Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by
NOTCH3
mutations and characterized by typical clinical, ...neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.
Myostatin is a negative regulator of skeletal muscle growth secreted by skeletal myocytes. In the past years, myostatin inhibition sparked interest among the scientific community for its potential to ...enhance muscle growth and to reduce, or even prevent, muscle atrophy. These characteristics make it a promising target for the treatment of muscle atrophy in motor neuron diseases, namely, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), which are rare neurological diseases, whereby the degeneration of motor neurons leads to progressive muscle loss and paralysis. These diseases carry a huge burden of morbidity and mortality but, despite this unfavorable scenario, several therapeutic advancements have been made in the past years. Indeed, a number of different curative therapies for SMA have been approved, leading to a revolution in the life expectancy and outcomes of SMA patients. Similarly, tofersen, an antisense oligonucleotide, is now undergoing clinical trial phase for use in ALS patients carrying the SOD1 mutation. However, these therapies are not able to completely halt or reverse progression of muscle damage. Recently, a trial evaluating apitegromab, a myostatin inhibitor, in SMA patients was started, following positive results from preclinical studies. In this context, myostatin inhibition could represent a useful strategy to tackle motor symptoms in these patients. The aim of this review is to describe the myostatin pathway and its role in motor neuron diseases, and to summarize and critically discuss preclinical and clinical studies of myostatin inhibitors in SMA and ALS. Then, we will highlight promises and pitfalls related to the use of myostatin inhibitors in the human setting, to aid the scientific community in the development of future clinical trials.
Background
During Covid-19 pandemic, the Italian government adopted restrictive limitations and declared a national lockdown on March 9, which lasted until May 4 and produced dramatic consequences on ...people’s lives. The aim of our study was to assess the impact of prolonged lockdown on behavioral and psychological symptoms of dementia (BPSD).
Methods
Between April 30 and June 8, 2020, we interviewed with a telephone-based questionnaire the caregivers of the community-dwelling patients with dementia who had their follow-up visit scheduled from March 9 to May 15 and canceled due to lockdown. Among the information collected, patients’ BPSDs were assessed by the Neuropsychiatric Inventory (NPI). Non-parametric tests to compare differences between NPI scores over time and logistic regression models to explore the impact of different factors on BPSD worsening were performed.
Results
A total of 109 visits were canceled and 94/109 caregivers completed the interview. Apathy, irritability, agitation and aggression, and depression were the most common neuropsychiatric symptoms experienced by patients both at baseline and during Covid-19 pandemic. Changes in total NPI and caregiver distress scores between baseline and during lockdown, although statistically significant, were overall modest. The logistic regression model failed to determine predictors of BPSD worsening during lockdown.
Conclusion
This is one of the first studies to investigate the presence of BPSD during SARS-CoV-2 outbreak and related nationwide lockdown, showing only slight, likely not clinically relevant, differences in BPSD burden, concerning mostly agitation and aggression, anxiety, apathy and indifference, and irritability.
Charcot-Marie-Tooth disease type 2A (CMT2A) is a rare inherited axonal neuropathy caused by mutations in MFN2 gene, which encodes Mitofusin 2, a transmembrane protein of the outer mitochondrial ...membrane. We performed a cross-sectional analysis on thirteen patients carrying mutations in MFN2, from ten families, describing their clinical and genetic characteristics. Evaluated patients presented a variable age of onset and a wide phenotypic spectrum, with most patients presenting a severe phenotype. A novel heterozygous missense variant was detected, p.K357E. It is located at a highly conserved position and predicted as pathogenic by in silico tools. At a clinical level, the p.K357E carrier shows a severe sensorimotor axonal neuropathy. In conclusion, our work expands the genetic spectrum of CMT2A, disclosing a novel mutation and its related clinical effect, and provides a detailed description of the clinical features of a cohort of patients with MFN2 mutations. Obtaining a precise genetic diagnosis in affected families is crucial both for family planning and prenatal diagnosis, and in a therapeutic perspective, as we are entering the era of personalized therapy for genetic diseases.
Objective
Whipple’s disease (WD) is a systemic, chronic, relapsing disease caused by
Tropheryma whipplei
, which can mimic signs and symptoms of various clinical entities. Typical manifestations ...are represented by gastrointestinal and systemic symptoms, among which neurological ones are frequent. We present the case of a patient with WD and rapidly progressive cognitive impairment and a review of literature aimed to report epidemiological, clinical, neuroimaging, and laboratory findings of cognitive impairment associated with WD.
Methods
A systematic review of medical literature published until November 22, 2020, was performed. Full-text, peer-reviewed case reports and series in English language presenting patients with WD and cognitive impairment were included. Data concerning demographic, clinical, neuroimaging, and laboratory characteristics were collected and synthesized qualitatively.
Results
The patient was a 54-year-old male who developed rapidly progressive dementia, fluctuating arousal disturbances, and supranuclear ophthalmoparesis associated with chronic diarrhea and fever spikes.
T. whipplei
was detected in the cerebrospinal fluid, and appropriate antimicrobial therapy was given with progressive clinical benefit. The systematic review of 114 case reports/series identified 147 patients with WD and cognitive impairment; this latter was rarely isolated. Neurological symptoms associated with cognitive decline were psychiatric disturbances, supranuclear ophthalmoplegia, hypothalamic involvement, and consciousness disorders. Brain imaging and cerebrospinal fluid findings were heterogeneous and nonspecific.
Conclusions
Cognitive impairment represents one of the most common neurological features associated with WD. The clinical suspicion of this disease in patients with rapidly progressive dementia is crucial to guide diagnostic strategies and proper antimicrobial therapy, which may revert the clinical deterioration.
Duchenne muscular dystrophy (DMD) is an X-linked recessive, infancy-onset neuromuscular disorder characterized by progressive muscle weakness and atrophy, leading to delay of motor milestones, loss ...of autonomous ambulation, respiratory failure, cardiomyopathy, and premature death. DMD originates from mutations in the
gene that result in a complete absence of dystrophin. Dystrophin is a cytoskeletal protein which belongs to the dystrophin-associated protein complex, involved in cellular signaling and myofiber membrane stabilization. To date, the few available therapeutic options are aimed at lessening disease progression, but persistent loss of muscle tissue and function and premature death are unavoidable. In this scenario, one of the most promising therapeutic strategies for DMD is represented by adeno-associated virus (AAV)-mediated gene therapy. DMD gene therapy relies on the administration of exogenous micro-dystrophin, a miniature version of the dystrophin gene lacking unnecessary domains and encoding a truncated, but functional, dystrophin protein. Limited transgene persistence represents one of the most significant issues that jeopardize the translatability of DMD gene replacement strategies from the bench to the bedside. Here, we critically review preclinical and clinical studies of AAV-mediated gene therapy in DMD, focusing on long-term transgene persistence in transduced tissues, which can deeply affect effectiveness and sustainability of gene replacement in DMD. We also discuss the role played by the overactivation of the immune host system in limiting long-term expression of genetic material. In this perspective, further studies aimed at better elucidating the need for immune suppression in AAV-treated subjects are warranted in order to allow for life-long therapy in DMD patients.
Repeat expansions in genes other than C9orf72 and ATXN2 have been recently associated with Amyotrophic Lateral Sclerosis (ALS). Indeed, an abnormal number of GGC repeats in NOTCH2NLC has been ...recently reported in 0.7% of sporadic ALS patients from mainland China. This finding was not confirmed in an ALS cohort of subjects from Taiwan. As the involvement of expanded NOTCH2NLC alleles in ALS is debated, we addressed this point by evaluating NOTCH2NLC repeat expansions in an Italian cohort of ALS patients. A screening analysis of NOTCH2NLC GGC repeats was performed by repeat-primed polymerase chain reaction (RP-PCR) in a cohort of 385 probable/definite ALS Italian patients. Mean age at onset was 60.5 years (SD 13.7), and 60.9% were males. Sporadic cases were 357 (92.7%), and most patients had a spinal onset (71.8%). None of our patients showed the typical sawtooth tail pattern on RP-PCR, thus excluding abnormal repeat expansion in NOTCH2NLC. Overall, we suggest that NOTCH2NLC expanded alleles might be absent or at least extremely rare in ALS Italian patients. Further investigations in larger cohorts with different ethnic backgrounds are required to support the involvement of NOTCH2NLC in ALS.
The reorganization of the healthcare system prompted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has posed unique challenges for Residency Training Programs worldwide. To ...mitigate its potential negative effects, it is crucial to assess how the pandemic influenced the activity and quality of life of residents. The purpose of this study was to assess the impact of the pandemic on residents' competencies, satisfaction, working load, training patterns and occupational exposure in the clinical, surgical, research and didactic fields and to quantify its effects on quality of life and risk perception.
An online cross-sectional survey was distributed between 1 June 2020 and 31 July 2020 to 1645 residents enrolled in all Residency Programs of four Universities in northern Italy. The survey included questions about clinical, surgical, and research competencies, educational activity, and quality of life pre- and post-pandemic, and on policies and workplace interventions to reduce exposure to SARS-CoV-2. The main outcome measure was the variation in self-perceived clinical, surgical and research competencies and in specialistic training. Data were analysed using the statistical package R Core Team 4.0.0, estimating mean and standard deviation or median and interquartile range for continuous variables. Variables were compared using chi-square test, Fisher exact tests or McNemar test, as appropriate.
A multivariate binary logistic regression analysis was performed to test the effect of different factors on the impact of coronavirus disease-2019 (COVID-19) on self-perceived clinical and research competencies and on didactic training.
A total of 498 residents completed the survey (response rate 30.3%). The mean age of respondents was 28.9 years, 62.9% were women, and 52.4% were enrolled in the first two years of Training Programs. On the first pandemic wave, over 60% of residents reported a negative impact of the pandemic on their specialistic training. In contrast, 40% of residents involved in clinical duties perceived an improvement in their clinical competences, especially those involved in COVID-19 care, and 34.5% perceived an improvement in their research competences, particularly junior residents, while only 3.5% reported an improvement in surgical skills. Most surgical residents (88.5%) reported a decrease in surgical activities, mainly due to reduced hospital bed capacity and reduction of elective surgery. Almost 90% of all residents experienced a reduction in their didactic activities, but 80% stated their Residency Program adopted virtual training methods. A statistically significant reduction in all examined quality of life items post-pandemic vs. pre-pandemic was found. Even though most survey participants reported the availability of personal protective equipment for residents, 44% considered themselves to be at higher risk of exposure compared to senior staff.
COVID-19 pandemic caused a significant disruption in surgical training, but it had a positive impact on clinical competencies among residents involved in COVID-19 and urgent care. The pandemic had a detrimental effect on all quality of life aspects, and most residents considered themselves at higher risk of SARS-CoV-2 infection compared to other healthcare professionals.
Key Messages
Coronavirus disease-2019 (COVID-19) pandemic caused a significant disruption in surgical training, but it had a positive impact on clinical competencies among residents involved in COVID-19 and urgent care.
Most residents experienced a reduction of didactic activities. Although the majority of training programs implemented virtual training methods to counteract the restrictions imposed by the pandemic, only half of the residents were satisfied of them.
A vast proportion of residents had a high occupational exposure to SARS-CoV-2 and considered themselves at higher risk of COVID-19 infection compared to senior staff.
The survey highlighted a statistically significant reduction in five key quality of life measures (i.e. sleep, mood, familiar relationships and social relationships quality and employment satisfaction) during the first wave, with mood and social relationships being the most affected. Notably, employment satisfaction was significantly higher in medical compared to surgical residents.
Cerebral small vessel disease (CSVD) includes various entities affecting the brain and, often, systemic small arteries, arterioles, venules, and capillaries. The underlying causes of CSVD are ...different, and some of them are genetic. Monogenic CSVDs are responsible for 1%-5% of all strokes and for several other disturbances. Despite many genes being involved, the phenotypes of monogenic CSVD partly overlap. Given that the genetic testing for different diseases can be challenging and time-consuming, the practicing neurologist should be adequately informed of the genetic background of CSVD and should be able to select patients to undergo genetic assessment and the genes to be analyzed. The purpose of this review was to summarize clinical, neurologic and non-neurologic, and neuroimaging features of monogenic CSVD and to provide a flowchart to be used in clinical practice to guide neurologists in this field. The proposed flowchart and the relative tables can be applied to 3 different settings, depending on the presentation: (1) ischemic stroke and/or transient ischemic attack, (2) cerebral hemorrhage, and (3) other neurologic, non-neurologic, and/or neuroimaging features of monogenic CSVD, in the absence of stroke syndromes because of infarction or hemorrhage.
The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. ...The aim of this work was to assess the impact of the TMEM106B rs1990622 (A–major risk allele; G–minor allele) on phenotypic variability of 865 patients with amyotrophic lateral sclerosis. Demographic and clinical features were compared according to genotypes by additive, dominant, and recessive genetic models. Bulbar onset was overrepresented among carriers of the AA risk genotype, together with enhanced upper motor neuron involvement and poorer functional status in patients harboring at least one major risk allele (A). In a subset of 195 patients, we found that the homozygotes for the minor allele (GG) showed lower scores at the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen, indicating a more severe cognitive impairment, mainly involving the amyotrophic lateral sclerosis-specific cognitive functions and memory. Moreover, lower motor neuron burden predominated among patients with at least one minor allele (G). Overall, we found that TMEM106B is a disease modifier of amyotrophic lateral sclerosis, whose phenotypic effects encompass both sites of onset and functional status (major risk allele), motor functions (both major risk and minor alleles), and cognition (minor allele).
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