Benefits of a prolonged-release amino acid mixture in four pregnant women with phenylketonuria.

Background: Maternal phenylketonuria (mPKU) is a pathologic condition occurring in the fetus of a mother with PKU that is caused by prolonged elevated intrauterine blood phenylalanine (Phe) levels, which can lead to congenital abnormalities and mental retardation of newborns. Management of PKU during pregnancy can be challenging as protein substitutes may exacerbate nausea, vomiting, and gastrointestinal symptoms. Aim: To report the successful management of four PKU pregnant women. Methods: The patients were administered with prolonged-release amino acid supplementation and were recommended to follow a strict diet. Blood Phe concentration, adherence to diet, and occurrence of adverse events were monitored. Results: All patients achieved safe levels of blood Phe concentration (120-360 µmol/L) since preconception and during pregnancy (mean Phe concentration values of 143.34 ± 137.59, 226.48 ± 194.57, 186.68 ± 133.67, and 187.47 ± 42.59 µmol/L). During the first trimester of pregnancy, all patients manifested gastrointestinal symptoms such as nausea, gastrointestinal reflux, and abdominal bloating, which were managed by either changing protein substitute or extending the time window between different meals and amino acid mixtures administration. The four women continued their pregnancies without experiencing further complications and delivered neonates with normal growth parameters and no malformations. Conclusion: Findings of this case series suggest that the intake of a prolonged-release amino acid mixture in granules is well tolerated by pregnant PKU patients, eventually leading to good metabolic control and fetal growth within normal ranges.

Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study.

Alpha-mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha-mannosidase deficiency that leads to the accumulation of mannose-rich oligosaccharides. AM symptoms and severity vary among individuals; consequently, AM is often not diagnosed until late childhood. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase product, is the first enzyme replacement therapy indicated to treat non-neurological symptoms of AM in Europe. Previous studies suggested that early VA treatment in children may produce greater clinical benefit over the disease course than starting treatment in adolescents or adults; however, long-term studies in children are limited, and very few studies include children under 6 years of age. The present phase 2, multicenter, open-label study evaluated the safety and efficacy of long-term VA treatment in children under 6 years of age with AM. Five children (three males) received VA weekly for ≥24 months, and all children completed the study. Four children experienced adverse drug reactions (16 events) and two experienced infusion-related reactions (12 events). Most (99.5%) adverse events were mild or moderate, and none caused study discontinuation. Four children developed antidrug antibodies (three were neutralizing). After VA treatment, all children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreases), hearing, immunological profile, and quality of life, suggesting a beneficial effect of early treatment. Although the small study size limits conclusions, these results suggest that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to patients with AM under 6 years of age.

Micronutrient Deficiency in Inherited Metabolic Disorders Requiring Diet Regimen: A Brief Critical Review.

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.

Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs.

Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite the great variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerative phenotype is observed, and no specific therapy exists for a complete recovery from the disease. The most used treatments are symptomatic and based on the administration of antioxidant cocktails combined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement. Nevertheless, the real utility of antioxidant cocktail treatments for patients affected by MDs still needs to be scientifically demonstrated. Unfortunately, clinical trials for antioxidant therapies using α-tocopherol, ascorbate, glutathione, riboflavin, niacin, acetyl-carnitine and coenzyme Q have met a limited success. Indeed, it would be expected that the employed antioxidants can only be effective if they are able to target the specific mechanism, i.e., involving the central and peripheral nervous system, responsible for the clinical manifestations of the disease. Noteworthily, very often the phenotypes characterizing MD patients are associated with mutations in proteins whose function does not depend on specific cofactors. Conversely, the administration of the antioxidant cocktails might determine the suppression of endogenous oxidants resulting in deleterious effects on cell viability and/or toxicity for patients. In order to avoid toxicity effects and before administering the antioxidant therapy, it might be useful to ascertain the blood serum levels of antioxidants and cofactors to be administered in MD patients. It would be also worthwhile to check the localization of mutations affecting proteins whose function should depend (less or more directly) on the cofactors to be administered, for estimating the real need and predicting the success of the proposed cofactor/antioxidant-based therapy.

Novel autophagic vacuolar myopathies: Phenotype and genotype features.

BACKGROUND: Autophagic vacuolar myopathies (AVMs) are an emerging group of heterogeneous myopathies sharing histopathological features on muscle pathology, in which autophagic vacuoles are the pathognomonic morphologic hallmarks. Glycogen storage disease type II (GSDII) caused by lysosomal acid α-glucosidase (GAA) deficiency is the best-characterised AVM. AIMS: This study aimed to investigate the mutational profiling of seven neuromuscular outpatients sharing clinical, myopathological and biochemical findings with AVMs. METHODS: We applied a diagnostic protocol, recently published by our research group for suspected late-onset GSDII (LO-GSDII), including counting PAS-positive lymphocytes on blood smears, dried blood spot (DBS)-GAA, muscle biopsy histological and immunofluorescence studies, GAA activity assay and expression studies on muscle homogenate, GAA sequencing, GAA multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES). RESULTS: The patients had a limb girdle-like muscular pattern with persistent hyperCKaemia; vacuolated PAS-positive lymphocytes, glycogen accumulation and impaired autophagy at muscle biopsy. Decreased GAA activity was also measured. While GAA sequencing identified no pathogenic mutations, WES approach allowed us to identify for each patient an unexpected mutational pattern in genes cooperating in lysosomal-autophagic machinery, some of which have never been linked to human diseases. CONCLUSIONS: Our data suggest that reduced GAA activity may occur in any condition of impaired autophagy and that WES approach is advisable in all genetically undefined cases of autophagic myopathy. Therefore, deficiency of GAA activity and PAS-positive lymphocytes should be considered as AVM markers together with LC3/p62-positive autophagic vacuoles.

The impact of COVID-19 pandemic on the diagnosis and management of inborn errors of metabolism: A global perspective.

Quantitative estimates for the global impact of COVID-19 on the diagnosis and management of patients with inborn errors of metabolism (IEM) are lacking. We collected relevant data from 16 specialized medical centers treating IEM patients in Europe, Asia and Africa. The median decline of reported IEM related services in March 1st-May 31st 2020 compared to the same period in 2019 were as high as 60-80% with a profound impact on patient management and care for this vulnerable patient group. More representative data along with outcome data and guidelines for managing IEM disorders under such extraordinary circumstances are needed.

Mechanisms of Enhanced Osteoclastogenesis in Alkaptonuria.

Alkaptonuria (AKU) is a rare disorder characterized by the deficiency of the enzyme homogentisate 1,2-dioxygenase and consequent homogentisate accumulation, which leads to progressive and severe osteoarthopathy starting from the second decade of life. Thus, in AKU patients, bone involvement represents an important clinical issue, which we investigated. Serum levels of receptor activator of NF-κB ligand (RANKL), osteoprotegerin, sclerostin, Dickkopf-1, and bone remodeling markers were measured in nine AKU patients (two children and seven adults) and 22 controls, together with lumbar spine bone mineral density (LS-BMD) and femoral-BMD. In the two AKU children, the average of LS-BMD and femoral-BMD Z-scores were within the normal range, but reduced with respect to the controls. Otherwise, in the adult AKU patients, LS-BMD T-score was inside the normal range, but femoral-BMD T-score reached osteopenic levels. Consistently, in AKU adults, higher RANKL and C-terminal telopeptide of collagen type 1 and lower osteoprotegerin levels were observed than in controls. Otherwise, spontaneous osteoclastogenesis was already evident in peripheral blood mononuclear cell cultures from AKU children, together with a high percentage of circulating osteoclast precursors. Osteoclastogenesis was sustained by the high levels of tumor necrosis factor-α, RANK, RANKL, and LIGHT. In conclusion, the altered osteoclastogenesis was observed already in AKU children, despite the absence of evident injury. Thus, a preventive approach in young patients, targeting osteoclast activity, may prevent the macroscopic bone disease that appears in adult AKU.

Plasma and dried blood spot lysosphingolipids for the diagnosis of different sphingolipidoses: a comparative study.

Background Lysosphingolipids, the N-deacylated forms of sphingolipids, have been identified as potential biomarkers of several sphingolipidoses, such as Gaucher, Fabry, Krabbe and Niemann-Pick diseases and in GM1 and GM2 gangliosidoses. To date, different methods have been developed to measure various lysosphingolipids (LysoSLs) in plasma. Here, we present a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for a simultaneous quantification of LysoSLs (HexSph, LysoGb3, LysoGM1, LysoGM2, LysoSM and LysoSM509) in dried blood spot (DBS). This LC-MS/MS method was used to compare the levels of LysoSLs in DBS and plasma in both affected patients and healthy controls. Methods Lysosphingolipids were extracted from a 3.2 mm diameter DBS with a mixture of methanol:acetonitrile:water (80:15:5, v/v) containing internal stable isotope standards. Chromatographic separation was performed using a C18 column with a gradient of water and acetonitrile both with 0.1% formic acid in a total run time of 4 min. The compounds were detected in the positive ion mode electrospray ionization (ESI)-MS/MS by multiple reaction monitoring (MRM). Results The method was validated on DBS to demonstrate specificity, linearity, lowest limit of quantification, accuracy and precision. The reference ranges were determined in pediatric and adult populations. The elevated levels of LysoSLs were identified in Gaucher disease (HexSph), Fabry disease (LysoGb3), prosaposin deficiency (HexSph and LysoGb3) and Niemann-Pick disease types A/B and C (LysoSM and LysoSM509). The correlation in the levels between DBS and plasma was excellent for LysoGb3 and HexSph but poor for LysoSM and LysoSM509. Conclusions Despite the fact that plasma LysoSLs determination remains the gold standard, our LC-MS/MS method allows a rapid and reliable quantification of lysosphingolipids in DBS. The method is a useful tool for the diagnosis of different sphingolipidoses except for Niemann-Pick type C.

Intake Modalities of Amino Acid Supplements: A Real-World Data Collection from Phenylketonuria Patients.

BACKGROUND: To achieve a normal nutritional status, patients suffering from phenylketonuria (PKU) are typically prescribed amino acid (AA) supplements with low or no phenylalanine (Phe) content. Studies evaluating patient preferences regarding the intake modalities of AA supplements are limited. This study aimed to collect real-world data regarding prescription adherence and intake modalities of AA supplements reported by PKU patients while monitoring metabolic control. METHODS: This cross-sectional study included 33 PKU patients (16 female and 17 male) with a mean age of 27.2 years. Questionnaires were provided to assess information on AA supplement intake, such as prescription adherence rate, frequency and timing of administration, supplement formulation, and combination with food or drinks. Plasma phenylalanine levels were monitored during the study period. RESULTS: 51.5% (n = 17) of patients reported to lay within an adherence range of 75-100%. The majority of patients consumed AA supplements twice daily, with breakfast (87.9%) and afternoon snacks (51.5%). Powder supplements were most commonly used (72.7%) and often combined with milk and/or fruit juices (45.4%). CONCLUSIONS: Despite the known concerns related to treatment compliance among PKU adolescents and adults, most of the study participants reported a high level of adherence to AA supplement prescription. The personalized dietary regimens followed by the patients included in the current study represent a treatment approach that might be worth trying in non-compliant patients.

Successful early management of a female patient with a metabolic stroke due to ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase deficiency (OTC-D) is a urea cycle disorder caused by dysfunction of ornithine transcarbamylase, which frequently leads to hyperammonemia. Hyperammonemia represents a medical emergency requiring prompt treatment to reduce plasma ammonia levels and prevent severe neurological damage, coma, and death, particularly in patients with acute decompensation-related coma. The clinical symptoms of OTC-D can manifest themselves either at an early stage, which is often associated with severe symptoms, or in later life (late-onset OTC-D), when symptoms may be less severe. There is currently little agreement over diagnostic signs of the condition or the most appropriate therapeutic approach. Hyperammonemia is usually treated with ammonia scavengers, continuous venovenous hemodialysis, and dietary changes. N-carbamylglutamate is approved for the treatment of hyperammonemia in N-acetylglutamate synthetase deficiency and may have efficacy in other urea cycle disorders. METHODS/RESULTS: Here, we report a 13-year-old girl who was diagnosed with OTC-D at the age of 3 years. On this occasion, the patient presented with vomiting, lethargy, and mental confusion. Despite biochemical parameters being within normal ranges, she was comatose within a few hours. She was promptly treated with a combined therapy of continuous venovenous hemodialysis and N-carbamylglutamate, resulting in a gradual normalization of clinical symptoms within 30 hours. No neurological damage was apparent at 18 months after treatment. CONCLUSIONS: This case demonstrates that clinical benefits can be obtained by beginning aggressive treatment of OTC-D within a few hours of the onset of severe neurological symptoms even in the absence of altered biochemical markers.

The Reciprocal Interplay between Infections and Inherited Metabolic Disorders.

Infections represent the main cause of acute metabolic derangements and/or the worsening of the clinical course of many inherited metabolic disorders (IMDs). The basic molecular mechanisms behind the role of infections in these conditions have not been completely clarified. This review points out the different mechanisms behind the relationship between IMDs and infections, providing an overview of this still-under-investigated area. Classically, infections have been considered as the consequence of a compromised immune system due to a biochemical defect of energy production. An adjunctive pathogenetic mechanism is related to a genetically altered protein-attached glycans composition, due to congenital glycosilation defects. In addition, a dietary regimen with a reduced intake of both micro- and macronutrients can potentially compromise the ability of the immune system to deal with an infection. There is recent pre-clinical evidence showing that during infections there may be a disruption of substrates of various metabolic pathways, leading to further cellular metabolic alteration. Therefore, infective agents may affect cellular metabolic pathways, by mediation or not of an altered immune system. The data reviewed here strongly suggest that the role of infections in many types of IMDs deserves greater attention for a better management of these disorders and a more focused therapeutic approach.

Brain-Type Creatine Kinase Release from Cultured Osteoclasts Exposed to Neridronate in Children Affected by Osteogenesis Imperfecta Type 1.

Brain-type creatine kinase (CK-BB) increases during osteoclastogenesis, with high circulating amounts in type I osteogenesis imperfecta (OI) following treatment with neridronate, a bisphosphonate able to inhibit osteoclast activity and survival. The aim of this study was to demonstrate the correlation between osteoclastogenesis and CK-BB release from OI patients' osteoclasts treated with different concentrations of neridronate. Our patients showed reduced bone quality, increased levels of CTX I, a marker of bone resorption, and decreased levels of OPG, an inhibitor of osteoclastogenesis. In OI patients, the presence of MCSF and RANKL determined an increased secretion of CK-BB from osteoclasts (p = 0.04) compared with control conditions without these cytokines; interestingly, in the absence of these factors, the secretion of CK-BB is significantly elevated at 3 µmol/L compared with 0.03 and 1 µmol/L (p = 0.007). In healthy donors' cultures, the higher concentration of CK-BB can be detected following stimulation with 3 µmol/L neridronate compared with the untreated condition both with and without MCSF and RANKL (p = 0.03 and p = 0.006, respectively). Consistently, in osteoclast cultures, neridronate treatment is associated with a decrease in multinucleated TRAP+ cells, together with morphology changes typical of apoptosis. Consistently, in the media of the same osteoclast cultures, we demonstrated a significant increase in caspase-3 levels. In conclusion, our findings support the idea that CK-BB levels increase in the serum of OI-treated patients.

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.

[Apheresis in children: procedures and outcome]. / Aferesi in eta' pediatrica: procedure e outcome.

Apheresis procedures are used in children to treat an increasing number of conditions by removing different types of substances from the bloodstream. In a previous study we evaluated the first results of our experience in children, emphasizing the solutions adopted to overcome technical difficulties and to adapt adult apheresis procedures to a pediatric population. The aim of the present study is to present data on a larger number of patients in whom apheresis was the main treatment. Ninety-three children (50 m, 43 f) affected by renal and/or extrarenal diseases were included. They were treated with LDL apheresis, protein A immunoadsorption, or plasma exchange. Our therapeutic protocol was the same as described in the previous study. Renal diseases and immunological disorders remained the most common conditions requiring this therapeutic approach. However, hemolytic uremic syndrome (HUS) was no longer the most frequent renal condition to be treated, as apheresis is currently the first treatment option only in cases of atypical HUS. In this series we also treated small children, showing that low weight should no longer be considered a contraindication to apheresis procedures. The low rate of complications and the overall satisfactory clinical results with increasingly advanced technical procedures make a wider use of apheresis in children realistic in the years to come.

Bone Remodeling in an Mps-1h Girl after Hematopoietic Stem Cell Transplantation along with Enzymatic Replacement Therapy.

BACKGROUND: Mucopolysaccharidosis-1H (Hurler syndrome, MPS-1H) is the most severe form of a lysosomal storage disorder (LSD) caused by variants in IDUA, encoding alpha- L-iduronidase (IDUA). MPS-1H is also associated with various degrees of skeletal defects due to the accumulation of partially degraded glycosaminoglycans (GAGs) in the lysosomes of connective tissue cells. The efficacy of hematopoietic stem cell transplantation (HSCT) and enzymatic replacement therapy (ERT) on MPS-1H skeletal manifestations is still considered unsatisfactory. CASE PRESENTATION: We report the case of a young girl, who manifested significant changes in bone remodeling markers and osteoclastogenesis potential after HSCT combined with ERT. She received ERT and underwent two HSCTs. The skeletal alterations at the time of diagnosis showed a trend toward improvement of both mobility and radiological features after HSCT. We observed the highest levels of Receptor activator of nuclear factor-kappa-Β ligand (RANKL) and RANK/osteoprotegerin (OPG) ratio at diagnosis and during ERT, consistently with spontaneous osteoclastogenesis. Conversely, after the successful HSCT with ongoing ERT, the highest levels of osteocalcin were observed and all markers of bone formation and resorption improved. CONCLUSION: The combination therapy of ERT and HSCT was effective in reducing osteoclast activity and increasing osteoblast activity, and these changes were according to the child's bone phenotype, IDUA activity, and Glycosaminoglycan (GAG) trends. These results represent one of the few pieces of human evidence in this context.

COVID-19 Vaccine in Inherited Metabolic Disorders Patients: A Cross-Sectional Study on Rate of Acceptance, Safety Profile and Effect on Disease.

BACKGROUND: Vaccines for COVID-19 have had a significant impact on the spread of COVID-19 infection, reducing the incidence and mortality of the infection in several countries. However, hesitancy toward this vaccine is a global health issue for the general population The Vaccine acceptance rate among patients affected with inherited metabolic disorders (IMD), as well as safety profile, has not been described. METHODS: We conducted a cross-sectional study, based on a telephone survey, investigating the COVID-19 vaccination rate, the incidence and type of adverse effects (AEs), the reasons for vaccine refusal and the effects on the underlying disease in a cohort of IMD patients followed at a single center and invited directly to vaccination by specialistic team. RESULTS: Seventy-four patients were included in the study, the median age was 23.4 years (min 12.1-max 61.7), 47% (n = 85) were females and 61% (107) were affected from impaired metabolism of phenylalanine. By October 2021, 94% (n = 163) of them had received at least one dose of the vaccine, which was, in 98% of cases, mRNA-based vaccine, given at the referral hospital in 65% of cases. Overall, 72% of patients with IMD reported AE to the vaccine: 60% after the first dose, 81% after the second. The highest rate of adverse events at the first dose was reported in patients with amino acids related disorders other than impaired phenylalanine metabolism (PKU/HPA) (88%). For the second dose, the PKU/HPA group reported the highest rate of AEs (89% of cases). There was no effect on the underlying disease or acute decompensation after the vaccine. Eleven patients (6%) were not vaccinated because they considered it dangerous. CONCLUSION: Among individuals with IMD, the vaccination rate was high, the incidence and severity of AEs were comparable to those in the general population with no effects on the disease. Direct contact with the specialist medical team, has proven to reassure patients and effectively contrast hesitancy.

The use of quantitative ultrasound in a tertiary-level children hospital: role in the follow-up of chronically ill patients.

PURPOSE: To evaluate the use of QUS for the bone status assessment in children cared because of a chronic disease such as: inherited metabolic disorder, kidney disease and endocrine defect and considered by the attending physician as at specific risk. METHODS: QUS outputs were calculated for each disorder and compared to: sex, age, Tanner stage, Z-score for height, weight and BMI (body mass index). RESULTS: One-hundred-sixty-eight subjects aged between 3.5 and 18 years met the inclusion criteria. The overall bone quality indexes were under the normal range in all the groups considered. Impairment of bone quality parameters was more evident in the group of patients with inherited metabolic disorders, in which 65% of patients in charge were studied by QUS. Older age and sexual development were associated with less pronounced bone quality impairment, as measured by QUS, in the vast majority of conditions. Overall, the diseases for which the prediction of outcome was the strongest were: hyperphenylalaninemia, nephrotic syndrome and insulin dependent diabetes mellitus. CONCLUSIONS: QUS is capable to provide information on skeletal status in children. Initial evaluation by QUS may allow defining patients with chronic disorders who deserve further, more invasive diagnostic studies. Inherited metabolic disorders warrant specific attention and strict monitoring for their potential effect on bone.

Food Habits and Lifestyle in Hyperphenylalaninemia Patients: Should These Be Monitored?

Studies on Hyperphenylalaninemia (HPA) patients are scarce and primarily focused on neurocognitive outcomes compared to PKU patients. In this study, we characterized the food habits and lifestyle of HPA patients compared with healthy peers. We performed a cross-sectional survey of a cohort of 30 patients (13 males, median age/range: 7.9; 2.2-16.7 years) and 28 controls (8 males, median age/range: 7.9; 2.1-16.7 years). Anthropometric parameters, food and nutrient intakes, and level of physical activity were assessed. Food neophobia, eating disorders, and body image perception was investigated by specific tests. Patients showed greater selectivity in the choice of foods than controls, preferring products with lower protein content (p-value: 0.03) and avoiding associating multiple protein and carbohydrate sources. A comparable tendency to distrust new foods emerged without elements suggestive of eating disorders. Patients had higher image dissatisfaction than peers (p-value: 0.01). This group of patients manifested more selective eating habits and worse body image acceptance. A regular evaluation of these aspects in these patients may result in a more effective follow-up of this disorder. More studies are needed to confirm these findings.

Body Composition in Adolescent PKU Patients: Beyond Fat Mass.

There is a lack of evidence on the impact on body composition of high protein intake and types of protein substitutes in PKU patients­particularly in adolescents, who are more inclined to dietary transgressions. In this observational, cross-sectional study, PKU patients were observed during prepubertal age (p) or after the pubertal spurt (P), assessing body composition and bone quality and correlating these parameters with dietary compliance and types of protein substitutes. Anthropometric and dietary data were evaluated together with bioelectrical impedance analysis (BIA), quantitative ultrasound (QUS) and branched-chain amino acids (BCAAs). A total of 36 patients (16 males, 17 prepubertal and 19 post-pubertal; mean ± SD age 11.4 ± 3.9 years) were included. A higher BMI was observed in adolescents (p-value: 0.018). The BIA revealed a significant increase in total body water (TBW) and muscle mass (MM) in P subjects either compliant (p-value: 0.001) or non-compliant with the diet (p-value: 0.001). MM content correlated with increased Phe intake (r = 0.63; p < 0.001). In the subgroup of five patients taking L-AAs and glycomacropeptides (GMPs), BCAA values tended to be lower than those taking only L-AA mixtures, with a significant trend for valine. Maintenance of body composition parameters within the normal range­for both fat and muscle mass­and levels of BCAAs can be helpful in reducing the risk of becoming overweight in adulthood. Further studies are needed to confirm these findings.

Novel approach to idursulfase and laronidase desensitization in type 2 and type 1 S mucopolysaccharidosis (MPS).

BACKGROUND: Idursulfase and laronidase are drugs used to treat Hunter syndrome (mucopolysaccharidosis type 2) and Scheie syndrome (mucopolysaccharidosis type 1 S), respectively. These are rare lysosomal storage disorders, leading to accumulation of glycosaminoglycans within lysosomes. Failure of early recognition of the disease and/or delay in starting the appropriate treatment result in severe clinical impairment and death. For almost 20 years, enzyme replacement therapy with recombinant proteins has represented the first line therapeutic option. However, administration of idursulfase and laronidase is associated with infusion-related hypersensitivity reactions, in approx. 20% of patients. In these patients, rapid desensitization by intravenous administration protocols has been used in order to avoid treatment discontinuation. This approach proved effective and safe. However, long-term tolerance could not be achieved. Thus, we decided to combine rapid desensitization with allergen immunotherapy-like desensitization. RESULTS: Two patients with Hunter syndrome and one patient with Scheie syndrome developed severe allergy to idursulfase and laronidase, respectively, preventing them from continuing the otherwise indispensable therapy. In all three patients, the possible IgE-mediated nature of the reactions suffered was suggested by positive skin tests with the two enzymes, respectively. By devising 12-step, 3-dilution rapid desensitization protocols, we resumed the enzyme replacement therapy. However, the prolonged time required for administration (a not negligible pitfall, since therapy should be given weekly for life) and the persistent occurrence of reactions (mild but still requiring anti-allergic medication at full dosage) led us to combine rapid desensitization with a compact 11-step, 24-day allergen immunotherapy-like desensitization protocol. Thus, idursulfase and laronidase were injected subcutaneously, with a 500-fold increase from step 1 to step 11 for idursulfase and a 222-fold increase for laronidase. This strategy led to restoration of long-term tolerance, allowing weekly intravenous therapy administration under standard conditions, according to the manufacturer instructions, in the absence of side effects and with only precautionary low-dose premedication. CONCLUSION: Rapid desensitization is a suitable and safe option in the case of idursulfase and laronidase allergy. Combination with subcutaneous allergen immunotherapy-like desensitization afforded restoration of enzyme replacement therapy given by the normal administration schedule, by inducing sustained tolerance.