Chiara Terracciano - Academia.edu (original) (raw)

Papers by Chiara Terracciano

Research paper thumbnail of COVID-19-Related Stroke: Barking up the Wrong Tree?

Research paper thumbnail of Stroke in COVID-19 patients—A case series from Italy

International Journal of Stroke

Only a few case series reporting a small number of stroke patients with COVID-19 have been publis... more Only a few case series reporting a small number of stroke patients with COVID-19 have been published. 1-5 We describe the characteristics of 19 consecutive strokes occurring in COVID-19-positive patients, admitted from 21 February to 28 April at the Guglielmo da Saliceto Hospital in Piacenza, one of the outbreak epicenters in Italy. Cases were identified retrospectively. Two cases (10.5%) were hemorrhagic and 17 (89.5%) ischemic. Mean age was 76.05 years (SD 8.83), 52.6% were male, mean National Institute of Health Stroke Scale (NIHSS) was 9.79 (SD 6.78). Stroke incidence among COVID-19 inpatients was 2.2%. Among the 19 cases, the risk factors were: diabetes 10.5%, hypertension 84.2%, and atrial fibrillation 31.6%. Fifteen patients had stroke onset during COVID-19; in four,

Research paper thumbnail of Novel autophagic vacuolar myopathies: Phenotype and genotype features

Neuropathology and Applied Neurobiology

Research paper thumbnail of Lactate dehydrogenase and C-reactive protein as predictors of respiratory failure in CoVID-19 patients

Research paper thumbnail of The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases

Nutrients

Autophagy is the major intracellular machinery for degrading proteins, lipids, polysaccharides, a... more Autophagy is the major intracellular machinery for degrading proteins, lipids, polysaccharides, and organelles. This cellular process is essential for the maintenance of the correct cellular balance in both physiological and stress conditions. Because of its role in maintaining cellular homeostasis, dysregulation of autophagy leads to various disease manifestations, such as inflammation, metabolic alterations, aging, and neurodegeneration. A common feature of many neurologic and neuromuscular diseases is the alteration of the autophagy-lysosomal pathways. For this reason, autophagy is considered a target for the prevention and/or cure of these diseases. Dietary intake of polyphenols has been demonstrated to prevent/ameliorate several of these diseases. Thus, natural products that can modulate the autophagy machinery are considered a promising therapeutic strategy. In particular, curcumin, a phenolic compound widely used as a dietary supplement, exerts an important effect in modulati...

Research paper thumbnail of Thymomatous myasthenia gravis: novel association with HLA DQB1*05:01 and strengthened evidence of high clinical and serological severity

Research paper thumbnail of Neurofibromatous neuropathy: An ultrastructural study

Ultrastructural pathology

Plexiform neurofibroma is pathognomonic of neurofibromatosis 1 (NF1). An NF1-associated periphera... more Plexiform neurofibroma is pathognomonic of neurofibromatosis 1 (NF1). An NF1-associated peripheral neuropathy has been described in a small minority of NF1 patients but its histopathological features are poorly characterized. We report the case of a 46-year-old woman presenting with bilateral supraclavicular painful masses without other stigmata of NF1. MRI showed bilateral plexiform lesions extending from cervical roots to the elbows. Nerve conduction studies documented a sensory motor polyneuropathy. Morphometric analysis of sural nerve biopsy showed a preferential loss of large-caliber myelinated fibers with a g ratio of 0.515, and the presence of regeneration clusters. By electron microscopy, marked and diffuse endoneurial fibrosis with an altered relationship between Schwann cells (SC) and collagen fibrils was observed. Moreover both myelinating and non-myelinating SC were characterized by the presence of various cell degradation products. These changes suggest that, in neurofi...

Research paper thumbnail of Successful long-term therapy with flecainide in a family with paramyotonia congenita

Journal of neurology, neurosurgery, and psychiatry, Feb 27, 2018

Research paper thumbnail of Vacuolated PAS-positive lymphocytes as an hallmark of Pompe disease and other myopathies related to impaired autophagy

Journal of cellular physiology, Jan 7, 2017

Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-α-gluco... more Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-α-glucosidase (GAA) gene. Deficiency of GAA enzyme leads to glycogen accumulation and autophagy impairment in cardiac and skeletal muscles, but also in lymphocytes. Since an effective therapy is available, a rapid, sensitive and specific test is crucial to early identify affected subjects. Number of lymphocytes containing PAS-positive vacuoles was evaluated on blood films from 72 consecutive adult patients with hyperckemia and/or muscle weakness, 13 genetically confirmed late-onset-Pompe-disease (LOPD) and 13 of their offspring. GAA activity, measured on dried blood spot (DBS) in all patients inversely correlated with number of PAS-positive lymphocytes. More than 4 PAS-positive lymphocytes were found in 11 out of the 72 patients (6 new diagnosis of LOPD, 3 different glycogen storage myopathies, 1 glucose-6-phosphate dehydrogenase deficiency, 1 caveolinopathy), in all 13 LOPD patients and in the...

Research paper thumbnail of Nodular morphea in a patient with Steinert disease

Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia, Jan 8, 2017

Research paper thumbnail of Cutaneous features of myotonic dystrophy types 1 and 2: Implication of premature aging and vitamin D homeostasis

Neuromuscular disorders : NMD, 2017

Skin changes have been described in myotonic dystrophy type 1 (DM1). However, whether and in whic... more Skin changes have been described in myotonic dystrophy type 1 (DM1). However, whether and in which way skin is a target of specific disease alterations in DM1 and DM2 has not been yet clarified. This study aims to explore cutaneous features of DM1 and DM2 patients. Skin examination was performed in 60 DM1, 15 DM2, and 103 control, unselected patients by means of dermoscopy. It revealed quantitative and qualitative abnormalities of nevi and typical signs of premature aging in both DM1 and DM2 patients, with a significantly higher frequency of dysplastic nevi, alopecia, xerosis and seborrheic dermatitis. Twenty-eight nevi were excised in DM patients and none showed histological features of melanoma, although 12 of them were diagnosed as dysplastic and the remaining 16 presented histological irregularity in melanin distribution. In DM1 patients, the number of nevi correlated with CTG expansion size, whereas the presence of dysplastic nevi and xerosis inversely correlated with vitamin D...

Research paper thumbnail of Neuromuscular transmission abnormalities in myotonic dystrophy type 1: A neurophysiological study

Clinical Neurology and Neurosurgery, 2016

Weakness and fatigue are frequent symptoms in myotonic dystrophy type 1 (DM1), mainly as a result... more Weakness and fatigue are frequent symptoms in myotonic dystrophy type 1 (DM1), mainly as a result of muscle impairment. However, neuromuscular junction (NMJ) abnormalities could play an additional role in determining these manifestations. We aimed to document the possible NMJ involvement in DM1. In order to substantiate this hypothesis we performed low rate repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG), in 14 DM1 subjects. RNS resulted abnormal in four patients while SFEMG revealed a pathological jitter in ten. A significative correlation was found between jitter values and decrementing response (p<0.000311; r=0.822). These results suggest a possible involvement of NMJ in DM1.

Research paper thumbnail of In AβPP‐overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AβPP751 and GSK3β activation: effects mitigated by lithium and apparently relevant to sporadic inclusion‐body myositis

Journal of Neurochemistry, 2010

Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumul... more Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-β-precursor protein 751 (AβPP 751), amyloid-β (Aβ), phosphorylated tau (p-tau), and other "Alzheimer-characteristic" proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer disease (AD) patients and AD transgenic mouse models, phosphorylation of neuronal AβPP 695 (p-AβPP) on Threonine 668 (T 668) (equivalent to T 724 of AβPP 751) is considered detrimental because it increases generation of cytotoxic Aβ and induces tau phosphorylation. Activated glycogen synthase kinase3β (GSK3β) is involved in phosphorylation of both AβPP and tau. Lithium, an inhibitor of GSK3β, was reported to reduce levels of both the total AβPP and p-AβPP in AD animal models. In relation to s-IBM, we now show for the first time that: 1. In AβPPoverexpressing cultured human muscle fibers (human muscle culture IBM model: a) proteasome inhibition significantly increases GSK3β activity and AβPP phosphorylation; b) treatment with lithium decreases i) phosphorylated-AβPP; ii) total amount of AβPP, iii) Aβ oligomers, and iv) GSK3β activity; and c) lithium improves proteasome function. 2. In biopsied s-IBM muscle fibers, GSK3β is significantly activated and AβPP is phosphorylated on Thr 724. Accordingly, treatment with lithium, or other GSK3β inhibitors, might benefit s-IBM patients.

Research paper thumbnail of An Age-Standardized Prevalence Estimate and a Sex and Age Distribution of Myotonic Dystrophy Types 1 and 2 in the Rome Province, Italy

Neuroepidemiology, 2016

Background: Prevalence estimates for the 2 forms of myotonic dystrophy types 1 and 2 (DM1 and DM2... more Background: Prevalence estimates for the 2 forms of myotonic dystrophy types 1 and 2 (DM1 and DM2) are not exhaustive or non-available. Our aim was to estimate the minimum prevalence of DM1 and DM2 in Italy in the Rome province, applying standards of descriptive epidemiology. Methods: All patients with a molecular diagnosis of DM1/DM2 and residents in the Rome province in 2013 have been enrolled, and the age-standardized prevalence has been calculated, assuming a Poisson distribution and adjusting for age. Results: We identified 395 DM1 patients: the age-standardized prevalence for total, females and males was 9.65, 8.35 and 11.07/100,000, respectively. The mean age of subjects differed considerably according to CTG repeat length (p = 0.001). Forty DM2 patients were identified. The age-standardized prevalence for total, females and males was 0.99, 1.07 and 0.90/100,000, respectively. The mean age was 57.05. Conclusions: We estimated for the first time the age-standardized prevalence...

Research paper thumbnail of In AβPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AβPP751 and GSK3β activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis

J Neurochem, 2010

Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumul... more Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-β-precursor protein 751 (AβPP 751), amyloid-β (Aβ), phosphorylated tau (p-tau), and other "Alzheimer-characteristic" proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer disease (AD) patients and AD transgenic mouse models, phosphorylation of neuronal AβPP 695 (p-AβPP) on Threonine 668 (T 668) (equivalent to T 724 of AβPP 751) is considered detrimental because it increases generation of cytotoxic Aβ and induces tau phosphorylation. Activated glycogen synthase kinase3β (GSK3β) is involved in phosphorylation of both AβPP and tau. Lithium, an inhibitor of GSK3β, was reported to reduce levels of both the total AβPP and p-AβPP in AD animal models. In relation to s-IBM, we now show for the first time that: 1. In AβPPoverexpressing cultured human muscle fibers (human muscle culture IBM model: a) proteasome inhibition significantly increases GSK3β activity and AβPP phosphorylation; b) treatment with lithium decreases i) phosphorylated-AβPP; ii) total amount of AβPP, iii) Aβ oligomers, and iv) GSK3β activity; and c) lithium improves proteasome function. 2. In biopsied s-IBM muscle fibers, GSK3β is significantly activated and AβPP is phosphorylated on Thr 724. Accordingly, treatment with lithium, or other GSK3β inhibitors, might benefit s-IBM patients.

Research paper thumbnail of Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors

Journal of Neurology, 2016

Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM... more Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM). Yet, none of these studies evaluated the contribution of common cancer risk factors in such observation. In this study, we included a cohort of patients (n = 255) with an established molecular diagnosis of DM type 1 (DM1), and who receives their treatment in one of the four centers with recognized expertise in neuromuscular disorders in Rome. We estimated the prevalence of benign and malignant tumors, and assessed if lifestyle factors and/or specific disease features would be associated to their occurrence. Overall, 59 benign tumors in 54 patients and 19 malignant tumors in 17 patients were diagnosed. The most common malignant neoplasms were cancers of the skin (31.6 %), thyroid (21.0 %), ovary (10.5 %), and breast (10.5 %). Uterine fibroid was the most common benign tumor (37.6 %) in women, while pilomatricoma was the most common in men (28.6 %). Age at enrollment (OR = 1.02, 95 % CI 1.00-1.05), and female gender (OR = 5.71, 95 % CI 2.90-11.22) were associated with tumor development in DM1 patients, while thyroid disorders was associated with malignant tumors only in women (OR = 5.12, 95 % CI 1.35-19.37). There was no association between tumor development and evaluated lifestyle factors. In conclusion, the lack of association between common cancer risk factors and tumor development in DM1 support a pathogenic link between tumors and DM1 itself, emphasizing the need for a systematic surveillance. Our observation of an association between thyroid diseases in women and cancer development needs confirmation.

Research paper thumbnail of Neutral lipid storage disease with myopathy and extended phenotype with novel PNPLA2 mutation

Muscle & Nerve, 2015

Neutral lipid storage disease with myopathy is caused by mutations in PNPLA2, which produce skele... more Neutral lipid storage disease with myopathy is caused by mutations in PNPLA2, which produce skeletal and cardiac myopathy. We report a man with multi-organ neutral lipid storage and unusual multisystem clinical involvement, including cognitive impairment. Quantitative brain MRI with voxel-based morphometry and extended neuropsychological assessment were performed. In parallel, the coding sequences and intron/exon boundaries of the PNPLA2 gene were screened by direct sequencing. Neuropsychological assessment revealed global cognitive impairment, and brain MRI showed reduced grey matter volume in the temporal lobes. Molecular characterization revealed a novel homozygous mutation in exon 5 of PNPLA2 (c.714C>A) resulting in a premature stop codon (p.Cys238*). Some PNPLA2 mutations, such as the one described here, may present with an extended phenotype, including brain involvement. In these cases, complete neuropsychological testing, combined with quantitative brain MRI, may help to characterize and quantify cognitive impairment. This article is protected by copyright. All rights reserved.

Research paper thumbnail of ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease

Brain, 2015

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical ... more Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for $40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease.

Research paper thumbnail of Novel HLA II associations in myasthenia gravis

Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases

Research paper thumbnail of Auto-reactions, auto-immunity and Psoriatic Arthritis

Autoimmunity Reviews, 2015

Evidence from the literature suggests that autoimmune processes may drive features of psoriatic a... more Evidence from the literature suggests that autoimmune processes may drive features of psoriatic arthritis (PsA). Such hypothesis is supported by the evidence that class I major histocompatibility complex (MHC) genes are associated with susceptibility to develop PsA and auto-reactive cells, such as CD8 T cells, T helper (h) 17 and plasma cells, have been demonstrated in PsA. However, no autoantigens have ever been demonstrated in PsA. The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA) patients. These autoantibodies have been associated with a worse disease progression independent of anti-citrulline antibodies (ACPA). In PsA, anti-CarP antibodies have not been evaluated yet. We aimed at analyzing, for the first time, the anti-CarP antibodies in sera of patients with active PsA who were negative for ACPA in order to explore both their presence and their relationship with disease activity. A total of 70 individuals, 30 patients with diagnosis of PsA (according to CASPAR criteria) and 40 healthy controls (HC) were enrolled. We found significantly increased levels of anti-CarP antibodies in PsA patients compared with HC (P<0.0001). Our findings indicate that anti-CarP antibodies are detectable with high specificity and sensibility in PsA patients suggesting an autoimmune background of PsA. Anti-CarP antibodies can be useful in improving the diagnosis of PsA and are correlated with disease activity.

Research paper thumbnail of COVID-19-Related Stroke: Barking up the Wrong Tree?

Research paper thumbnail of Stroke in COVID-19 patients—A case series from Italy

International Journal of Stroke

Only a few case series reporting a small number of stroke patients with COVID-19 have been publis... more Only a few case series reporting a small number of stroke patients with COVID-19 have been published. 1-5 We describe the characteristics of 19 consecutive strokes occurring in COVID-19-positive patients, admitted from 21 February to 28 April at the Guglielmo da Saliceto Hospital in Piacenza, one of the outbreak epicenters in Italy. Cases were identified retrospectively. Two cases (10.5%) were hemorrhagic and 17 (89.5%) ischemic. Mean age was 76.05 years (SD 8.83), 52.6% were male, mean National Institute of Health Stroke Scale (NIHSS) was 9.79 (SD 6.78). Stroke incidence among COVID-19 inpatients was 2.2%. Among the 19 cases, the risk factors were: diabetes 10.5%, hypertension 84.2%, and atrial fibrillation 31.6%. Fifteen patients had stroke onset during COVID-19; in four,

Research paper thumbnail of Novel autophagic vacuolar myopathies: Phenotype and genotype features

Neuropathology and Applied Neurobiology

Research paper thumbnail of Lactate dehydrogenase and C-reactive protein as predictors of respiratory failure in CoVID-19 patients

Research paper thumbnail of The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases

Nutrients

Autophagy is the major intracellular machinery for degrading proteins, lipids, polysaccharides, a... more Autophagy is the major intracellular machinery for degrading proteins, lipids, polysaccharides, and organelles. This cellular process is essential for the maintenance of the correct cellular balance in both physiological and stress conditions. Because of its role in maintaining cellular homeostasis, dysregulation of autophagy leads to various disease manifestations, such as inflammation, metabolic alterations, aging, and neurodegeneration. A common feature of many neurologic and neuromuscular diseases is the alteration of the autophagy-lysosomal pathways. For this reason, autophagy is considered a target for the prevention and/or cure of these diseases. Dietary intake of polyphenols has been demonstrated to prevent/ameliorate several of these diseases. Thus, natural products that can modulate the autophagy machinery are considered a promising therapeutic strategy. In particular, curcumin, a phenolic compound widely used as a dietary supplement, exerts an important effect in modulati...

Research paper thumbnail of Thymomatous myasthenia gravis: novel association with HLA DQB1*05:01 and strengthened evidence of high clinical and serological severity

Research paper thumbnail of Neurofibromatous neuropathy: An ultrastructural study

Ultrastructural pathology

Plexiform neurofibroma is pathognomonic of neurofibromatosis 1 (NF1). An NF1-associated periphera... more Plexiform neurofibroma is pathognomonic of neurofibromatosis 1 (NF1). An NF1-associated peripheral neuropathy has been described in a small minority of NF1 patients but its histopathological features are poorly characterized. We report the case of a 46-year-old woman presenting with bilateral supraclavicular painful masses without other stigmata of NF1. MRI showed bilateral plexiform lesions extending from cervical roots to the elbows. Nerve conduction studies documented a sensory motor polyneuropathy. Morphometric analysis of sural nerve biopsy showed a preferential loss of large-caliber myelinated fibers with a g ratio of 0.515, and the presence of regeneration clusters. By electron microscopy, marked and diffuse endoneurial fibrosis with an altered relationship between Schwann cells (SC) and collagen fibrils was observed. Moreover both myelinating and non-myelinating SC were characterized by the presence of various cell degradation products. These changes suggest that, in neurofi...

Research paper thumbnail of Successful long-term therapy with flecainide in a family with paramyotonia congenita

Journal of neurology, neurosurgery, and psychiatry, Feb 27, 2018

Research paper thumbnail of Vacuolated PAS-positive lymphocytes as an hallmark of Pompe disease and other myopathies related to impaired autophagy

Journal of cellular physiology, Jan 7, 2017

Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-α-gluco... more Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-α-glucosidase (GAA) gene. Deficiency of GAA enzyme leads to glycogen accumulation and autophagy impairment in cardiac and skeletal muscles, but also in lymphocytes. Since an effective therapy is available, a rapid, sensitive and specific test is crucial to early identify affected subjects. Number of lymphocytes containing PAS-positive vacuoles was evaluated on blood films from 72 consecutive adult patients with hyperckemia and/or muscle weakness, 13 genetically confirmed late-onset-Pompe-disease (LOPD) and 13 of their offspring. GAA activity, measured on dried blood spot (DBS) in all patients inversely correlated with number of PAS-positive lymphocytes. More than 4 PAS-positive lymphocytes were found in 11 out of the 72 patients (6 new diagnosis of LOPD, 3 different glycogen storage myopathies, 1 glucose-6-phosphate dehydrogenase deficiency, 1 caveolinopathy), in all 13 LOPD patients and in the...

Research paper thumbnail of Nodular morphea in a patient with Steinert disease

Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia, Jan 8, 2017

Research paper thumbnail of Cutaneous features of myotonic dystrophy types 1 and 2: Implication of premature aging and vitamin D homeostasis

Neuromuscular disorders : NMD, 2017

Skin changes have been described in myotonic dystrophy type 1 (DM1). However, whether and in whic... more Skin changes have been described in myotonic dystrophy type 1 (DM1). However, whether and in which way skin is a target of specific disease alterations in DM1 and DM2 has not been yet clarified. This study aims to explore cutaneous features of DM1 and DM2 patients. Skin examination was performed in 60 DM1, 15 DM2, and 103 control, unselected patients by means of dermoscopy. It revealed quantitative and qualitative abnormalities of nevi and typical signs of premature aging in both DM1 and DM2 patients, with a significantly higher frequency of dysplastic nevi, alopecia, xerosis and seborrheic dermatitis. Twenty-eight nevi were excised in DM patients and none showed histological features of melanoma, although 12 of them were diagnosed as dysplastic and the remaining 16 presented histological irregularity in melanin distribution. In DM1 patients, the number of nevi correlated with CTG expansion size, whereas the presence of dysplastic nevi and xerosis inversely correlated with vitamin D...

Research paper thumbnail of Neuromuscular transmission abnormalities in myotonic dystrophy type 1: A neurophysiological study

Clinical Neurology and Neurosurgery, 2016

Weakness and fatigue are frequent symptoms in myotonic dystrophy type 1 (DM1), mainly as a result... more Weakness and fatigue are frequent symptoms in myotonic dystrophy type 1 (DM1), mainly as a result of muscle impairment. However, neuromuscular junction (NMJ) abnormalities could play an additional role in determining these manifestations. We aimed to document the possible NMJ involvement in DM1. In order to substantiate this hypothesis we performed low rate repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG), in 14 DM1 subjects. RNS resulted abnormal in four patients while SFEMG revealed a pathological jitter in ten. A significative correlation was found between jitter values and decrementing response (p<0.000311; r=0.822). These results suggest a possible involvement of NMJ in DM1.

Research paper thumbnail of In AβPP‐overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AβPP751 and GSK3β activation: effects mitigated by lithium and apparently relevant to sporadic inclusion‐body myositis

Journal of Neurochemistry, 2010

Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumul... more Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-β-precursor protein 751 (AβPP 751), amyloid-β (Aβ), phosphorylated tau (p-tau), and other "Alzheimer-characteristic" proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer disease (AD) patients and AD transgenic mouse models, phosphorylation of neuronal AβPP 695 (p-AβPP) on Threonine 668 (T 668) (equivalent to T 724 of AβPP 751) is considered detrimental because it increases generation of cytotoxic Aβ and induces tau phosphorylation. Activated glycogen synthase kinase3β (GSK3β) is involved in phosphorylation of both AβPP and tau. Lithium, an inhibitor of GSK3β, was reported to reduce levels of both the total AβPP and p-AβPP in AD animal models. In relation to s-IBM, we now show for the first time that: 1. In AβPPoverexpressing cultured human muscle fibers (human muscle culture IBM model: a) proteasome inhibition significantly increases GSK3β activity and AβPP phosphorylation; b) treatment with lithium decreases i) phosphorylated-AβPP; ii) total amount of AβPP, iii) Aβ oligomers, and iv) GSK3β activity; and c) lithium improves proteasome function. 2. In biopsied s-IBM muscle fibers, GSK3β is significantly activated and AβPP is phosphorylated on Thr 724. Accordingly, treatment with lithium, or other GSK3β inhibitors, might benefit s-IBM patients.

Research paper thumbnail of An Age-Standardized Prevalence Estimate and a Sex and Age Distribution of Myotonic Dystrophy Types 1 and 2 in the Rome Province, Italy

Neuroepidemiology, 2016

Background: Prevalence estimates for the 2 forms of myotonic dystrophy types 1 and 2 (DM1 and DM2... more Background: Prevalence estimates for the 2 forms of myotonic dystrophy types 1 and 2 (DM1 and DM2) are not exhaustive or non-available. Our aim was to estimate the minimum prevalence of DM1 and DM2 in Italy in the Rome province, applying standards of descriptive epidemiology. Methods: All patients with a molecular diagnosis of DM1/DM2 and residents in the Rome province in 2013 have been enrolled, and the age-standardized prevalence has been calculated, assuming a Poisson distribution and adjusting for age. Results: We identified 395 DM1 patients: the age-standardized prevalence for total, females and males was 9.65, 8.35 and 11.07/100,000, respectively. The mean age of subjects differed considerably according to CTG repeat length (p = 0.001). Forty DM2 patients were identified. The age-standardized prevalence for total, females and males was 0.99, 1.07 and 0.90/100,000, respectively. The mean age was 57.05. Conclusions: We estimated for the first time the age-standardized prevalence...

Research paper thumbnail of In AβPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AβPP751 and GSK3β activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis

J Neurochem, 2010

Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumul... more Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-β-precursor protein 751 (AβPP 751), amyloid-β (Aβ), phosphorylated tau (p-tau), and other "Alzheimer-characteristic" proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer disease (AD) patients and AD transgenic mouse models, phosphorylation of neuronal AβPP 695 (p-AβPP) on Threonine 668 (T 668) (equivalent to T 724 of AβPP 751) is considered detrimental because it increases generation of cytotoxic Aβ and induces tau phosphorylation. Activated glycogen synthase kinase3β (GSK3β) is involved in phosphorylation of both AβPP and tau. Lithium, an inhibitor of GSK3β, was reported to reduce levels of both the total AβPP and p-AβPP in AD animal models. In relation to s-IBM, we now show for the first time that: 1. In AβPPoverexpressing cultured human muscle fibers (human muscle culture IBM model: a) proteasome inhibition significantly increases GSK3β activity and AβPP phosphorylation; b) treatment with lithium decreases i) phosphorylated-AβPP; ii) total amount of AβPP, iii) Aβ oligomers, and iv) GSK3β activity; and c) lithium improves proteasome function. 2. In biopsied s-IBM muscle fibers, GSK3β is significantly activated and AβPP is phosphorylated on Thr 724. Accordingly, treatment with lithium, or other GSK3β inhibitors, might benefit s-IBM patients.

Research paper thumbnail of Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors

Journal of Neurology, 2016

Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM... more Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM). Yet, none of these studies evaluated the contribution of common cancer risk factors in such observation. In this study, we included a cohort of patients (n = 255) with an established molecular diagnosis of DM type 1 (DM1), and who receives their treatment in one of the four centers with recognized expertise in neuromuscular disorders in Rome. We estimated the prevalence of benign and malignant tumors, and assessed if lifestyle factors and/or specific disease features would be associated to their occurrence. Overall, 59 benign tumors in 54 patients and 19 malignant tumors in 17 patients were diagnosed. The most common malignant neoplasms were cancers of the skin (31.6 %), thyroid (21.0 %), ovary (10.5 %), and breast (10.5 %). Uterine fibroid was the most common benign tumor (37.6 %) in women, while pilomatricoma was the most common in men (28.6 %). Age at enrollment (OR = 1.02, 95 % CI 1.00-1.05), and female gender (OR = 5.71, 95 % CI 2.90-11.22) were associated with tumor development in DM1 patients, while thyroid disorders was associated with malignant tumors only in women (OR = 5.12, 95 % CI 1.35-19.37). There was no association between tumor development and evaluated lifestyle factors. In conclusion, the lack of association between common cancer risk factors and tumor development in DM1 support a pathogenic link between tumors and DM1 itself, emphasizing the need for a systematic surveillance. Our observation of an association between thyroid diseases in women and cancer development needs confirmation.

Research paper thumbnail of Neutral lipid storage disease with myopathy and extended phenotype with novel PNPLA2 mutation

Muscle & Nerve, 2015

Neutral lipid storage disease with myopathy is caused by mutations in PNPLA2, which produce skele... more Neutral lipid storage disease with myopathy is caused by mutations in PNPLA2, which produce skeletal and cardiac myopathy. We report a man with multi-organ neutral lipid storage and unusual multisystem clinical involvement, including cognitive impairment. Quantitative brain MRI with voxel-based morphometry and extended neuropsychological assessment were performed. In parallel, the coding sequences and intron/exon boundaries of the PNPLA2 gene were screened by direct sequencing. Neuropsychological assessment revealed global cognitive impairment, and brain MRI showed reduced grey matter volume in the temporal lobes. Molecular characterization revealed a novel homozygous mutation in exon 5 of PNPLA2 (c.714C>A) resulting in a premature stop codon (p.Cys238*). Some PNPLA2 mutations, such as the one described here, may present with an extended phenotype, including brain involvement. In these cases, complete neuropsychological testing, combined with quantitative brain MRI, may help to characterize and quantify cognitive impairment. This article is protected by copyright. All rights reserved.

Research paper thumbnail of ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease

Brain, 2015

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical ... more Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for $40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease.

Research paper thumbnail of Novel HLA II associations in myasthenia gravis

Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases

Research paper thumbnail of Auto-reactions, auto-immunity and Psoriatic Arthritis

Autoimmunity Reviews, 2015

Evidence from the literature suggests that autoimmune processes may drive features of psoriatic a... more Evidence from the literature suggests that autoimmune processes may drive features of psoriatic arthritis (PsA). Such hypothesis is supported by the evidence that class I major histocompatibility complex (MHC) genes are associated with susceptibility to develop PsA and auto-reactive cells, such as CD8 T cells, T helper (h) 17 and plasma cells, have been demonstrated in PsA. However, no autoantigens have ever been demonstrated in PsA. The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA) patients. These autoantibodies have been associated with a worse disease progression independent of anti-citrulline antibodies (ACPA). In PsA, anti-CarP antibodies have not been evaluated yet. We aimed at analyzing, for the first time, the anti-CarP antibodies in sera of patients with active PsA who were negative for ACPA in order to explore both their presence and their relationship with disease activity. A total of 70 individuals, 30 patients with diagnosis of PsA (according to CASPAR criteria) and 40 healthy controls (HC) were enrolled. We found significantly increased levels of anti-CarP antibodies in PsA patients compared with HC (P<0.0001). Our findings indicate that anti-CarP antibodies are detectable with high specificity and sensibility in PsA patients suggesting an autoimmune background of PsA. Anti-CarP antibodies can be useful in improving the diagnosis of PsA and are correlated with disease activity.