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Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Methylenetetrahydrofolate Reductase (MTHFR) deficiency, is avery rare congenital defect of folate metabolism, inherited in an autosomal recessive pattern included in newbornscreening (NBS) programs in Italy. It is caused by mutations in the MTHFRgene and is characterized by elevatedplasma homocysteine and borderline-low or normal methionine levels, causing severe neurological signs, recurrentapnoea, microcephaly and convulsions, generally during the neonatal period. An early treatment may prevent theclinical manifestations with a positive impact on patient’s health. We report a new case of MTHFRdeficiency, identified during NBS that showed hypomethioninemia 4.6 μmol/L (r.i.6-20). The second level-test revealed hyperhomocysteinemia (106.7 μM, r.i. 5-15). The whole sequencing of theMTHFRgene showed two missense mutation: c.176G>C (p.Trp59Ser), reported as disease causing and the novelc.1769T>G (p.Leu590Arg), classified as likely pathogenetic. The baby was immediately treated with vitamin B12,folate and betaine; after 12 months of follow-up he has no signs or symptoms of the disease. In conclusion, this case report highlights the importance of NBS for inborn errors of metabolism and genetic analysis,that can prevent the establishment of a serious disorder of folate metabolism.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat. METHODS: The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if ≥3/4 domain scores were lower/unchanged, and as 'progressed' if

Alpha-dystroglycanopathies are a group of progressive and untreatable neuromuscular disorders, due to aberrant alpha-dystroglycan glycosylation. We describe the effects of a short-term cycle of corticosteroid therapy in a 9-year-old boy, affected by an alpha-dystroglycanopathy due to GMPPB gene mutations. The patient was affected by a congenital progressive muscular dystrophy since the first month of life, associated with psychomotor delay, seizures, and congenital bilateral cataracts. Despite physical therapy he had a progressive motor impairment. At the age of 9 years, he was treated with 0.75 mg/kg/day of prednisone for 3 months and showed improvements in muscle strength and function scores and creatine kinase reduction. When steroid therapy was discontinued he showed again clinical and biochemical deterioration. These data suggest that corticosteroid may be considered as a treatment for patients with alpha-dystroglycanopathies due to GMPPB mutations. (C) 2018 Elsevier B.V. All rights reserved.

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare disease, and several gaps of knowledge on various issues remain, particularly at a regional/national level. Expert opinions collected through well-defined consensus methodologies are increasingly used to make available reliable information in the context of rare/ultra-rare diseases. With the aim to provide indications on infantile neurovisceral ASMD (also formerly known as Niemann–Pick disease type A), chronic neurovisceral ASMD (formerly known as Niemann–Pick disease type A/B) and chronic visceral ASMD (formerly known as Niemann–Pick disease type B) in Italy, we conducted a Delphi consensus of experts focused on five main areas: (i) patients and disease characteristics; (ii) unmet needs and quality of life; (iii) diagnostic issues; (iv) treatment-related aspects; and (v) patient journey. Pre-specified, objective criteria were used to outline the multidisciplinary panel, based on 19 Italian experts in ASMD in paediatric and adult patients from different Italian Regions, including both clinicians (n = 16) and ASMD patients’ advocacy or payors with expertise in rare diseases (n = 3). During two Delphi rounds, a high ratio of agreement was found on several topics related to ASMD characteristics, diagnosis, management and disease burden. Our findings may provide valuable indications for management of ASMD at a public health level in Italy.

Summary Background Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease. Methods We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov , NCT03729362 . Findings Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. Interpretation Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. Funding Amicus Therapeutics.

Biallelic variants in nuclear gene NDUFA2 have been reported so far in only three children with variable presentations including Leigh syndrome or leukoencephalopathy. Herein, we report a further female child affected by NDUFA2‐related disorder presenting with cavitating and tigroid‐like pattern of leukodystrophy and without systemic biochemical abnormalities of mitochondrial disorders.

Pompe disease is a metabolic myopathy due to acid alpha‐glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha‐glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy. We found elevated oxidative stress levels in tissues from the Pompe disease murine model and in patients’ cells. In cells, stress levels inversely correlated with the ability of rhGAA to correct the enzymatic deficiency. Antioxidants (N‐acetylcysteine, idebenone, resveratrol, edaravone) improved alpha‐glucosidase activity in rhGAA‐treated cells, enhanced enzyme processing, and improved mannose‐6‐phosphate receptor localization. When co‐administered with rhGAA, antioxidants improved alpha‐glucosidase activity in tissues from the Pompe disease mouse model. These results indicate that oxidative stress impacts on the efficacy of enzyme replacement therapy in Pompe disease and that manipulation of secondary abnormalities may represent a strategy to improve the efficacy of therapies for this disorder., Enzyme replacement therapy (ERT) with recombinant human alpha‐glucosidase (rhGAA) is currently the standard of care for the treatment of Pompe disease. However, this approach shows important limitations. We have tested whether modulation of oxidative stress may improve the efficacy of ERT.

Hypoglycemia is the result of defects/impairment in glucose homeostasis. The main etiological causes are metabolic and/or endocrine and/or other congenital disorders. Despite hypoglycemia is one of the most common emergencies in neonatal age and childhood, no consensus on the definition and diagnostic work-up exists yet. Aims of this review are to present the current age-related definitions of hypoglycemia in neonatal-pediatric age, to offer a concise and practical overview of its main causes and management and to discuss the current diagnostic-therapeutic approaches. Since a systematic and prompt approach to diagnosis and therapy is essential to prevent hypoglycemic brain injury and long-term neurological complications in children, a comprehensive diagnostic flowchart is also proposed.

The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders.

Pompe disease is a metabolic myopathy, due to deficiency of alpha glucosidase, with a wide clinical spectrum. Enzyme replacement therapy is the only available treatment to improve morbidity and mortality, especially in infantile-onset form. However, some patients experience infusion-associated reactions, which may restrict their access to this treatment. We report on two patients (respectively 12 and 3 months old) with infantile-onset Pompe disease and severe cardiomyopathy, that presented with severe reactions during infusion of enzyme replacement therapy and were successfully desensitized with a new individualized protocol. Our protocol, using microdilution and a premedication with antihistamines, corticosteroids, and tranexamic acid, seems safe and effective and it may allow the continuation of therapy in Pompe patients resulting in the reduction of morbidity and mortality related to this disease.

Introduction Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB. Methods We measured the aortic diameters in 15 KO male mice, 5 for each LSD: 5 GLA-/- mice for FD, 5 NAGLU-/- mice for MPS IIIB, 5 GAA-/- mice for PD, and 15 wild type (WT) mice: 5 for each strain. In order to compare the aortic parameters between KO and WT mice deriving from the same colonies, different diameters were echocardiographically measured: aortic annulus, aortic sinus, sino-tubular junction, ascending aorta, aortic arch and descending aorta. Storage material content and aortic defects of the KO mice were also analyzed by histology, when available. Results Compared to their correspondent WT mice: GAA-/- mice showed greater diameters of ascending aorta (1.61mm vs. 1.11mm, p-value = 0.01) and descending aorta (1.17mm vs 1.02mm, p-value 0.04); GLA-/- mice showed greater diameters of aortic annulus (1.35mm vs. 1.22mm, p-value = 0.01), sinus of Valsalva (1.6mm vs. 1.38mm, p-value

In the last years tandem mass spectrometry (MS/MS) has become a leading technology used for neonatal screening purposes. Newborn screening by MS/MS on dried blood spot samples (DBS) has one of its items in methionine levels: the knowledge of this parameter allows the identification of infant affected by homocystinuria (cystathionine β-synthase, CBS, deficiency) but can also lead, as side effect, to identify cases of methionine adenosyltransferase (MAT) type I/III deficiency.We started an expanded newborn screening for inborn errors of metabolism in Campania region in 2007. Here we report our ten years experience on expanded newborn screening in identifying patients affected by hypermethioninemia. During this period we screened approximately 77,000 infants and identified two cases: one case of classical homocystinuria and one patient affected by defect of MAT I/III. In this paper we describe these patients and their biochemical follow-up and review the literature concerning worldwide newborn screening reports on incidence of CBS and MAT deficiency. Keywords: Newborn screening, Hypermethioninemia, MAT I/III deficiency, CBS deficiency

Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Preexisting immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of gene therapy. In the prospect of an AAV8-mediated, liver-directed gene therapy clinical trial for mucopolysaccharidosis VI (MPS VI), a lysosomal storage disorder caused by arylsulfatase B (ARSB) deficiency, we investigated in a multiethnic cohort of MPS VI patients the prevalence of neutralizing antibodies (Nab) to AAV8 and the presence of ARSB cross-reactive immunologic material (CRIM), which will either affect the efficacy of gene transfer or the duration of phenotypic correction. Thirty-six MPS VI subjects included in the study harbored 45 (62.5%) missense, 13 (18%) nonsense, 9 (12.5%) frameshift (2 insertions and 7 deletions), and 5 (7%) splicing ARSB mutations. The detection of ARSB protein in 24 patients out of 34 (71%) was predicted by the type of mutations. Preexisting Nab to AAV8 were undetectable in 19/33 (58%) analyzed patients. Twelve out of 31 patients (39%) tested were both negative for Nab to AAV8 and CRIM-positive. In conclusion, this study allows estimating the number of MPS VI patients eligible for a gene therapy trial by intravenous injections of AAV8.

PURPOSE. To evaluate the suitability of gene delivery-based approaches as potential treatment of Leber Congenital Amaurosis 4 (LCA4) due to AIPL1 mutations. METHODS. Genomic DNA from patients was analyzed using a microarray chip and direct sequencing. A detailed clinical evaluation including fundus autofluorescence (FAF) and optical coherence tomography (OCT) was performed in patients with AIPL1 mutations. Aipl1 null mice and porcine eyes were subretinally injected with adeno-associated viral (AAV) vectors harboring the human AIPL1 coding sequence. RESULTS. We identified ten LCA4 patients with mutations in AIPL1. The p.W278X sequence variation was the one most frequently found. Clinical assessment revealed common features including diffuse retinal dystrophies and maculopathy. However, OCT showed partially retained photoreceptors in extra-macular regions at all ages. The FAF was elicitable at the posterior pole and absent in the fovea. AAV-mediated gene transfer in Aipl1 -/- mice was associated with restoration of AIPL1 and βPDE expression in photoreceptors and protection from degeneration. Administration of a clinically relevant dose of AAV2/8-AIPL1 to the pre-clinical large porcine retina resulted in high level of AIPL1 photoreceptor expression in the absence of toxicity. CONCLUSIONS. Using advanced imaging diagnostics we showed that maculopathy is a main feature of LCA4. We identified retinal areas at the posterior pole with surviving photoreceptors present even in adult LCA4 patients, which could be the target of gene therapy. The possible use of gene therapy for LCA4 is additionally supported by the protection from photoreceptor degeneration observed in Aipl 1-/- mice and by the high levels of photoreceptor transduction in the absence of toxicity observed following AAV2/8 delivery to the large porcine retina. PMID: 21474771 [PubMed - as supplied by publisher]

Aim Dysphagia is a known complication in Pompe Disease (PD), a severe metabolic myopathy due to alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) with alglucosidase alfa is the only approved therapy for PD. Presently no data are available on the effects of ERT on dysphagia in PD patients. The aim of this work is to evaluate the course of this complication in a 6 years old boy affected by PD after treatment with ERT. Methods Dysphagia was assessed by Videofluoroscopic Swallowing Study (VFSS) at baseline, before the start of ERT and after 36 months of therapy. We used the Dysphagia Severity Rating Scale (DSS) to define the severity grade of dysphagia. Results VFSS performed at baseline revealed complete incoordination of oral stage swallowing which was classified as a grade 1 dysphagia according to DSS. After 36 months of treatment VFSS revealed normal swallowing, classified as grade 0 by DSS. Conclusion Our results suggest that ERT is effective in improving dysphagia. VFSS may be a useful tool to investigate and monitor swallowing disorders in patients affected by PD.

Lysinuric protein intolerance (LPI; MIM 222700) is a rare, autosomal recessive metabolic disorder caused by mutations in the SLC7A7 gene, which encodes the light chain of the cationic amino acids (CAA) transporter y+. The clinical presentation of LPI includes gastrointestinal symptoms, failure to thrive, episodes of coma, hepatosplenomegaly and osteoporosis. However, other findings have also been reported, and these suggest a multisystem involvement. We report a girl with confirmed LPI who presented with severe short stature that was unresponsive to adequate LPI treatment. The girl was found to have a classic growth hormone deficiency (GHD) and responded well to growth hormone (GH) replacement therapy. While it is not known whether the mechanisms involved in the GHD of our patient are related to LPI, this case suggests that GH/IGF-I axis should be investigated in LPI children with persistent growth failure.

Background: To determine diagnostic accuracy of anti–Saccharomyces cerevisiae antibodies (ASCA) in identifying children with inflammatory bowel disease (IBD) and to differentiate Crohn's disease (CD) from other IBD forms; and to determine the effect of medical or surgical treatment and of disease location and activity on ASCA titers. Methods: Serum samples were obtained from 196 IBD children and 142 controls. ASCA IgA and IgG titers were measured by ELISA. Measurements were repeated during the follow up of CD children. Results: ASCA titers were significantly higher in CD than in other IBD and in control patients. Combination of IgA and IgG ASCA positivity was highly specific for CD. Medical treatment and disease location did not influence assay results. Significantly lower ASCA titers were obtained in CD children with intestinal resection compared to CD-affected children who did not undergo surgical resection. ASCA titers correlated significantly with disease activity, and children with severe active disease showed higher ASCA values compared to those in remission. A signficant reduction of ASCA was observed during the follow-up of CD children when clinical remission was achieved. Conclusions: The diagnostic accuracy of ASCA is influenced by disease activity and this suggests an additional use for the follow-up of CD children of this assay.