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11 pages, 1295 KiB

Open AccessArticle

Cognitive Impairment in Adult Patients with 5q-Associated Spinal Muscular Atrophy

by Kathrin Kizina, Yakup Akkaya, Daniel Jokisch, Benjamin Stolte, Andreas Totzeck, Juan Munoz-Rosales, Andreas Thimm, Saskia Bolz, Svenja Brakemeier, Refik Pul, Derya Aslan, Jana Hackert, Christoph Kleinschnitz and Tim Hagenacker

Brain Sci. 2021, 11(9), 1184; https://doi.org/10.3390/brainsci11091184 - 9 Sep 2021

Cited by 8 | Viewed by 3047

Abstract

In previous studies, a below-average, average, or above-average intelligence quotient (IQ) in children with SMA was detected but, aside from a severe physical disability, the cognitive performance of adult SMA patients has not yet been evaluated. The intelligence test used in this study, [...] Read more.

In previous studies, a below-average, average, or above-average intelligence quotient (IQ) in children with SMA was detected but, aside from a severe physical disability, the cognitive performance of adult SMA patients has not yet been evaluated. The intelligence test used in this study, the Wechsler Adult Intelligence Scale, fourth edition (WAIS-IV), was used to measure major intelligence components of adult SMA patients. The WAIS-IV determines four index scores representing verbal comprehension, perceptual reasoning, working memory, and processing speed. Due to time-dependent demands on motor function, the processing speed index score was excluded. IQ index scores of 33 adult SMA patients did not differ from IQ index scores of the normal population. In SMA type-3 patients, the index scores for verbal comprehension, perceptual reasoning, and working memory did not differ from the normal population but showed a trend of IQ scores towards lower points. Patients with SMA type 2 had lower IQ index scores for working memory (90.33 ± 12.95; p = 0.012) and perceptual reasoning (90.73 ± 12.58; p = 0.013) than the normal population. This study provided further evidence that SMA is a multi-systemic disease and may refute the widespread hypothesis that SMA patients might improve their cognitive skills to compensate for their physical impairment. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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6 pages, 389 KiB

Open AccessArticle

Renal Involvement in Hereditary Transthyretin Amyloidosis: An Italian Single-Centre Experience

by Pietro Manuel Ferraro, Viola D’Ambrosio, Andrea Di Paolantonio, Valeria Guglielmino, Paolo Calabresi, Mario Sabatelli and Marco Luigetti

Brain Sci. 2021, 11(8), 980; https://doi.org/10.3390/brainsci11080980 - 24 Jul 2021

Cited by 21 | Viewed by 1998

Abstract

Objective: Hereditary transthyretin amyloidosis (ATTRv) represents a diagnostic challenge considering the great variability of clinical presentation and multiorgan involvement. In the present study, we report the prevalence of kidney involvement and kidney function over time in a cohort of ATTRv patients with different [...] Read more.

Objective: Hereditary transthyretin amyloidosis (ATTRv) represents a diagnostic challenge considering the great variability of clinical presentation and multiorgan involvement. In the present study, we report the prevalence of kidney involvement and kidney function over time in a cohort of ATTRv patients with different transthyretin gene mutations. Patients and Methods: For this study, we systematically collected data from all patients with a diagnosis of ATTRv followed at the Neurology Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS. Kidney involvement was defined as presence of estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² obtained with CKD-EPI equation, abnormal urinary protein excretion (UPE) (>150 mg/24 h) and/or albuminuria > 30 mg/24 h (or mg/g creatinine). The analysis included data from 46 patients with 122 measurements of serum creatinine. Results: Among the 46 patients included in the analysis, kidney involvement was present in 37%, with 15% showing reduced eGFR and 22% abnormal UPE (63% of patients with available UPE data). No single predictor was associated with either eGFR values or its slope over time. Conclusions: Kidney involvement is quite common in patients with ATTRv regardless of the underlying genetic variant. In particular, abnormal UPE appears to be a common feature of the disease. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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11 pages, 1236 KiB

Open AccessArticle

Use of Drugs for ATTRv Amyloidosis in the Real World: How Therapy Is Changing Survival in a Non-Endemic Area

by Massimo Russo, Luca Gentile, Vincenzo Di Stefano, Gianluca Di Bella, Fabio Minutoli, Antonio Toscano, Filippo Brighina, Giuseppe Vita and Anna Mazzeo

Brain Sci. 2021, 11(5), 545; https://doi.org/10.3390/brainsci11050545 - 27 Apr 2021

Cited by 19 | Viewed by 2704

Abstract

Background: Over the past decade, three new drugs have been approved for the treatment of hereditary amyloid transthyretin (ATTRv) polyneuropathy. The aim of this work was to analyze whether current therapies prolong survival for patients affected by ATTRv amyloidosis. Methods: The study was [...] Read more.

Background: Over the past decade, three new drugs have been approved for the treatment of hereditary amyloid transthyretin (ATTRv) polyneuropathy. The aim of this work was to analyze whether current therapies prolong survival for patients affected by ATTRv amyloidosis. Methods: The study was conducted retrospectively, analyzing the medical records of 105 patients with genetic diagnoses of familial amyloidotic polyneuropathy followed at the two referral centers for the disease in Sicily, Italy. Of these, 71 received disease-modifying therapy, while 34 received only symptomatic treatment or no therapy. Results: The most used treatment in our patient cohort was tafamidis, followed by liver transplantation, patisiran, inotersen, and diflunisal. The median survival was significantly longer for treated vs. untreated patients (12 years vs. 8 years). In the 71 patients who received disease-modifying treatment, the presence of cardiac involvement, weight loss, or autonomic dysfunction at diagnosis was not related to survival. Conversely, patients diagnosed in the early stage of the disease (PND 1) had significantly longer survival than those diagnosed in the late stage (PND 2–4). Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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12 pages, 1559 KiB

Open AccessArticle

A Phase 1/2 Study of Flavocoxid, an Oral NF-κB Inhibitor, in Duchenne Muscular Dystrophy

by Gian Luca Vita, Maria Sframeli, Norma Licata, Alessandra Bitto, Sara Romeo, Francesca Frisone, Annamaria Ciranni, Giovanni Pallio, Federica Mannino, M’Hammed Aguennouz, Carmelo Rodolico, Francesco Squadrito, Antonio Toscano, Sonia Messina and Giuseppe Vita

Brain Sci. 2021, 11(1), 115; https://doi.org/10.3390/brainsci11010115 - 16 Jan 2021

Cited by 10 | Viewed by 3252

Abstract

Flavocoxid is a blended extract containing baicalin and catechin with potent antioxidant and anti-inflammatory properties due to the inhibition of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, nuclear factor-κB (NF-κB), tumor necrosis factor (TNF)-alpha, and the mitogen-activated protein kinases (MAPKs) pathways. This phase [...] Read more.

Flavocoxid is a blended extract containing baicalin and catechin with potent antioxidant and anti-inflammatory properties due to the inhibition of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, nuclear factor-κB (NF-κB), tumor necrosis factor (TNF)-alpha, and the mitogen-activated protein kinases (MAPKs) pathways. This phase 1/2 study was designed to assess the safety and tolerability of flavocoxid in patients with Duchenne muscular dystrophy (DMD). Thirty-four patients were recruited: 17 were treated with flavocoxid at an oral dose of 250 or 500 mg, according to body weight, for one year; 17 did not receive flavocoxid and served as controls. The treatment was well tolerated and nobody dropped out. Flavocoxid induced a significant reduction in serum interleukin (IL)-1 beta and TNF-alpha only in the group of DMD boys on add-on therapy (flavocoxid added to steroids for at least six months). The decrease in IL-1 beta was higher in younger boys. The serum H₂O₂ concentrations significantly decreased in patients treated with flavocoxid alone with a secondary reduction of serum glutathione peroxidase (GPx) levels, especially in younger boys. The exploratory outcome measures failed to show significant effects but there was a trend showing that the younger boys who received treatment were faster at performing the Gowers’ maneuver, while the older boys who received treatment were faster at doing the 10-m walk test (10MWT). Therefore, a double-blind, placebo-controlled study for at least two/three years is warranted to verify flavocoxid as a steroid substitute or as add-on therapy to steroids. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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Review

Jump to: Research

13 pages, 257 KiB

Open AccessReview

Psychopharmacological Treatments for Mental Disorders in Patients with Neuromuscular Diseases: A Scoping Review

by Chiara Brusa, Giulio Gadaleta, Rossella D’Alessandro, Guido Urbano, Martina Vacchetti, Chiara Davico, Benedetto Vitiello, Federica S. Ricci and Tiziana E. Mongini

Brain Sci. 2022, 12(2), 176; https://doi.org/10.3390/brainsci12020176 - 28 Jan 2022

Cited by 4 | Viewed by 2960

Abstract

Mental disorders are observed in neuromuscular diseases, especially now that patients are living longer. Psychiatric symptoms may be severe and psychopharmacological treatments may be required. However, very little is known about pharmacotherapy in these conditions. We aimed to summarize the current knowledge on [...] Read more.

Mental disorders are observed in neuromuscular diseases, especially now that patients are living longer. Psychiatric symptoms may be severe and psychopharmacological treatments may be required. However, very little is known about pharmacotherapy in these conditions. We aimed to summarize the current knowledge on the use of psychopharmacological treatments for mental disorders in patients living with a neuromuscular disease. A scoping review was performed using the methodology of the Joanna Briggs Institute. Four databases were searched from January 2000 to July 2021. Articles were screened based on titles and abstracts. Full-text papers published in peer-reviewed journals in English were selected. Twenty-six articles met eligibility criteria, all being case reports/series focusing on the psychopharmacological control of psychiatric symptoms for the following conditions: myasthenia gravis (n = 11), Duchenne (n = 5) and Becker (n = 3) muscular dystrophy, mitochondrial disorders (n = 3), glycogen storage disease (n = 1), myotonic dystrophy (n = 1), hyperkalemic periodic paralysis (n = 1), and congenital myasthenic syndrome (n = 1). None of the articles provided details on the decision-making process to choose a specific drug/regimen or on follow-up strategies to monitor safety and efficacy. Larger studies showing real-world data would be required to guide consensus-based recommendations, thus improving current standards of care and, ultimately, the quality of life of patients and their families. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

14 pages, 10052 KiB

Open AccessReview

Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives

by Chiara Pisciotta, Paola Saveri and Davide Pareyson

Brain Sci. 2021, 11(11), 1447; https://doi.org/10.3390/brainsci11111447 - 29 Oct 2021

Cited by 25 | Viewed by 5339

Abstract

There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find [...] Read more.

There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the PMP22 gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second-phase III trial is ongoing. Gene therapy to substitute defective genes or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene and of neurotoxic glycosphingolipids in HSN1. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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26 pages, 774 KiB

Open AccessReview

Animal Models as a Tool to Design Therapeutical Strategies for CMT-like Hereditary Neuropathies

by Luca Bosco, Yuri Matteo Falzone and Stefano Carlo Previtali

Brain Sci. 2021, 11(9), 1237; https://doi.org/10.3390/brainsci11091237 - 18 Sep 2021

Cited by 5 | Viewed by 3432

Abstract

Since ancient times, animal models have provided fundamental information in medical knowledge. This also applies for discoveries in the field of inherited peripheral neuropathies (IPNs), where they have been instrumental for our understanding of nerve development, pathogenesis of neuropathy, molecules and pathways involved [...] Read more.

Since ancient times, animal models have provided fundamental information in medical knowledge. This also applies for discoveries in the field of inherited peripheral neuropathies (IPNs), where they have been instrumental for our understanding of nerve development, pathogenesis of neuropathy, molecules and pathways involved and to design potential therapies. In this review, we briefly describe how animal models have been used in ancient medicine until the use of rodents as the prevalent model in present times. We then travel along different examples of how rodents have been used to improve our understanding of IPNs. We do not intend to describe all discoveries and animal models developed for IPNs, but just to touch on a few arbitrary and paradigmatic examples, taken from our direct experience or from literature. The idea is to show how strategies have been developed to finally arrive to possible treatments for IPNs. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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12 pages, 1755 KiB

Open AccessReview

Intensive Care Unit-Acquired Weakness and Positioning-Related Peripheral Nerve Injuries in COVID-19: A Case Series of Three Patients and the Latest Literature Review

by Keiichi Hokkoku, Carmen Erra, Cristina Cuccagna, Daniele Coraci, Dario Mattia Gatto, Davide Glorioso and Luca Padua

Brain Sci. 2021, 11(9), 1177; https://doi.org/10.3390/brainsci11091177 - 6 Sep 2021

Cited by 9 | Viewed by 3348

Abstract

A subgroup of COVID-19 patients requires intensive respiratory care. The prolonged immobilization and aggressive treatments predispose these patients to develop intensive care unit-acquired weakness (ICUAW). Furthermore, this condition could increase the chance of positioning-related peripheral nerve injuries. On the basis of the latest [...] Read more.

A subgroup of COVID-19 patients requires intensive respiratory care. The prolonged immobilization and aggressive treatments predispose these patients to develop intensive care unit-acquired weakness (ICUAW). Furthermore, this condition could increase the chance of positioning-related peripheral nerve injuries. On the basis of the latest literature review, we describe a case series of three patients with COVID-19 who developed ICUAW complicated by positioning-related peripheral nerve injuries Every patient presented sensorimotor axonal polyneuropathy and concomitant myopathy in electrophysiological studies. Furthermore, muscle MRI helped the diagnosis of ICUAW, showing massive damage predominantly in the proximal muscles. Notably, nerve ultrasound detected positioning-related peripheral nerve injuries, even though the concomitant ICUAW substantially masked their clinical features. During the acute phase of severe COVID-19 infection, most medical attention tends to be assigned to critical care management, and neuromuscular complications such as ICUAW and positioning-related peripheral nerve injuries could be underestimated. Hence, when starting post-ICU care for COVID-19 cases, the combination of electrophysiological and imaging studies will aid appropriate evaluation on the patients with COVID-19-related ICUAW. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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17 pages, 1444 KiB

Open AccessReview

Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

by Maria Pia Giannoccaro, Patrizia Avoni and Rocco Liguori

Brain Sci. 2021, 11(8), 1035; https://doi.org/10.3390/brainsci11081035 - 3 Aug 2021

Cited by 7 | Viewed by 4276

Abstract

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia [...] Read more.

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ. Full article

(This article belongs to the Special Issue Advanced Research in Neuromuscular Disorders)

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