Impact of COVID-19 related healthcare crisis on treatments for patients with lysosomal storage disorders, the first Italian experience.

The direct and indirect effects of Coronavirus Disease-19 (COVID-19) pandemic, on Italian patients with lysosomal storage disorders receiving therapy, were analyzed by a phone questionnaire. No proved COVID-19 emerged among 102 interviewed. No problems were reported by patients receiving oral treatments. Forty-nine% of patients receiving enzyme replacement therapy in hospitals experienced disruptions, versus 6% of those home-treated. The main reasons of missed infusions were fear of infection (62.9%) and re-organization of the infusion centers (37%).

Vitamin D deficiency in a population of migrant children: an Italian retrospective cross-sectional multicentric study.

BACKGROUND: Vitamin D is a hot topic in the scientific community. Its deficiency and the implications for the children's health became increasingly discussed during the last 20 years. The main aim of this retrospective study was to determinate the prevalence of vitamin D metabolism disorders in a population of adopted children and their risk factors. METHODS: We gathered data from 2140 children observed in five different National Working Group for the Migrant Children of the Italian Society of Pediatrics centers, variously located in Italy. Serum 25-hydroxy (OH)-D concentration was used to determine every child's vitamin D status, defined as severely deficient (serum 25-OH-D < 10 ng/ml), moderately deficient (serum 25-OH-D {≥10 ng/ml U < 20 ng/ml}), mildly deficient (serum 25-OH-D {≥20 ng/ml U < 30 ng/ml}) and normal (serum 25-OH-D ≥ 30 ng/ml). RESULTS: Mean value of serum 25-OH-D was 22.7 ng/ml (SD ± 12.1). Vitamin D status was deemed as normal in 483 (22.6%) children, mildly deficient in 718 (33.6%) children, moderately deficient in 730 (34.1%) children and severely deficient in 209 (9.8%) children. CONCLUSIONS: A very high percentage of migrant children is affected by hypovitaminosis D, with a strong association with age, geographic origin, season of blood sample collection and time spent in Italy after the arrival. This finding highlights the need for corrective measures. However, these measures cannot be applied without increasing the access of migrant populations to healthcare services.

Plasma Neurofilament Light (NfL) in Patients Affected by Niemann-Pick Type C Disease (NPCD).

(1) Background: Niemann-Pick type C disease (NPCD) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. The clinical presentation is characterized by visceral and neurological involvement. Apart from a small group of patients presenting a severe perinatal form, all patients develop progressive and fatal neurological disease with an extremely variable age of onset. Different biomarkers have been identified; however, they poorly correlate with neurological disease. In this study we assessed the possible role of plasma NfL as a neurological disease-associated biomarker in NPCD. (2) Methods: Plasma NfL levels were measured in 75 healthy controls and 26 patients affected by NPCD (24 NPC1 and 2 NPC2; 39 samples). (3) Results: Plasma NfL levels in healthy controls correlated with age and were significantly lower in pediatric patients as compared to adult subjects (p = 0.0017). In both pediatric and adult NPCD patients, the plasma levels of NfL were significantly higher than in age-matched controls (p < 0.0001). Most importantly, plasma NfL levels in NPCD patients with neurological involvement were significantly higher than the levels found in patients free of neurological signs at the time of sampling, both in the pediatric and the adult group (p = 0.0076; p = 0.0032, respectively). Furthermore, in adults the NfL levels in non-neurological patients were comparable with those found in age-matched controls. No correlations between plasma NfL levels and NPCD patient age at sampling or plasma levels of cholestan 3ß-5α-6ß-triol were found. (4) Conclusions: These data suggest a promising role of plasma NfL as a possible neurological disease-associated biomarker in NPCD.

In vitro and in vivo effects of Ambroxol chaperone therapy in two Italian patients affected by neuronopathic Gaucher disease and epilepsy.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the acid ß-glucosidase encoding gene (GBA1), resulting in the deficient activity of acid ß-glucosidase (GCase). To date, there is no approved treatment for the neurological manifestations of the disease. The role of Ambroxol as a chaperone for mutant GCase has been extensively demonstrated in vitro. Furthermore, different authors have reported beneficial effects of high doses of Ambroxol on neurological manifestations in patients affected by GD. In this report, we describe the in vitro and in vivo effects of Ambroxol in two patients (P1 and P2) affected by the neurological form of GD and epilepsy, carrying mutations already reported as responsive to the chaperone. Indeed, P1 presented the N188S mutation in compound heterozygous with a null allele (IVS2 + 1G > A) and P2 was homozygous for the L444P mutation. As expected, a beneficial effect of Ambroxol was observed in cultured fibroblasts as well as in vivo, both on epilepsy and on biomarkers of GD, in P1. However, Ambroxol was completely undefective in P2, suggesting that other factors besides the GBA1 mutation itself would be involved in the response therapy which would be difficult to predict based on the patient genotype. The present report expands the experience of Ambroxol treatment in neurological GD patients and highlights the need to in vitro test the individual response to Ambroxol even in patients carrying mutations already classified as responsive to the chaperone.

Improving diagnosis for rare diseases: the experience of the Italian undiagnosed Rare diseases network.

BACKGROUND: For a number of persons with rare diseases (RDs) a definite diagnosis remains undiscovered with relevant physical, psychological and social consequences. Undiagnosed RDs (URDs) require other than specialised clinical centres, outstanding molecular investigations, common protocols and dedicated actions at national and international levels; thus, many "Undiagnosed RDs programs" have been gradually developed on the grounds of a well-structured multidisciplinary approach. METHODS: The Italian Undiagnosed Rare Diseases Network (IURDN) was established in 2016 to improve the level of diagnosis of persons with URD living in Italy. Six Italian Centres of Expertise represented the network. The National Centre for Rare Diseases at the Istituto Superiore di Sanità coordinates the whole project. The software PhenoTips was used to collect the information of the clinical cases. RESULTS: One hundred and ten cases were analysed between March 2016 and June 2019. The age of onset of the diseases ranged from prenatal age to 51 years. Conditions were predominantly sporadic; almost all patients had multiple organs involvements. A total of 13/71 family cases were characterized by WES; in some families more than one individual was affected, so leading to 20/71 individuals investigated. Disease causing variants were identified in two cases and were associated to previously undescribed phenotypes. In 5 cases, new candidate genes were identified, although confirmatory tests are pending. In three families, investigations were not completed due to the scarce compliance of members and molecular investigations were temporary suspended. Finally, three cases (one familial) remain still unsolved. Twelve undiagnosed clinical cases were then selected to be shared at International level through PhenomeCentral in accordance to the UDNI statement. CONCLUSIONS: Our results showed a molecular diagnostic yield of 53,8%; this value is comparable to the diagnostic rates reported in other international studies. Cases collected were also pooled with those collected by UDNI International Network. This represents a unique example of global initiative aimed at sharing and validating knowledge and experience in this field. IURDN is a multidisciplinary and useful initiative linking National and International efforts aimed at making timely and appropriate diagnoses in RD patients who still do not have a confirmed diagnosis even after a long time.