the literature. In our study, samples obtained from BH4-responsive PKU patients were on treatment. This may have affected the results. Preliminary findings on pterin profiles may need to be replicated in a prospective cohort of samples collected at the time of diagnosis to confirm the results.

OBJECTIVES:The mitochondrial elongation factor Tu (EF-Tu), encoded by the TUFM gene, is a GTPase, which is part of the mitochondrial protein translation mechanism. If it is activated, it delivers the aminoacyl-tRNAs to the mitochondrial ribosome. Here, a patient was described with a homozygous missense variant in the TUFM [c.1016G>A (p.Arg339Gln)] gene. To date, only six patients have been reported with bi-allelic pathogenic variants in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis, encephalopathy, and cardiomyopathy.CASE PRESENTATION:The patient presented here had the phenotypic features of TUFM-related disease, lactic acidosis, hypotonia, liver dysfunction, optic atrophy, and mild encephalopathy.CONCLUSIONS:We aimed to expand the clinical spectrum of pathogenic variants of TUFM.

Abstract:OBJECTIVES: Quality of life (QoL) is directly associated with physical-psychological well-being, family and environmental factors in patients with Mucopolysaccharidosis (MPS). The present study aims to investigate the factors affecting QoL in both MPS patients and their caregivers. Abstract:METHODS: The sociodemographic characteristics, clinical findings, and special needs of 37 patients with MPS were questioned, among which 28 pediatric patients were evaluated for QoL using the KINDL-parents scale. The World Health Organization Quality of Life Assessment (WHO-QoL-BREF) was used to assess the QoL of 37 caregivers of patients. Abstract:RESULTS: The patients with MPS type III had the lowest median score in the self-esteem domain among the other types. The patients undergoing enzyme replacement therapy scored high in the friends domain, while the physical-psychological/emotional domain scores of the patients with sleep disturbance and their parents were lower than those without. Patients with appetite/eating problems scored low in the self-esteem domain and their caregivers scored low in the social relationship domain. The psychological/emotional domain scores of the patients who needed special education and their parents were lower than those who did not. Total scores and KINDL disease domain scores were decreased in those receiving psychiatric medical treatment. Abstract:CONCLUSIONS: In this study, the aim was to simultaneously assess the quality of life of MPS patients and their parents. Sleep disturbances, appetite problems, special education, and psychiatric treatment negatively impacted QoL.

Objectives: Glycogen storage disease type V is caused by the mutations in muscle glycogen phosphorylase gene. This is the first report which DL-3-hydroxybutyric acid was used in combination with modified Atkins diet for the treatment of a patient with glycogen storage disease type V and quadriceps femoris shear wave elastography was performed to evaluate the treatment efficacy. Case presentation: A 13-year-old girl was referred with fatigue and muscle cramps with exercise and there were no pathological findings in physical examination. Creatine kinase levels with 442 U/L. No phosphorylase enzyme activity was detected in muscle biopsy, a homozygous c.1A>G (p.M1V) pathogenic mutation was found in PYGM gene. She was started on DL-3-hydroxybutyric acid and modified Atkins diet at age 16. Her walking and stair climbing capacity increased, the need for rest during exercise decreased. The stiffness of the quadriceps femoris exhibited a reduction. Conclusions: DL-3-hydroxybutyric acid and modified Atkins diet may provide an alternative fuel and shear wave elastography may be useful in demonstrating treatment efficacy. More clinical and pre-clinical studies are obviously needed to reach more definite conclusions.

Aim Dietary therapy of glycogen storage disease I (GSD I) is based on frequent feeding, with a high intake of complex carbohydrates (supplied by uncooked cornstarch), restriction of sugars, and a lower amount of lipids. There is limited information about the dietary regimen in patients with GSD, which might affect the intestinal luminal pH and microbiota composition. The aim of this study to investigate the intestinal microbiota composition in patients with GSD receiving diet treatment. Method Twelve patients who were followed up with GSD I after the diagnosis receiving diet therapy and 11 healthy children have been enrolled. Intestinal microbiota composition was evaluated by 16 s rRNA gene sequencing. Results A significant difference was found for beta-diversity between the GSD group and controls. A significantly lower abundance of Firmicutes and higher abundance of Actinobacteria was found in GSD group compared to the controls. Akkermansia, Pseudoalteromonas, Uruburella, and Castellaniella were dominant in the GSD patients at the genus level, while Faecalibacterium, Bacterioides, Gemmiger, Parabacteroides in the control group. At species level, Faecalibacterium prausnitzii decreased, and Akkermansia muciniphila were dominant in children with GSD. Discussion There is a substantial change in the composition of the gut microbiota, reduction of F. prausnitzii and an increase of A. muciniphila in children with GSD receiving consumption of uncooked cornstarch. Alterations of the intestinal microbiota might be related with the disease itself or dietary restrictions in patients with GSD, however, in certain condition, dysbiosis can negatively affect the course and make it difficult to control the disease.

Lysosomal storage disorders (LSD) are a group of inherited inborn metabolism errors that are characterized by a deficiency in the lysosomal enzyme. In patients with suspected lipid storage disorders, confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and molecular genetic studies. New approaches to the measurement of lysosphingolipids have been developed that may serve as a rapid first-tier screening tests for the evaluation of lysosomal storage disorders. The present study evaluates the results of lysosphingolipid screening tests in patients with suspected lysosomal storage diseases. Lysosphingolipid elevation was detected in five patients examined with suspected lysosomal storage disease, and a definitive diagnosis was reached based on genetic analysis. Our data support recent evidence of the primary role of LysoSLs in the diagnosis of sphingolipidosis, and suggest that these biomarkers may be used for diagnosis and treatment monitoring in the future.

Background: Mevalonate kinase (MVK) plays a role in cholesterol and non-sterol isoprenoid biosynthe-sis and its deficiency-related diseases are caused by bi-allelic pathogenic mutations in the MVK gene, (MVK), which leads to rare hereditary autoinflammatory diseases. The disease may manifest different clinical phenotypes depending on the degree of the deficiency in the enzyme activity. The complete defi-ciency of the enzyme activity results in the severe metabolic disease called mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentations called hyper-immunoglobulin D syndrome (HIDS). Serum immunoglobulin (Ig) D and urine mevalonic acid levels may be increased during inflammatory attacks of HIDS.Case Presentation: Herein, for the first time in the literature, we present a 6-year-old male patient who suffered from recurrent episodes of fever, polyarthritis, skin rash, diarrhea, abdominal pain, and inflam-matory bowel disease-like manifestations with elevated levels of serum IgD, and urine mevalonic acid. Eventually we detected compound heterozygous mutations in the phosphomevalonate kinase (PMVK) gene coding the second enzyme after mevalonate kinase in the mevalonate pathway. Conclusion: For patients presenting with HIDS-like findings, disease exacerbations and persistent chronic inflammation, and having high urinary mevalonic acid and serum IgD levels, raising suspicion in terms of MVK deficiency (MVKD), it is recommended to study all mevalonate pathway enzymes, even if there is no mutation in the MVK gene. It should be kept in mind that novel mutations might be seen such as PMVK gene.(c) 2022 Published by Elsevier Masson SAS on behalf of Socie acute accent te acute accent franc , aise de rhumatologie.

Abstract Purpose Gaucher Disease (GD) is a lysosomal storage disease. Mutations in GBA1 gene cause glucocerebrosidase enzyme deficiency that leads accumulation of its substrates. Clinical presentations of GD are cytopenia, hepatosplenomegaly, bone involvement and neurological impairment. Besides; abdominal pain, painful bone crises, bleeding, growth retardation, delayed puberty, pulmonary involvement, fatigue are other manifestations. This study has revealed event-based outcomes in GD patients undergoing ERT to evaluate real-life data to assess the impact of ERT on GD patients' lives. Methods The events consist of hematopoietic system related events, musculoskeletal system related events, gastrointestinal system related events, growth and puberty related events, respiratory system related events, neurological system related, routine daily activities related events and tumoral formation. Events were collected starting from 1 year before and up to 3 years form initiation of ERT and all events were collected every 6 months periods. Results Total of 31 events were reported between − 12 to -6 months and 17 events from − 6 months to baseline in all patients. After the initiation of ERT, the number of events decreased to 10 in 6–12 months. At the end of the follow-up period, between 30–36 months, only 1 event was recorded, the minimum event number overall. For all groups, there was a trend to decrease or stabilization of the events. Conclusion In conclusion, this is the first study that evaluate event-based outcomes in GD patients receiving ERT and show the real-life data by evaluating not only laboratory parameters but also clinical consequences of the treatment, providing practical clinical follow up.