18F-Florbetapir and 18F-FDG PET studies in the diagnostic evaluation of Alzheimer's disease

Clinical diagnosis of AD remains a challenge since there are no validated tests for an affirmative diagnosis and moreover several conditions can mimic it and their accuracy is suboptimal. Positron Emission Tomography (PET), is a modality for early detection of AD. 18F-Florbetapir is a novel PET tracer for amyloid brain pathology and AD imaging, while PET images with 18F-fluorodeoxyglucose (FDG) for cerebral glucose metabolism can provide complementary information to amyloid plaque imaging for diagnosis of AD. Aim of our study was to evaluate: (a) to witch degree amyloid imaging data could alter our clinical and diagnostic approach to AD, (b) the concordance degree with FDG PET imaging

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

Report of Five Years of Experience in Neonatal Screening for Mucopolysaccharidosis Type I and Review of the Literature

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disease, with neurological and visceral involvement, in which early diagnosis through newborn screening (NBS) and early treatment can improve outcomes. We present our first 5 years of experience with laboratory and clinical management of NBS for MPS I. Since 2015, we have screened 160,011 newborns by measuring alpha-L-iduronidase (IDUA) activity and, since 2019, glycosaminoglycans (GAGs) in dried blood spot (DBS) as a second-tier test. Positive screening patients were referred to our clinic for confirmatory clinical and molecular testing. We found two patients affected by MPS I (incidence of 1:80,005). Before the introduction of second-tier testing, we found a high rate of false-positives due to pseudodeficiency. With GAG analysis in DBS as a second-tier test, no false-positive newborns were referred to our clinic. The confirmed patients were early treated with enzyme replacement therapy and bone-marrow transplantation. For both, the clinical outcome of the disease is in the normal range. Our experience confirms that NBS for MPS I is feasible and effective, along with the need to include GAG assay as a second-tier test. Follow-up of the two positive cases identified confirms the importance of early diagnosis through NBS and early treatment to improve the outcome of these patients

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

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

Frontotemporal Dementia, Where Do We Stand? A Narrative Review

: Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered

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

Cerebral Venous Thrombosis during Thyrotoxicosis: Case Report and Literature Update

Cerebral venous thrombosis (CVT) is a rare cause of stroke, particularly in young adults. Several known thrombophilic conditions may lead to an increased CVT risk. Interestingly, few cases in the literature have reported an association between CVT and thyrotoxicosis. Here, we describe the case of a young woman with CVT and concomitant thyrotoxicosis, without any other known prothrombotic conditions. We also performed a literature review of CVT cases and hyperthyroidism, searching for all articles published in peer-reviewed journals. We identified 39 case reports/case series concerning patients with CVT associated with thyrotoxicosis, highlighting, in most cases, the association with additional known prothrombotic factors. We then discussed the possible mechanisms by which hyperthyroidism could underlie a pro-coagulative state resulting in CVT. Thyroid disease might be a more common prothrombotic risk factor than expected in determining CVT. However, in most cases, a coexistence of multiple risk factors was observed, suggesting a multifactorial genesis of the disorder. We hope that this work may alert clinicians to consider thyrotoxicosis as a potential risk factor for CVT, even in patients who apparently have no other pro-coagulative conditions

Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel

BACKGROUND: Classic infantile onset of Pompe disease (c-IOPD) leads to hypotonia and hypertrophic cardiomyopathy within the first days to weeks of life and, without treatment, patients die of cardiorespiratory failure in their first 1–2 years of life. Enzymatic replacement therapy (ERT) with alglucosidase alfa is the only available treatment, but adverse immune reactions can reduce ERT’s effectiveness and safety. It is therefore very important to identify strategies to prevent and manage these complications. Several articles have been written on this disease over the last 10 years, but no univocal indications have been established. METHODS: Our study presents a review of the current literature on management of immune responses to ERT in c-IOPD as considered by an Italian study group of pediatric metabolists and immunologists in light of our shared patient experience. RESULTS: We summarize the protocols for the management of adverse reactions to ERT, analyzing their advantages and disadvantages, and provide expert recommendations for their optimal management, to the best of current knowledge. However, further studies are needed to improve actual management protocols, which still have several limitations