Effect of enzyme substitution therapy on brain magnetic resonance imaging and cognition in adults with phenylketonuria: A case series of three patients.

Phenylketonuria, the most common inherited metabolic disease, results from a deficiency of phenylalanine hydroxylase enzyme activity that causes high blood phenylalanine levels. Most adults do not adhere to the gold standard therapy: lifelong treatment with a low-phenylalanine diet. Elevated and fluctuating phenylalanine levels in untreated adults can cause white matter abnormalities, neurological symptoms, and cognitive dysfunction (executive function). Pegvaliase, a derivative of the phenylalanine ammonia-lyase enzyme, metabolizes phenylalanine to trans-cinnamic acid and ammonia, and is approved by the US Food and Drug Administration and European Medicines Agency for subcutaneous administration in adults with phenylketonuria and blood phenylalanine concentrations > 600 µmol/L. In clinical trials, it reduced blood phenylalanine, even in patients consuming an unrestricted diet. We report longitudinal results on the first three such adults, in whom phenylalanine levels were quantified monthly, starting 1 year before pegvaliase administration and continuing through achievement of a pegvaliase response (defined as six consecutive monthly blood phenylalanine concentrations < 360 µmol/L while consuming an unrestricted diet). Brain magnetic resonance imaging (MRI) and neuropsychological assessments were performed before starting therapy and after response was achieved. Our results show that all three patients had significantly reduced white matter hyperintensities on brain MRI and improved executive function on neuropsychological assessment, especially on the Paced Auditory Serial Addition Test, which is known to be very sensitive to white matter functioning. To the best of our knowledge, this is the first report of concomitant improvements in cognitive performance and white matter damage after a pharmacological intervention to normalize phenylalanine levels in adults with phenylketonuria consuming an unrestricted diet.

Long-term follow-up of a patient with neonatal form of Gaucher disease.

Gaucher disease is the most common of the lysosomal storage diseases. It presents a wide phenotypic continuum, in which one may identify the classically described phenotypes, including type 1 form with visceral involvement, type 2 acute neuropathic early-infantile form, and type 3 subacute neuronopathic form. At the most severe end there is the perinatal form with onset in utero or during the neonatal period. The very few reported cases of neonatal onset Gaucher disease presented high and early mortality, due to neurological or visceral involvement, including liver failure. We report our experience treating a patient with the neonatal form of Gaucher disease who presented at birth with thrombocytopenia, hepatosplenomegaly and cholestasis. Despite early enzyme replacement therapy, liver disease was progressive. Liver biopsy showed hepatocellular giant-cell transformation, a nonspecific finding consistent with inflammation. The lack of response to enzyme replacement therapy and the microscopic findings suggested that mechanisms apart from substrate accumulation and Gaucher cells may play a role in the hepatic pathogenesis in Gaucher disease. An attempt to use corticosteroids at the age of 3 months resulted in a dramatic improvement in liver function and resulted in long-term survival. The patient is alive and 2 years old at this writing. Our case suggests that inflammatory processes may be important in the early pathogenesis of Gaucher disease and that early use of corticosteroids may open the way to a new therapeutic approach.

Newborn screening of mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I), a lysosomal storage disease caused by a deficiency of α-L-iduronidase, leads to storage of the glycosaminoglycans, dermatan sulfate and heparan sulfate. Available therapies include enzyme replacement and hematopoietic stem cell transplantation. In the last two decades, newborn screening (NBS) has focused on early identification of the disorder, allowing early intervention and avoiding irreversible manifestations. Techniques developed and optimized for MPS I NBS include tandem mass-spectrometry, digital microfluidics, and glycosaminoglycan quantification. Several pilot studies have been conducted and screening programs have been implemented worldwide. NBS for MPS I has been established in Taiwan, the United States, Brazil, Mexico, and several European countries. All these programs measure α-L-iduronidase enzyme activity in dried blood spots, although there are differences in the analytical strategies employed. Screening algorithms based on published studies are discussed. However, some limitations remain: one is the high rate of false-positive results due to frequent pseudodeficiency alleles, which has been partially solved using post-analytical tools and second-tier tests; another involves the management of infants with late-onset forms or variants of uncertain significance. Nonetheless, the risk-benefit ratio is favorable. Furthermore, long-term follow-up of patients detected by neonatal screening will improve our knowledge of the natural history of the disease and inform better management.

Detection of 3-O-methyldopa in dried blood spots for neonatal diagnosis of aromatic L-amino-acid decarboxylase deficiency: The northeastern Italian experience.

OBJECTIVE: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited autosomal recessive disorder of biogenic amine metabolism. Diagnosis requires analysis of neurotransmitter metabolites in cerebrospinal fluid, AADC enzyme activity analysis, or molecular analysis of the DDC gene. 3-O-methyldopa (3-OMD) is a key screening biomarker for AADC deficiency. METHODS: We describe a rapid method for 3-OMD determination in dried blood spots (DBS) using flow-injection analysis tandem mass spectrometry with NeoBase™ 2 reagents and 13C6-tyrosine as an internal standard, which are routinely used in high-throughput newborn screening. We assessed variability using quality control samples over a range of 3-OMD concentrations. RESULTS: Within-day and between-day precision determined with quality control samples demonstrated coefficients of variation <15%. 3-OMD concentrations in 1000 healthy newborns revealed a mean of 1.33 µmol/L (SD ± 0.56, range 0.61-3.05 µmol/L), 100 non-AADC control subjects (age 7 days - 1 year) showed a mean of 1.19 µmol/L (SD ± 0.35-2.00 µmol/L), and 81 patients receiving oral L-Dopa had a mean 3-OMD concentration of 14.90 µmol/L (SD ± 14.18, range 0.4-80.3 µmol/L). A patient with confirmed AADC was retrospectively analyzed and correctly identified (3-OMD 10.51 µmol/L). In April 2020, we started a pilot project for identifying AADC deficiency in DBSs routinely submitted to the expanded newborn screening program. 3-OMD concentrations were measured in 21,867 samples; no patients with AADC deficiency were identified. One newborn had a high 3-OMD concentration due to maternal L-Dopa treatment. DISCUSSION: We demonstrated a rapid new method to identify AADC deficiency using reagents and equipment already widely used in newborn screening programs. Although our study is limited, introduction of our method in expanded neonatal screening is feasible and could facilitate deployment of screening, allowing for early diagnosis that is important for effective treatment.

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.

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.

Non-Hodgkin lymphoma in a kidney transplanted patient with methylmalonic acidemia: Metabolic susceptibility and the role of immunosuppression.

Methylmalonic acidemia cblB type (MMA cblB) is an autosomal recessive inborn error of amino acid metabolism that results in impaired synthesis of adenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. It presents with episodes of coma, vomiting, hypotonia, metabolic acidosis, and hyperammonemia. End-stage kidney disease is a long-term complication. Treatments include vitamin B12 supplementation, L-carnitine, and a low-protein diet. Liver, kidney, or combined liver-kidney transplantations are promising options, but they are not without complications. We report a patient suffering from MMA cblB who developed end-stage kidney disease at 18 years of age. Kidney transplantation allowed him to recover normal kidney function and good metabolic control. Unfortunately, after two decades, he developed non-Hodgkin lymphoma and severe chemotherapy toxicity which led to his death. The risk of lymphoproliferative diseases is known to increase after solid organ transplantation. However, in MMA, factors including mitochondrial dysfunction and oncometabolites, may further increase the risk of malignancy and drug toxicity. Our report highlights the importance of considering the increased risk of cancer in long-term follow-up of MMA cblB patients, especially after solid organ transplantation. Moreover, when chemotherapy is needed, the increased risk of toxicity and metabolic decompensation should be considered and monitored.

The European reference network for metabolic diseases (MetabERN) clinical pathway recommendations for Pompe disease (acid maltase deficiency, glycogen storage disease type II).

Clinical pathway recommendations (CPR) are based on existing guidelines and deliver a short overview on how to deal with a specific diagnosis, resulting therapy and follow-up. In this paper we propose a methodology for developing CPRs for Pompe disease, a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase. The CPR document was developed within the activities of the MetabERN, a non-profit European Reference Network for Metabolic Diseases established by the European Union. A working group was selected among members of the MetabERN lysosomal storage disease subnetwork, with specific expertise in the care of Pompe disease, and patient support group representatives. The working strategy was based on a systematic literature search to develop a database, followed by quality assessment of the studies selected from the literature, and by the development of the CPR document according to a matrix provided by MetabERN. Quality assessment of the literature and collection of citations was conducted according to the AGREE II criteria and Grading of Recommendations, Assessment, Development and Evaluation methodology. General aspects were addressed in the document, including pathophysiology, genetics, frequency, classification, manifestations and clinical approach, laboratory diagnosis and multidisciplinary evaluation, therapy and supportive measures, follow-up, monitoring, and pregnancy. The CPR document that was developed was intended to be a concise and easy-to-use tool for standardization of care for patients among the healthcare providers that are members of the network or are involved in the care for Pompe disease patients.

Effects of antiepileptic therapy on bone mineral status evaluated by phalangeal quantitative ultrasound in pediatric patients with epilepsy and motor impairment.

BACKGROUND: In epileptic patients with motor disability, it's difficult to disentangle the effects of antiepileptic drugs (AEDs) on bone health from those provoked by impaired mobility. The aim of this study was to evaluate the effects of AEDs on bone mineral status by phalangeal quantitative ultrasound (QUS), a no-radiation and non-invasive method, in pediatric patients with motor impairment and epilepsy. METHODS: We enrolled 56 patients (31 females, 25 males) with epilepsy and motor impairment and 24 children with only motor disability (13 females, 11 males). Patients were stratified by Gross Motor Function Classification System Scale (GMFCS) in 4 groups: group A1 with epilepsy and mild motor impairment (GMFCS levels I-II), group A2 with only mild motor impairment, group B1 with epilepsy and severe motor impairment (GMFCS levels III-V), group B2 with only severe motor impairment. The bone mineral status was evaluated by phalangeal QUS and amplitude-dependent speed of sound (AD-SoS) Z-score was calculated for each patient. RESULTS: The four groups showed no significant differences in age, gender and 25-hydroxyvitamin D levels. The group B1 had a statistically lower amplitude-dependent speed of sound Z-score as compared to group A2 (P<0.05). The multivariate analysis of independent factors revealed a significant correlation between amplitude-dependent speed of sound Z-score and Gross Motor Function Classification System levels (P=0.004). The mean Z-score value decreased by 0.53, increasing the motor impairment. CONCLUSIONS: The bone mineral status measured as AD-SoS strongly correlates with severity of motor disability evaluated by GMFCS as compared to antiepileptic therapy and 25-hydroxyvitamin D levels.

Unusual Evolution of Hypertrophic Cardiomyopathy in Non-Compaction Myocardium in a Pompe Disease Patient.

Classic infantile Pompe disease is characterized by a severe phenotype with cardiomyopathy and hypotonia. Cardiomyopathy is generally hypertrophic and rapidly regresses after enzyme replacement therapy. In this report, for the first time, we describe a patient with infantile Pompe disease and hypertrophic cardiomyopathy that evolved into non-compaction myocardium after treatment. The male newborn had suffered since birth with hypertrophic cardiomyopathy and heart failure. He was treated with standard enzyme replacement therapy (ERT) (alglucosidase alfa) and several immunomodulation cycles due to the development of anti-ERT antibodies, without resolution of the hypertrophic cardiomyopathy. At the age of 2.5 years, he was treated with a new combination of ERT therapy (cipaglucosidase alfa) and a chaperone (miglustat) for compassionate use. After 1 year, the cardiac hypertrophy was resolved, but it evolved into non-compaction myocardium. Non-compaction cardiomyopathy is often considered to be a congenital, primitive cardiomyopathy, due to an arrest of compaction of the myocardium wall during the embryonal development. Several genetic causes have been identified. We first describe cardiac remodeling from hypertrophic cardiomyopathy to a non-compaction form in a patient with infantile Pompe disease treated with a new ERT. This has important implications both for the monitoring of Pompe disease patients and for the understanding of the pathophysiological basis of non-compaction myocardium.

Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation.

The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms "propionic acidemia" OR "propionate" AND "cardiomyopathy" OR "Long QT syndrome". We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin-angiotensin-aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options.

Variant in the allosteric domain of CPS1 protein associated with effectiveness of N-carbamoyl glutamate therapy in neonatal onset CPS1 deficiency.

OBJECTIVES: Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a severe urea cycle disorder. Patients can present with hyperammonemic coma in the first days of life. Treatment includes nitrogen scavengers, reduced protein intake and supplementation with L-arginine and/or L-citrulline. N-carbamoyl glutamate (NCG) has been hypothesized to stimulate the residual CPS1 function, although only few patients are reported. CASE PRESENTATION: We report a patient with neonatal-onset CPS1 deficiency who received NCG in association with nitrogen scavenger and L-citrulline. The patient carried the novel variants CPS1-c.2447A>G p.(Gln816Arg) and CPS1-c.4489T>C p.(Tyr1497His). The latter is localized in the C-terminal allosteric domain of the protein, and is implicated in the binding of the natural activator N-acetyl-L-glutamate. NCG therapy was effective in controlling ammonia levels, allowing to increase the protein intake. CONCLUSIONS: Our data show that the response to NCG can be indicated based on the protein structure. We hypothesize that variants in the C-terminal domain may be responsive to NCG therapy.

Newborn Screening for Fabry Disease: Current Status of Knowledge.

Fabry disease is an X-linked progressive lysosomal disorder, due to α-galactosidase A deficiency. Patients with a classic phenotype usually present in childhood as a multisystemic disease. Patients presenting with the later onset subtypes have cardiac, renal and neurological involvements in adulthood. Unfortunately, the diagnosis is often delayed until the organ damage is already irreversibly severe, making specific treatments less efficacious. For this reason, in the last two decades, newborn screening has been implemented to allow early diagnosis and treatment. This became possible with the application of the standard enzymology fluorometric method to dried blood spots. Then, high-throughput multiplexable assays, such as digital microfluidics and tandem mass spectrometry, were developed. Recently DNA-based methods have been applied to newborn screening in some countries. Using these methods, several newborn screening pilot studies and programs have been implemented worldwide. However, several concerns persist, and newborn screening for Fabry disease is still not universally accepted. In particular, enzyme-based methods miss a relevant number of affected females. Moreover, ethical issues are due to the large number of infants with later onset forms or variants of uncertain significance. Long term follow-up of individuals detected by newborn screening will improve our knowledge about the natural history of the disease, the phenotype prediction and the patients' management, allowing a better evaluation of risks and benefits of the newborn screening for Fabry disease.

Light and Shadows in Newborn Screening for Lysosomal Storage Disorders: Eight Years of Experience in Northeast Italy.

In the last two decades, the development of high-throughput diagnostic methods and the availability of effective treatments have increased the interest in newborn screening for lysosomal storage disorders. However, long-term follow-up experience is needed to clearly identify risks, benefits and challenges. We report our 8-year experience of screening and follow-up on about 250,000 neonates screened for four lysosomal storage diseases (Pompe disease, mucopolysaccharidosis type I, Fabry disease, Gaucher disease), using the enzyme activity assay by tandem mass spectrometry, and biomarker quantification as a second-tier test. Among the 126 positive newborns (0.051%), 51 infants were confirmed as affected (positive predictive value 40%), with an overall incidence of 1:4874. Of these, three patients with infantile-onset Pompe disease, two with neonatal-onset Gaucher disease and four with mucopolysaccharidosis type I were immediately treated. Furthermore, another four Gaucher disease patients needed treatment in the first years of life. Our study demonstrates the feasibility and effectiveness of newborn screening for lysosomal storage diseases. Early diagnosis and treatment allow the achievement of better patient outcomes. Challenges such as false-positive rates, the diagnosis of variants of uncertain significance or late-onset forms and the lack of treatment for neuronopathic forms, should be addressed.

Abnormal activation of MAPKs pathways and inhibition of autophagy in a group of patients with Zellweger spectrum disorders and X-linked adrenoleukodystrophy.

BACKGROUND: Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs. METHODS: Three patients with ZSD (2 M, 1 F; age range 8-17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy. RESULTS: X-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20-19.92) and 2.90-fold (range 1.43-4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio. CONCLUSIONS: In our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.

Congenital hyperinsulinism in clinical practice: From biochemical pathophysiology to new monitoring techniques.

Congenital hyperinsulinism comprises a group of diseases characterized by a persistent hyperinsulinemic hypoglycemia, due to mutation in the genes involved in the regulation of insulin secretion. The severity and the duration of hypoglycemic episodes, primarily in the neonatal period, can lead to neurological impairment. Detecting blood sugar is relatively simple but, unfortunately, symptoms associated with hypoglycemia may be non-specific. Research in this field has led to novel insight in diagnosis, monitoring and treatment, leading to a better neurological outcome. Given the increased availability of continuous glucose monitoring systems that allow glucose level recognition in a minimally invasive way, monitoring the glycemic trend becomes easier and there are more possibilities of a better follow-up of patients. We aim to provide an overview of new available technologies and new discoveries and their potential impact on clinical practice, convinced that only with a better awareness of the disease and available tools we can have a better impact on CHI diagnosis, prevention and clinical sequelae.

Atherogenic lipid profile in patients with Niemann-Pick disease type B: What treatment strategies?

Niemann-Pick disease (NPD) type A and type B are part of the spectrum disease of the acid sphingomyelinase deficiency (ASMD). Plasma lipid abnormalities are frequently associated with both NPD-A and NPD-B, and include decreased high-density lipoprotein cholesterol (HDL-C), increased low-density lipoprotein cholesterol (LDL-C), and hypertriglyceridemia. The atherogenic lipid profile has been associated to early atherosclerotic vascular disease and coronary artery disease in NPD-B patients. Thus, early treatment of dyslipidemia in these patients is advisable. We present here a pediatric case of NPD-B with an atherogenic lipid profile not responding to lifestyle changes, low fat diet, and daily supplementation with plant sterols. We reviewed the existing literature about the treatment strategies for dyslipidemia in ASMD patients, with a special focus on the pediatric age. Finally, we speculated on the mechanisms underlying dyslipidemia in this disorder. The clinical experiences in lipid-lowering strategies in NPD-B patients are limited, in particular in the pediatric age. Olipudase alfa appears as the most promising candidate for improving lipid profile. Since olipudase alfa is not yet approved and, due to its costs, it will probably not be available for all patients worldwide, further research is needed to broaden our knowledge on this clinical need and to evaluate the efficacy and the long-term effects of lipid-lowering agents in ASMD patients. A deep understanding of the pathophysiology of dyslipidemia in ASMD may promote the identification of new targets and support the identification of new therapeutic strategies.

A new strategy of desensitization in mucopolysaccharidosis type II disease treated with idursulfase therapy: A case report and review of the literature.

Mucopolysaccharidosis type II (MPS II) is a multisystemic lysosomal storage disorder caused by deficiency of the iduronate 2-sulfatase enzyme. Currently, enzyme replacement therapy (ERT) with recombinant idursulfase is the main treatment available to decrease morbidity and improve quality of life. However, infusion-associated reactions (IARs) are reported and may limit access to treatment. When premedication or infusion rate reductions are ineffective for preventing IARs, desensitization can be applied. To date, only two MPS II patients are reported to have undergone desensitization. We report a pediatric patient with recurrent IARs during infusion successfully managed with gradual desensitization. Our protocol started at 50% of the standard dosage infused at concentrations from 0.0006 to 0.06 mg/ml on weeks 1 and 2, followed by 75% of the standard dosage infused at concentrations from 0.0009 to 0.09 mg/ml on weeks 3 and 4, and full standard dosage thereafter, infused at progressively increasing concentrations until the standard infusion conditions were reached at 3 months. Our experience can be used in the management of MPS II patients presenting IARs to idursulfase infusion, even when general preventive measures are already administered.

Bone disease in early detected Gaucher Type I disease: A case report.

Gaucher disease (GD) is a lysosomal disorder characterized by the storage of glucosylceramide in macrophages ("Gaucher cells"), particularly in the spleen, liver, and bone marrow. The most common phenotype, GD type 1, usually presents with hepatosplenomegaly, cytopenias, and sometimes bone involvement at variable age. Enzyme replacement therapy (ERT) is available and effective, but some severe manifestations are irreversible (e.g., osteonecrosis), so that early treatment is crucial. We describe a 4-year-old Albanian male with GD type 1, diagnosed through newborn screening (NBS), presented during follow up with multiple osteonecrotic areas in both femurs. He had no other symptoms or signs of disease, except for increasing of lyso-Gb1 biomarker. Early initiation of ERT allowed a partial improvement of bone lesions. Our case highlights the importance of NBS for GD and of close follow-up of presymptomatic patients, especially if biomarker levels are increasing. In the absence of NBS, GD should be considered in patients who present with bone lesions, also isolated. Early diagnosis and treatment improve the course of disease and avoid irreversible sequelae.

Newborn screening for Pompe disease in Italy: Long-term results and future challenges.

Pompe disease (PD) is a progressive neuromuscular disorder caused by a lysosomal acid α-glucosidase (GAA) deficiency. Enzymatic replacement therapy is available, but early diagnosis by newborn screening (NBS) is essential for early treatment and better outcomes, especially with more severe forms. We present results from 7 years of NBS for PD and the management of infantile-onset (IOPD) and late-onset (LOPD) patients, during which we sought candidate predictive parameters of phenotype severity at baseline and during follow-up. We used a tandem mass spectrometry assay for α-glucosidase activity to screen 206,741 newborns and identified 39 positive neonates (0.019%). Eleven had two pathogenic variants of the GAA gene (3 IOPD, 8 LOPD); six carried variants of uncertain significance (VUS). IOPD patients were treated promptly and had good outcomes. LOPD and infants with VUS were followed; all were asymptomatic at the last visit (mean age 3.4 years, range 0.5-5.5). Urinary glucose tetrasaccharide was a useful and biomarker for rapidly differentiating IOPD from LOPD and monitoring response to therapy during follow-up. Our study, the largest reported to date in Europe, presents data from longstanding NBS for PD, revealing an incidence in North East Italy of 1/18,795 (IOPD 1/68,914; LOPD 1/25,843), and the absence of mortality in IOPD treated from birth. In LOPD, rigorous long-term follow-up is needed to evaluate the best time to start therapy. The high pseudodeficiency frequency, ethical issues with early LOPD diagnosis, and difficulty predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study.