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Hereditary transthyretin amyloidosis (hATTR) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensory-motor nerves, heart, autonomic function, and other organs. There are over 130 mutations known in the TTR gene. The His90Asn mutation has been previously reported in several reports, but its pathogenetic role is still debated. We report two sporadic cases of adult women with a heterozygous His90Asn mutation in TTR gene and neurological involvement extensively investigated. A typical Congo red-positive pathologic deposition of amyloid fibrils in the salivary glands was documented in one subject. Patients were successfully treated with patisiran with a good clinical outcome. These data support a pathogenetic role of His90Asn mutation in hATTR, and suggest early treatment in symptomatic carriers of His90Asn mutation. [ABSTRACT FROM AUTHOR]

Background: Law 219/2017 was approved in Italy in December 2017, after a years-long debate on the autonomy of healthcare choices. This Law, for the first time in Italian legislation, guarantees the patient's right to request for withdrawal of life-sustaining treatments, including mechanical ventilation (MV). Objective: To investigate the current status of MV withdrawal in amyotrophic lateral sclerosis (ALS) patients in Italy and to assess the impact of Law 219/2017 on this practice. Methods: We conducted a Web-based survey, addressed to Italian neurologists with expertise in ALS care, and members of the Motor Neuron Disease Study Group of the Italian Society of Neurology. Results: Out of 40 ALS Italian centers, 34 (85.0%) responded to the survey. Law 219/2017 was followed by an increasing trend in MV withdrawals, and a significant increase of neurologists involved in this procedure (p 0.004). However, variations across Italian ALS centers were observed, regarding the inconsistent involvement of community health services and palliative care (PC) services, and the intervention and composition of the multidisciplinary team. Conclusions: Law 219/2017 has had a positive impact on the practice of MV withdrawal in ALS patients in Italy. The recent growing public attention on end-of-life care choices, along with the cultural and social changes in Italy, requires further regulatory frameworks that strengthen tools for self-determination, increased investment of resources in community and PC health services, and practical recommendations and guidelines for health workers involved. [ABSTRACT FROM AUTHOR]

Few studies have focused on elderly (>80 years) amyotrophic lateral sclerosis (ALS) patients, who represent a fragile subgroup generally not included in clinical trials and often neglected because they are more difficult to diagnose and manage. We analyzed the clinical and genetic features of very late-onset ALS patients through a prospective, population-based study in the Emilia Romagna Region of Italy. From 2009 to 2019, 222 (13.76%) out of 1613 patients in incident cases were over 80 years old at diagnosis, with a female predominance (F:M = 1.18). Elderly ALS patients represented 12.02% of patients before 2015 and 15.91% from 2015 onwards (p = 0.024). This group presented with bulbar onset in 38.29% of cases and had worse clinical conditions at diagnosis compared to younger patients, with a lower average BMI (23.12 vs. 24.57 Kg/m2), a higher progression rate (1.43 vs. 0.95 points/month), and a shorter length of survival (a median of 20.77 vs. 36 months). For this subgroup, genetic analyses have seldom been carried out (25% vs. 39.11%) and are generally negative. Finally, elderly patients underwent less frequent nutritional- and respiratory-supporting procedures, and multidisciplinary teams were less involved at follow-up, except for specialist palliative care. The genotypic and phenotypic features of elderly ALS patients could help identify the different environmental and genetic risk factors that determine the age at which disease onset occurs. Since multidisciplinary management can improve a patient's prognosis, it should be more extensively applied to this fragile group of patients. [ABSTRACT FROM AUTHOR]

A concomitant presentation of relapsing remitting multiple sclerosis (RRMS) and amyotrophic lateral sclerosis (ALS) is quite rare. However, a review of the literature showed an increased co-occurrence of both diseases, including in genetically determined cases. We report the case of a 49-year-old woman with a history of RRMS who developed a progressive subacute loss of strength in her left arm. The patient's father died from ALS, and her paternal uncle had Parkinson's disease. Brain and cervical MRIs were performed, and new demyelinating lesions were excluded. Electromyography (EMG) of the upper limbs showed fibrillations and fasciculations in distal muscles of both arms. In the following months, the patient presented a progressive loss of strength in the proximal and distal muscles of the right arm and hyperreflexia in the lower limbs. EMG and central motor conduction were consistent with ALS. A genetic test was carried out, revealing a mutation in the FUS gene (exon 15; c. 1562 G>A). To our knowledge, the co-occurrence of MS and ALS in patients with FUS mutation is extremely rare. We hypothesize a common pathway for both diseases based on the possibility of a shared oligodendroglial dysfunction due to FUS mutation. [ABSTRACT FROM AUTHOR]

Increased incidence rates of amyotrophic lateral sclerosis (ALS) have been recently reported across various Western countries, although geographic and temporal variations in terms of incidence, clinical features and genetics are not fully elucidated. This study aimed to describe demographic, clinical feature and genotype–phenotype correlations of ALS cases over the last decade in the Emilia Romagna Region (ERR). From 2009 to 2019, our prospective population-based registry of ALS in the ERR of Northern Italy recorded 1613 patients receiving a diagnosis of ALS. The age- and sex-adjusted incidence rate was 3.13/100,000 population (M/F ratio: 1.21). The mean age at onset was 67.01 years; women, bulbar and respiratory phenotypes were associated with an older age, while C9orf72-mutated patients were generally younger. After peaking at 70–75 years, incidence rates, among women only, showed a bimodal distribution with a second slight increase after reaching 90 years of age. Familial cases comprised 12%, of which one quarter could be attributed to an ALS-related mutation. More than 70% of C9orf72-expanded patients had a family history of ALS/fronto-temporal dementia (FTD); 22.58% of patients with FTD at diagnosis had C9orf72 expansion (OR 6.34, p = 0.004). In addition to a high ALS incidence suggesting exhaustiveness of case ascertainment, this study highlights interesting phenotype–genotype correlations in the ALS population of ERR. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about the relations between amyotrophic lateral sclerosis (ALS) and sarcoidosis based on the magnetic resonance imaging analysis.

We describe the rare case of a young woman with hereditary neuropathy with liability to compression palsy (HNPP), who developed a rapidly progressive ALS. We suggest that underexpression of PMP22 protein in the nervous system might interfere with motor neuron function by impairing myelin formation and exposure of the axon to injury. Patients with ALS and evidence of demyelination should be screened for HNPP. [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Myotonia is rare in newborns, and not well-known. Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including sodium channel myotonias. We reported a 4-year-old female who presented with diffuse stiffness, bilateral clubfoot, hip dislocation, facial dysmorphisms and myotonia at birth. At 4 years of age the neurological examination showed characteristic “Hercules-like appearance” hyporeflexia, mild grip myotonia and bilateral pes cavus. The stiffness was worst at rest and in the early morning which improves with exercise. The clinical features, electromyography findings and diagnostic work-up of this patient and of child’s mother were described. The clinical follow-up led us to the diagnosis of sodium channel myotonia with atypical neonatal onset. Mutation analysis in the patient and in child’s mother revealed a novel heterozygous p.N1180I mutation in exon 19 of SCN4A gene. We recommend that in newborns with stiffness, peripheral contractures and myotonia, the sequence analysis of SCN4A gene should be performed. [ABSTRACT FROM AUTHOR]

Vaccines targeting the human papillomavirus (HPV) minor capsid protein L2 are emerging as chemico-physically robust and broadly protective alternatives to the current HPV (L1-VLP) vaccines. We have previously developed a trivalent L2 vaccine prototype exploiting Pyrococcus furiosus thioredoxin (PfTrx) as a thermostable scaffold for the separate presentation of three distinct HPV L2(20-38) epitopes. With the aim of achieving a highly immunogenic, yet simpler and more GMP-production affordable formulation, we report here on a novel thermostable nanoparticle vaccine relying on genetic fusion of PfTrx-L2 with the heptamerizing coiled-coil polypeptide OVX313. A prototype HPV16 monoepitope version of this nanoparticle vaccine (PfTrx-L2-OVX313; median radius: 8.6 ± 1.0 nm) proved to be approximately 10-fold more immunogenic and with a strikingly enhanced cross-neutralization capacity compared to its monomeric counterpart. Vaccine-induced (cross-)neutralizing responses were further potentiated in a multiepitope derivative displaying eight different L2(20-38) epitopes, which elicited neutralizing antibodies against 10 different HPVs including three viral types not represented in the vaccine. Considering the prospective safety of the PfTrx scaffold and of the OVX313 heptamerization module, PfTrx-OVX313 nanoparticles lend themselves as robust L2-based immunogens with a high translational potential as a 3 rd generation HPV vaccine, but also as a novel and extremely versatile peptide-antigen presentation platform.

Current prophylactic virus-like particle (VLP) human papillomavirus (HPV) vaccines are based on the L1 major capsid protein and provide robust but virus type-restricted protection. Moreover, VLP vaccines have a high production cost, require cold-chain storage, and are thus not readily implementable in developing countries, which endure 85% of the cervical cancer-related death burden worldwide. In contrast with L1, immunization with minor capsid protein L2 elicits broad cross-neutralization, and we previously showed that insertion of a peptide spanning amino acids 20-38 of L2 into bacterial thioredoxin (Trx) greatly enhances its immunogenicity. Building on this finding, we use, here, four different neutralization assays to demonstrate that low doses of a trivalent Trx-L2 vaccine, incorporating L2(20-38) epitopes from HPV16, HPV31 and HPV51, and formulated in a human-compatible adjuvant, induce broadly protective responses. Specifically, we show that this vaccine, which uses a far-divergent archaebacterial thioredoxin as scaffold and is amenable to an easy one-step thermal purification, induces robust cross-neutralization against 12 of the 13 known oncogenic HPV types. Immune performance measured with two different in vitro neutralization assays was corroborated by the results of mouse cervico-vaginal challenge and passive transfer experiments indicating robust cross-protection also in vivo. Altogether, our results attest to the potential of Trx-L2 as a thermostable second-generation HPV vaccine particularly well suited for low-resource countries., (©2015 American Association for Cancer Research.)

Fusion to carrier proteins is an effective strategy for stabilizing and providing immunogenicity to peptide epitopes. This is commonly achieved by cross-linking of chemically synthesized peptides to carrier proteins. An alternative approach is internal grafting of selected peptide epitopes to a scaffold protein via double stranded-oligonucleotide insertion or gene synthesis, followed by recombinant expression of the resulting chimeric polypeptide. The scaffold protein should confer immunogenicity to the stabilized and structurally constrained peptide, but also afford easy production of the antigen in recombinant form. A macromolecular scaffold that meets the above criteria is the redox protein thioredoxin, especially bacterial thioredoxin. Here we describe our current methodology for internal grafting of selected peptide epitopes to thioredoxin as tandemly arranged multipeptide repeats ("Thioredoxin Displayed Multipeptide Immunogens"), bacterial expression and purification of the recombinant thioredoxin-multipeptide fusion proteins and their use as antigens for the production of anti-peptide antibodies for prophylactic vaccine as well as diagnostic purposes.