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1.
Mult Scler ; : 13524585241261549, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39077876

RESUMO

OBJECTIVES: neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. METHODS: We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. RESULTS: The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. DISCUSSION: aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD.

2.
J Peripher Nerv Syst ; 29(2): 279-285, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38874107

RESUMO

AIM: Biallelic mutations in the PTRH2 gene have been associated with infantile multisystem neurological, endocrine, and pancreatic disease (IMNEPD), a rare autosomal recessive disorder of variable expressivity characterized by global developmental delay, intellectual disability or borderline IQ level, sensorineural hearing loss, ataxia, and pancreatic insufficiency. Various additional features may be included, such as peripheral neuropathy, facial dysmorphism, hypothyroidism, hepatic fibrosis, postnatal microcephaly, cerebellar atrophy, and epilepsy. Here, we report the first Italian family presenting only predominant neurological features. METHODS: Extensive neurological and neurophysiological evaluations have been conducted on the two affected brothers and their healthy mother since 1996. The diagnosis of peripheral neuropathy of probable hereditary origin was confirmed through a sural nerve biopsy. Exome sequencing was performed after the analysis of major neuropathy-associated genes yielded negative results. RESULTS: Whole-exome sequencing analysis identified the homozygous substitution c.256C>T (p.Gln86Ter) in the PTRH2 gene in the two siblings. According to American College of Medical Genetics and Genomics (ACMG) guidelines, the variant has been classified as pathogenic. At 48 years old, the proband's reevaluation confirmed a demyelinating sensorimotor polyneuropathy with bilateral sensorineural hearing loss that had been noted since he was 13. Additionally, drug-resistant epileptic seizures occurred when he was 32 years old. No hepatic or endocrinological signs developed. The younger affected brother, 47 years old, has an overlapping clinical presentation without epilepsy. INTERPRETATION: Our findings expand the clinical phenotype and further demonstrate the clinical heterogeneity related to PTRH2 variants. We thereby hope to better define IMNEPD and facilitate the identification and diagnosis of this novel disease entity.


Assuntos
Pancreatopatias , Humanos , Masculino , Itália , Feminino , Pancreatopatias/genética , Pancreatopatias/fisiopatologia , Pessoa de Meia-Idade , Códon sem Sentido , Linhagem , Adulto
3.
Neurol Sci ; 45(3): 849-859, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38169013

RESUMO

INTRODUCTION: Guillain-Barré syndrome associated with Coronavirus-2-related severe acute respiratory syndrome (COV-GBS) occurs as para- or post-infectious forms, depending on the timing of disease onset. In these two forms, we aimed to compare the cerebrospinal fluid (CSF) and serum proinflammatory cytokine profiles to evaluate differences that could possibly have co-pathogenic relevance. MATERIALS AND METHODS: We studied a retrospective cohort of 26 patients with either post-COV-GBS (n = 15), with disease onset occurring > 7 days after SARS-CoV-2 infection, or para-COV-GBS (n = 11), with disease onset 7 days or less. TNF-α, IL-6, and IL-8 were measured in the serum with SimplePlex™ Ella™ immunoassay. In addition to the para-/post-COV-GBS patients, serum levels of these cytokines were determined in those with non-COVID-associated-GBS (NC-GBS; n = 43), paucisymptomatic SARS-CoV-2 infection without GBS (COVID, n = 20), and in healthy volunteers (HV; n = 12). CSF cytokine levels were measured in patients with para-/post-COV-GBS, in those with NC-GBS (n = 29), or with Alzheimer's disease (AD; n = 24). RESULTS: Serum/CSF cytokine levels did not differ in para- vs post-COV-GBS. We found that SARS-CoV-2 infection raises the serum levels of TNF-α, IL-6, and IL-8, as well as an increase of IL-6 (in serum and CSF) and IL-8 (in CSF) in either NC-GBS or COV-GBS than controls. CSF and serum cytokine levels resulted independent one with another. CONCLUSIONS: The change of cytokines linked to SARS-CoV-2 in COV-GBS appears to be driven by viral infection, although it has unique characteristics in GBS as such and does not account for cases with para- or post-infectious onset.


Assuntos
COVID-19 , Síndrome de Guillain-Barré , Humanos , COVID-19/complicações , SARS-CoV-2 , Síndrome de Guillain-Barré/complicações , Citocinas , Interleucina-6/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa , Estudos Retrospectivos , Interleucina-8
4.
Haematologica ; 109(3): 888-894, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37646655

RESUMO

Autologous peripheral blood stem cell transplantation (aPBSCT) provides optimal outcomes in POEMS syndrome but the definition of the best treatment before aPBSCT remains to be defined because of the rarity of the disease and the heterogeneity of published case series. We collected clinical and laboratory data of patients with POEMS syndrome undergoing aPBSCT from 1998 to 2020 in ten Italian centers. The primary endpoint of the study was to evaluate the impact of prior therapies and mobilization regimen on outcome. We divided the patients into three groups: patients who did not receive any treatment before transplant (15 patients, group A: front-line), patients pre-treated with other agents (14 patients, group B) and patients treated with cyclophosphamide as their mobilizing regimen (16 patients, group C). The three groups did not show differences in terms of demographic and clinical characteristics. All 45 patients underwent aPBSCT after a high-dose melphalan conditioning regimen, with a median follow-up of 77 months (range, 37-169 months). The responses were not statistically different between the three groups (P=0.38). Progression-free and overall survival rates at 6 years were: 70% (95% confidence interval: 55-85%) and 91% (95% confidence interval: 82-99) 65%, respectively, and did not differ between the three groups. The cumulative incidence of transplant-related mortality and relapse was 4% and 36%, respectively. In conclusion, in a relatively large number of patients with POEMS syndrome, undergoing an autologous transplant, pre-treatment and disease status at transplant did not appear to have an impact on major transplant outcomes.


Assuntos
Síndrome POEMS , Transplante de Células-Tronco de Sangue Periférico , Humanos , Síndrome POEMS/diagnóstico , Síndrome POEMS/terapia , Transplante Autólogo , Autoenxertos , Ciclofosfamida/uso terapêutico
5.
J Peripher Nerv Syst ; 28(4): 620-628, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37897416

RESUMO

BACKGROUND AND AIMS: POLR3B gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in POLR3B are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in POLR3B with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers. METHODS: Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method. RESULTS: Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in POLR3B, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure. INTERPRETATION: Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in POLR3B-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.


Assuntos
Doenças Desmielinizantes , Doenças do Sistema Nervoso Periférico , Polineuropatias , RNA Polimerase III , Adolescente , Humanos , Axônios , Doenças Desmielinizantes/genética , Mutação , Fibras Nervosas/metabolismo , Doenças do Sistema Nervoso Periférico/genética , Polineuropatias/genética , Proteínas/genética , RNA Polimerase III/genética , RNA Polimerase III/metabolismo
6.
Eur J Neurol ; 30(8): 2461-2470, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37170966

RESUMO

BACKGROUND AND PURPOSE: Data are reported from the Italian CMT Registry. METHODS: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted. RESULTS: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT. CONCLUSIONS: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.


Assuntos
Doença de Charcot-Marie-Tooth , Feminino , Humanos , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/diagnóstico , Mutação , Progressão da Doença , Itália/epidemiologia
7.
Acta Myol ; 42(4): 113-117, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38406380

RESUMO

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as a genetic cause of autosomal recessive axonal Charcot-Marie-Tooth disease 2 (CMT2) and distal hereditary motor neuropathy (dHMN). We herein review the main phenotypes associated with SORD mutations and report the case of a 16-year-old man who was referred to our outpatient clinic for a slowly worsening gait disorder with wasting and weakness of distal lower limbs musculature. Since creatine phosphokinase (CPK) values were persistently raised (1.5fold increased) and a Next-Generation Sequencing CMT-associated panel failed in identifying pathogenic variants, a muscle biopsy was performed with evidence of alterations suggestive of a protein surplus distal myopathy. Finally, Whole-Exome Sequencing (WES) identified two pathogenic SORD variants in the heterozygous state: c.458C > A (p.Ala153Asp) and c.757delG (p.Ala253Glnfs*27). This is an isolated report of compound heterozygosity for two SORD mutations associated with clinical and histological signs of skeletal muscle involvement, expanding the phenotypic expression of SORD mutations.


Assuntos
Doença de Charcot-Marie-Tooth , L-Iditol 2-Desidrogenase , Masculino , Humanos , Adolescente , L-Iditol 2-Desidrogenase/genética , Doença de Charcot-Marie-Tooth/genética , Músculo Esquelético/patologia , Mutação , Fenótipo , Linhagem
8.
Neurol Sci ; 43(11): 6441-6447, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35953578

RESUMO

BACKGROUND: The immunotherapy strategy for autoimmune encephalitis is based on several types and schedules of both first- and second-line drugs. Failing to respond to the latter prompts the use of non-conventional rescue therapies, with higher risks of severe adverse effects. We report on a protocol that entails the use of intravenous immunoglobulin cycles to bridge the 4-month period that the second-line drug rituximab needs to exert its full therapeutic effects. METHODS: Three patients with NMDAR encephalitis who were non-responders to first-line treatments entered the study. The protocol consisted of six monthly cycles of intravenous immunoglobulins (IVIG, 0.4 mg/kg/die for 5 days), starting 1 month after the last rituximab infusion (1000 mg at days 0 and 15). Brain MRI and [18F]-FDG-PET were performed at onset and at six and 18 months after onset. RESULTS: In the three patients, substantial improvements of disability or complete recovery were achieved, without modifications over the 30-to-50-month follow-up. No adverse events nor laboratory test abnormalities were recorded. Imaging findings paralleled the favorable disease courses. Brain [18F]-FDG-PET was more sensitive than MRI in detecting abnormalities. DISCUSSION: Our observations suggest that the herein-described protocol might be used in patients with NMDAR encephalitis at risk for poor prognosis in the mid-term when they need to shift to rituximab. [18F]-FDG-PET confirmed to be a sensitive tool to detect the minimal brain lesions that can underlie isolated cognitive and psychiatric symptoms.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Imunoglobulinas Intravenosas , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Rituximab/uso terapêutico , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico por imagem , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Fluordesoxiglucose F18 , Receptores de N-Metil-D-Aspartato
9.
Expert Rev Neurother ; 22(1): 65-76, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34894974

RESUMO

INTRODUCTION: Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. AREAS COVERED: We systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. EXPERT OPINION: This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the gap in the identification of effective rehabilitation and treatment options for CIPN.


Assuntos
Antineoplásicos , Neoplasias , Doenças do Sistema Nervoso Periférico , Antineoplásicos/efeitos adversos , Consenso , Exercício Físico , Prova Pericial , Humanos , Neoplasias/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/terapia
10.
Crit Rev Oncol Hematol ; 171: 103575, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34968623

RESUMO

Pharmacological strategies for chemotherapy-induced peripheral neurotoxicity (CIPN) are very limited. We systematically reviewed data on rehabilitation, exercise, physical therapy, and other physical non-pharmacological interventions and offered evidence-based recommendations for the prevention and treatment of CIPN. A literature search using PubMed, Web of Science and CINAHL was conducted from database inception until May 31st, 2021. 2791 records were title-abstract screened, 71 papers were full-text screened, 41 studies were included, 21 on prevention and 20 on treatment of CIPN. Treatment type, cancer type, chemotherapy compounds were heterogeneous, sample size was small (median: N = 34) and intention-to-treat analysis was lacking in 26/41 reports. Because of the methodological issues of included studies, the reviewed evidence should be considered as preliminary. Exercise, endurance, strength, balance, and sensorimotor training have been studied in low-to-moderate quality studies, while the evidence for other treatments is preliminary/inconclusive. We offer recommendation for the design of future trials on CIPN.


Assuntos
Antineoplásicos , Neoplasias , Doenças do Sistema Nervoso Periférico , Antineoplásicos/efeitos adversos , Exercício Físico , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/terapia
11.
J Med Case Rep ; 15(1): 589, 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34903275

RESUMO

BACKGROUND: Parsonage-Turner syndrome is an acute peripheral neuropathy that affects the upper brachial plexus region. Previously published reports demonstrate that the condition can be triggered by surgery, infection, autoimmune diseases, strenuous exercise, trauma, radiation, and vaccination. Parsonage-Turner syndrome has already been reported in three other patients who were vaccinated against coronavirus disease 2019. CASE PRESENTATION: We report the case of a 51-year-old Caucasian man without comorbidities who received the first dose of the ChAdOx1-S recombinant vaccine (Vaxzevria, AstraZeneca, Oxford, UK) against coronavirus disease 2019 and was diagnosed with Parsonage-Turner syndrome. A few days after getting vaccinated, the patient reported a progressive increase in pain in the region of vaccine administration. One month later, the shoulder pain was followed by symptoms of hypoesthesia and muscle weakness on abduction and elevation of the left upper limb. Neurological examination revealed an atrophy of the proximal muscles of the left upper limb, accompanied by paresis of the left deltoid, biceps brachii, triceps brachii, and infraspinatus muscles. Electroneuromyography carried out 3 months after the onset of symptoms showed signs consistent with brachial plexus neuritis. The adverse reaction has been properly reported to the Italian Pharmacovigilance System (Italian Medicines Agency-Agenzia Italiana del Farmaco. CONCLUSION: The increased awareness of such association is essential for early identification and diagnosis and, thus, better clinical outcomes.


Assuntos
Neurite do Plexo Braquial , COVID-19 , Vacinas , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Vacinação
12.
J Peripher Nerv Syst ; 26 Suppl 2: S3-S10, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34768314

RESUMO

It is always a challenge to acquire a clear picture of the pathological processes and changes in any disease. For this purpose, it is advantageous to directly examine the affected organ. Nerve biopsy has been a method of choice for decades to classify peripheral neuropathies and to find clues to uncover their etiology. The histologic examination of the peripheral nerve provides information on axonal or myelin pathology as well as on the surrounding connective tissue and vascularization of the nerve. Minimal requirements of the workup include paraffin histology as well as resin semithin section histology. Cryostat sections, teased fiber preparations and electron microscopy are potentially useful in a subset of cases. Here we describe our standard procedures for the workup of the tissue sample and provide examples of diagnostically relevant findings.


Assuntos
Doenças do Sistema Nervoso Periférico , Axônios/patologia , Biópsia/métodos , Humanos , Bainha de Mielina/patologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/patologia , Nervo Sural/patologia
13.
Neurology ; 97(7): e660-e672, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34078718

RESUMO

BACKGROUND AND OBJECTIVE: There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN. METHODS: Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score-clinical [TNSc], used to calculate Total Neuropathy Score-nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups. RESULTS: Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index r = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn. CONCLUSIONS: MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale.


Assuntos
Antineoplásicos/toxicidade , Técnicas de Diagnóstico Neurológico/normas , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Psicometria/normas , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Síndromes Neurotóxicas/etiologia , Enfermeiras e Enfermeiros , Pacientes , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Médicos , Estudos Prospectivos , Psicometria/instrumentação , Adulto Jovem
14.
Brain ; 144(5): 1542-1550, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-33969391

RESUMO

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren's syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.


Assuntos
Polineuropatias/genética , Proteína de Replicação C/genética , Adulto , Idoso , Expansão das Repetições de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33653949

RESUMO

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P2, with a preference for PtdIns(3,5)P2 A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3'-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P2 levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P2 synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.


Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Bainha de Mielina/metabolismo , Fosfatos de Fosfatidilinositol/biossíntese , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Transdução de Sinais , Animais , Doença de Charcot-Marie-Tooth/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Bainha de Mielina/genética , Miosina Tipo II/genética , Miosina Tipo II/metabolismo , Fosfatos de Fosfatidilinositol/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
16.
Joint Bone Spine ; 88(4): 105153, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33561533

RESUMO

OBJECTIVE: Recent studies have highlighted that about 50% of fibromyalgic patients has a neuropathy of small- and/or large-fibers which could partially explain the puzzling symptoms of fibromyalgia (FM). Our aim was to investigate the estimated prevalence of self-reported neuropathic pain and small-fiber neuropathic symptoms (SFNS) indicative for the presence of small-fiber pathology in FM patients. METHODS: A nationwide sample of patients was recruited to participate in an on-line survey. Two groups of patients were considered in post-hoc analysis: those positive (FM+) to the Fibromyalgia Research Criteria (FRC) and those complaining typical symptoms of fibromyalgia without fulfilling the FRC (FM-). RESULTS: We collected data from 854 patients (749 FM+ and 105 FM-). Patients that scored=50/100 at the Neuropathic Pain Symptoms Inventory (NPSI), indicating severe neuropathic pain, were 57.3% (62.4% in FM+ and 21.0% in FM-). Around 46% of patients presented three or more SFNS that could be suggestive of small fiber pathology, the most frequent being dry eyes/mouth, allodynia, and dyshidrosis. The NPSI score showed significant moderate/strong associations with disability (Spearman's rho=0.61), pain (rho=0.66), stiffness level (rho=0.46), number of painful sites (rho=0.40), and SFNS (rho=0.44). Despite the high prevalence of neuropathic pain and other symptoms attributable to potential small and/or large fibers pathology, neurophysiologic investigations were performed in 43.6% of cases and skin punch biopsy only in 1.9% of patients enrolled, as well as the assumption of anti-neuropathic pain drugs (13.2%). CONCLUSIONS: Our findings underscore the high estimated prevalence of neuropathic pain and SFNS in FM patients.


Assuntos
Fibromialgia , Neuralgia , Neuropatia de Pequenas Fibras , Fibromialgia/diagnóstico , Fibromialgia/epidemiologia , Humanos , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Neuralgia/etiologia , Medição da Dor , Pele , Neuropatia de Pequenas Fibras/diagnóstico , Neuropatia de Pequenas Fibras/epidemiologia
17.
Neurol Sci ; 42(4): 1405-1409, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32783159

RESUMO

INTRODUCTION: In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi. CASE REPORTS: The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. DISCUSSION AND CONCLUSION: We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also "older" and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated "off-target" pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.


Assuntos
Melanoma , Miastenia Gravis , Neoplasias Cutâneas , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Masculino , Melanoma/tratamento farmacológico , Qualidade de Vida
18.
Brain Sci ; 10(11)2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33114611

RESUMO

Pathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. Patients and Methods: We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies. Diagnosis was formulated after a positive genetic test for transthyretin (TTR) mutations. Sural nerve biopsy was performed according to standard protocols. Results: Sixty-nine sural nerve biopsies from hATTR-PN patients were examined. Congo red positive deposits were found in 73% of cases. Only the Phe64Leu mutation failed to show amyloid deposits in a high percentage of biopsies (54%), as already described. Unusual pathological findings, such as myelin abnormalities or inflammatory infiltrates, were detected in occasional cases. Conclusions: Even if no longer indicated to confirm hATTR-PN clinical suspicion, nerve biopsy remains, in expert hands, a rapid and inexpensive tool to detect amyloid deposition. In Italy, clinicians should be aware that a negative biopsy does not exclude hATTR-PN, particularly for Phe64Leu, one of the most frequent mutations in this country.

19.
J Neurol Neurosurg Psychiatry ; 91(10): 1092-1099, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32868387

RESUMO

OBJECTIVES: To determine the prevalence of different comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and their impact on outcome, treatment choice and response. METHODS: Using a structured questionnaire, we collected information on comorbidities from 393 patients with CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria included in the Italian CIDP database. RESULTS: One or more comorbidities were reported by 294 patients (75%) and potentially influenced treatment choice in 192 (49%) leading to a less frequent use of corticosteroids. Response to treatment did not differ, however, from that in patients without comorbidities. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general European population. Patients with diabetes had higher disability scores, worse quality of life and a less frequent treatment response compared with patients without diabetes. Patients with IgG-IgA or IgM MGUS had an older age at CIDP onset while patients with other immune disorders had a younger age at onset and were more frequently females. IgM MGUS was more frequent in patients with motor CIDP than in patients with typical CIDP. CONCLUSIONS: Comorbidities are frequent in patients with CIDP and in almost 50% of them have an impact on treatment choice. Diabetes, MGUS and other immune diseases are more frequent in patients with CIDP than in the general population. Only diabetes seems, however, to have an impact on disease severity and treatment response possibly reflecting in some patients a coexisting diabetic neuropathy.


Assuntos
Diabetes Mellitus/epidemiologia , Neuropatias Diabéticas/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/epidemiologia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/epidemiologia , Criança , Comorbidade , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Troca Plasmática , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia , Qualidade de Vida , Distribuição por Sexo , Resultado do Tratamento , Adulto Jovem
20.
Orphanet J Rare Dis ; 15(1): 216, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32819406

RESUMO

Fabry disease (FD) is a systemic X-linked lysosomal disorder. A 'peripheral nerve variant' of FD has been hypothesized in subjects with neuropathy, without the early manifestations of the classic phenotype. A cohort of undiagnosed neuropathy patients with chronic polyneuropathy of undetermined aetiology and demyelinating neuropathy, unresponsive to immunomodulating treatment, were screened for FD. A total of 103 patients (64% males), were enrolled. No typical pathogenetic mutations for FD were identified. We are aware that the study sample was very small, but only a large, unfeasible theoretical sample size could demonstrate a statistically significant increased prevalence of FD in neuropathy patients, as peripheral neuropathy of undetermined cause is uncommon and there is a low prevalence of FD in the general population. Therefore, we are of the opinion that including tailored FD screening in the neuropathy diagnostic work-up, particularly when there are additional clinical characteristics, should be considered.


Assuntos
Doença de Fabry , Doenças do Sistema Nervoso Periférico , Polineuropatias , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Feminino , Humanos , Masculino , Programas de Rastreamento , Nervos Periféricos , Doenças do Sistema Nervoso Periférico/diagnóstico , Polineuropatias/diagnóstico , Polineuropatias/genética
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