Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy.

BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD. METHODS: This retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported. RESULTS: Patients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients' total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment. CONCLUSIONS: The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

The Impact of Diet on Body Composition in a Cohort of Pediatric and Adult Patients with Maple Syrup Urine Disease.

The treatment for Maple Syrup Urine Disease (MSUD) consists of a hypoproteic diet with integration therapy to limit leucine intake, ensuring adequate energy, macronutrients, and micronutrients to prevent catabolism and promote anabolism. We conducted a retrospective cross-sectional study at the Metabolic Rare Disease Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. Patients with MSUD who were over 3 years old, not treated with liver transplantation, and who provided written consent, were included. The study aimed to describe the dietary treatment of patients with MSUD, evaluate growth data, and analyze the effect of a low-protein and semi-synthetic diet on body composition. Data on height, weight, BMI, waist circumference, food intake, physical activity, and DEXA scans were collected. Thirteen subjects (11 classic MSUD, 2 intermediate MSUD) were included, of which 5 < 18 years old. Results indicated that patients with MSUD follow a balanced diet and have body compositions like healthy subjects in terms of fat and lean mass. A high incidence of osteopenia was observed from a young age, with a positive correlation between protein intake and lean mass and a negative correlation between BCAA-free mixture consumption and bone mineral density z-score. The study highlights the positive effects and potential consequences of the semi-synthetic diet on the body composition of patients with MSUD. A similar study involving all Italian metabolic centers treating MSUD is recommended.

Avalglucosidase alfa in infantile-onset Pompe disease: A snapshot of real-world experience in Italy.

Introduction: Infantile-onset Pompe disease (IOPD) is due to mutations in the GAA gene leading to profound deficiency of the lysosomal enzyme α-1,4-glucosidase. The disease is characterized by severe hypotonia, hypertrophic cardiomyopathy, macroglossia, and liver enlargement with onset in the first months of life. In the late-onset form (LOPD), muscle signs predominate with a clinical picture resembling muscle dystrophies. Enzyme replacement therapy with alglucosidase alfa (rhGAA) has been available since 2006 and patients treated with the enzyme show improved outcomes. Nevertheless, there is evidence that some patients have a suboptimal response or, after an initial improvement, reach a plateau with stabilization of the clinical picture. Thus, a new enzyme formulation, avalglucosidase alfa (neoGAA), with a higher degree of mannosylation, was developed. Methods: We conducted a multicenter survey that collected data on four patients with IOPD, aged 6 to 16 years, who were switched to neoGAA thanks to a compassionate use program, after being treated for an average of 11.5 years with rhGAA. Follow-up data, including biochemical parameters and clinical features, were analyzed to determine clinical outcomes and the safety profile after a mean of 9 months. Results: Patients with IOPD who were treated with neoGAA showed a positive change in biomarker levels. Moreover, the clinical picture revealed improved motor performance and cardiac parameters in patients who previously responded poorly. Conclusion: This study highlights the improved efficacy of neoGAA, as a next generation enzyme replacement therapy, in 4 Italian patients with IOPD. Several clinical parameters showed a positive response to the new formulation suggesting that, if used at diagnosis, neoGAA may result in better outcomes for patients with IOPD.

Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.

Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome.

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial.

Background: Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes. Methods: This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses. Findings: From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 µmol/L to 86.4 µmol/L at Week 24 vs 464.7 to 426.6 µmol/L for placebo (95% CI: -67.1%, -83.5%; p < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity. Interpretation: These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility. Funding: Aeglea BioTherapeutics.

Extensive and Persistent Dermal Melanocytosis in a Male Carrier of Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome): A Case Report.

Congenital dermal melanocytosis (DM) represents a common birthmark mainly found in children of Asian and darker skin phototype descent, clinically characterized by an oval blue-grey macule or macules, commonly located on the lumbosacral area. In rare DM cases, when presenting with diffuse macules persisting during the first years of life, it could represent a cutaneous feature of mucopolysaccharidoses (MPS). Extensive congenital DM is actually associated with Hurler syndrome (MPS type I) and Hunter syndrome (MPS type II), although several reports also described this association with MPS type VI and other lysosomal storage disorders (LySD), including GM1 gangliosidosis, mucolipidosis, Sandhoff disease, and Niemann-Pick disease. Here, we present the case of a two-year-old boy presenting with extensive dermal melanocytosis, generalized hypertrichosis, and chronic itch, harboring a heterozygous variant of uncertain significance, NM_152419.3: c.493C>T (p.Pro165Ser), in the exon 4 of HGSNAT gene, whose mutations are classically associated with MPS IIIC, also known as Sanfilippo syndrome. This is the first report that highlights the association between extensive congenital DM and MPS type IIIC, as well as a pathogenetic link between heterozygous LySD carrier status and congenital DM. We speculate that some cases of extensive congenital DM could be related to heterozygous LySD carriers, as a manifestation of a mild clinical phenotype.

Crohn-like disease long remission in a pediatric patient with glycogen storage disease type Ib treated with empagliflozin: a case report.

Glycogen storage disease type Ib (GSD Ib) is a rare hereditary glycogen disorder that results in inadequate maintenance of glucose homeostasis, accumulation of glycogen in different organs, loss and dysfunction of neutrophils. Crohn's-like disease is observed in up to 24-77% of GDS Ib cases. Recently, empagliflozin has been recommended as a treatment for neutrophil dysfunction in GDS Ib patients with or without Crohn's-like disease. There are no guidelines for the treatment of inflammatory bowel disease (IBD) manifestation in GSD Ib patients, although some cases have been treated with granulocyte colony-stimulating factor and others with IBD conventional therapy, resulting in partial IBD remission. Herein, we describe a child with GDS Ib and Crohn's-like disease who was treated with empagliflozin and achieved complete remission after 2 years of treatment. This case is the first one with such a long follow-up evaluation including endoscopic and magnetic resonance enterography assessment. Our clinical evidence of remission of IBD manifestation in our GSD Ib patient and the role of neutrophils in GDS Ib described in the literature suggest a strong association with IBD pathophysiology and neutrophil function. The use of empagliflozin resulted in significant improvements in gastrointestinal symptoms, reduced drug usage, and enhanced quality of life in the patient, with a favorable safety profile, offering a promising new therapeutic option for this population.

Safety outcomes and patients' preferences for home-based intravenous enzyme replacement therapy (ERT) in pompe disease and mucopolysaccharidosis type I (MPS I) disorder: COVID-19 and beyond.

BACKGROUND: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting. RESULTS: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%). CONCLUSIONS: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.

Antibody Deficiency in Patients with Biallelic KARS1 Mutations.

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

Treatment Dilemma in Children with Late-Onset Pompe Disease.

In recent years, there has been a significant increase in the diagnosis of asymptomatic Late-Onset Pompe Disease (LOPD) patients, who are detected via family screening or Newborn Screening (NBS). The dilemma is when to start Enzyme Replacement Therapy (ERT) in patients without any clinical sign of the disease, considering its important benefits in terms of loss of muscle but also its very high cost, risk of side effects, and long-term immunogenicity. Muscle Magnetic Resonance Imaging (MRI) is accessible, radiation-free, and reproducible; therefore, it is an important instrument for the diagnosis and follow-up of patients with LOPD, especially in asymptomatic cases. European guidelines suggest monitoring in asymptomatic LOPD cases with minimal MRI findings, although other guidelines consider starting ERT in apparently asymptomatic cases with initial muscle involvement (e.g., paraspinal muscles). We describe three siblings affected by LOPD who present compound heterozygosis and wide phenotypic variability. The three cases differ in age at presentation, symptoms, urinary tetrasaccharide levels, and MRI findings, confirming the significant phenotypic variability of LOPD and the difficulty in deciding when to start therapy.

Parents' experience of the communication process of positivity at newborn screening for metabolic diseases: A qualitative study.

BACKGROUND: The process of receiving a communication of positivity for metabolic diseases at expanded newborn screening (ENBS) is extremely articulated, involves a variety of actors (parents, maternal and child departments, clinical centres and laboratories) and is open to a variety of outcomes from false positive to true positive cases. Receiving communication of positivity can be highly stressful for parents and requires an adequate communication process to give clear and reliable information without causing excessive worry. This qualitative study describes the parents' experience of receiving a communication of positivity to metabolic diseases at ENBS, and their assessment of the quality of the communication process and steps, with the main aim to identify the process' strengths and weaknesses and to advance tailored recommendations to improve the communication process. METHOD: Fourteen in-depth, semi-structured phone interviews were conducted with parents whose children resulted positive to the ENBS. As part of the ENBS communication process, parents received a first phone call communication of positivity and a second in-person communication at metabolic clinical centres (MCC). The framework analysis method was used to organize the data and identify emerging themes. RESULTS: Parents were largely dissatisfied with the quality and depth of the information received and with the way the healthcare staff delivered the first communication phone call, which failed to create a caring, empathic and safe setting. Many parents tried to reduce the uncertainty by searching online information or consulting with other providers. Nevertheless, the majority of parents described the in-person visit at MCC as clear, welcoming and reassuring. CONCLUSION: More efforts are needed to improve the quality of the communication process of the ENBS. Guidelines, recommendations and standard scripts to communicate positivity are needed along with programmes and educational resources to train tailored communication skills.

Long-Term Management of Patients with Mild Urea Cycle Disorders Identified through the Newborn Screening: An Expert Opinion for Clinical Practice.

Urea cycle disorders (UCDs) are a group of rare inborn errors of metabolism caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. Current guidelines suggest that early diagnosis and treatment of mild UCDs may improve survival and prevent decompensation and neurocognitive impairment. Nevertheless, clinical studies are very difficult to carry out in this setting due to the rarity of the diseases, and high-level evidence is scant and insufficient to draw conclusions and provide clinical guidelines. With the early introduction of newborn screening, the Italian healthcare organization fostered an advancement in expertise in metabolic disease management and screening programs, by allocating resources, and favoring the expansion of newborn screening. A group of experts operating in Italian centers decided to share their experience and provide advice for the management of mild UCDs in clinical practice. A consensus was reached by the Estimate-Talk-Estimate (ETE) method. Five items were identified, and statements for each item were agreed. Briefly, the panel advised completing the diagnosis by expanded newborn screening (ENS) with biochemical and genetic confirmation and by following up with the patient during the first year of life, with a routine laboratory and metabolic profile as well as with clinical observation. Early initiation of therapy is advised and should be followed by therapy adjustment once the diagnostic profile is completed. The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment, clinical and neurocognitive evaluation, and laboratory and instrumental parameter monitoring.

Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H2S homeostasis.

Regulation of H2S homeostasis in humans is poorly understood. Therefore, we assessed the importance of individual enzymes in synthesis and catabolism of H2S by studying patients with respective genetic defects. We analyzed sulfur compounds (including bioavailable sulfide) in 37 untreated or insufficiently treated patients with seven ultrarare enzyme deficiencies and compared them to 63 controls. Surprisingly, we observed that patients with severe deficiency in cystathionine ß-synthase (CBS) or cystathionine γ-lyase (CSE) - the enzymes primarily responsible for H2S synthesis - exhibited increased and normal levels of bioavailable sulfide, respectively. However, an approximately 21-fold increase of urinary homolanthionine in CBS deficiency strongly suggests that lacking CBS activity is compensated for by an increase in CSE-dependent H2S synthesis from accumulating homocysteine, which suggests a control of H2S homeostasis in vivo. In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions. Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine, increased renal losses of sulfur compounds and concomitant strong reduction in plasma total cysteine. Our results demonstrate the value of a comprehensive assessment of sulfur compounds in severe disorders of homocysteine/cysteine metabolism and provide evidence for redundancy and compensatory mechanisms in the maintenance of H2S homeostasis.

Expanded Newborn Screening in Italy Using Tandem Mass Spectrometry: Two Years of National Experience.

Newborn screening (NBS) for inborn errors of metabolism is one of the most advanced tools for secondary prevention in medicine, as it allows early diagnosis and prompt treatment initiation. The expanded newborn screening was introduced in Italy between 2016 and 2017 (Law 167/2016; DM 13 October 2016; DPCM 12-1-2017). A total of 1,586,578 infants born in Italy were screened between January 2017 and December 2020. For this survey, we collected data from 15 Italian screening laboratories, focusing on the metabolic disorders identified by tandem mass spectrometry (MS/MS) based analysis between January 2019 and December 2020. Aminoacidemias were the most common inborn errors in Italy, and an equal percentage was observed in detecting organic acidemias and mitochondrial fatty acids beta-oxidation defects. Second-tier tests are widely used in most laboratories to reduce false positives. For example, second-tier tests for methylmalonic acid and homocysteine considerably improved the screening of CblC without increasing unnecessary recalls. Finally, the newborn screening allowed us to identify conditions that are mainly secondary to a maternal deficiency. We describe the goals reached since the introduction of the screening in Italy by exchanging knowledge and experiences among the laboratories.

Hepatic glycogen storage diseases type 0, VI and IX: description of an italian cohort.

BACKGROUND: Glycogen storage disease (GSD) type 0, VI and IX are inborn errors of metabolism involving hepatic glycogen synthesis and degradation. We performed a characterization of a large Italian cohort of 30 patients with GSD type 0a, VI, IXa, IXb and IXc. A retrospective evaluation of genetical, auxological and endocrinological data, biochemical tests, and nutritional intakes was assessed. Eventual findings of overweight/obesity and insulin-resistance were correlated with diet composition. RESULTS: Six GSD-0a, 1 GSD-VI, and 23 GSD-IX patients were enrolled, with an age of presentation from 0 to 72 months (median 14 months). Diagnosis was made at a median age of 30 months, with a median diagnostic delay of 11 months and a median follow-up of 66 months. From first to last visit, patients gained a median height of 0.6 SDS (from - 1.1 to 2.1 SDS) and a median weight of 0.5 SDS (from - 2.5 to 3.3 SDS); mean and minimal glucose values significant improved (p < 0.05). With respect to dietary intakes, protein intake (g/kg) and protein intake (g/kg)/RDA ratio directly correlated with the glucose/insulin ratio (p < 0.05) and inversely correlated with HOMA-IR (Homeostasis model assessment of insulin resistance, p < 0.05), BMI SDS (p < 0.05) and %ibw (ideal body weight percentage, p < 0.01). CONCLUSION: A prompt establishment of specific nutritional therapy allowed to preserve growth, improve glycemic control and prevent liver complication, during childhood. Remarkably, the administration of a high protein diet appeared to have a protective effect against overweight/obesity and insulin-resistance.

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.