Francesco Mari
@meyer.it
Neuroscience Department, Pediatric Neurology Unit
AOU A Meyer, Florence, Italy
RESEARCH INTERESTS
Pediatric Neurology
Epilepsy
Sleep Disorders
Headache
Scopus Publications
Scopus Publications
Rodolfo Tonin, Federica Feo, Silvia Falliano, Laura Giunti, Martino Calamai, Elena Procopio, Francesco Mari, Vittorio Sciruicchio, Valerio Conti, Ilaria Fanelli,et al.
Elsevier BV
Simone Gasparini, Simona Balestrini, Luigi Francesco Saccaro, Giacomo Bacci, Giorgia Panichella, Martino Montomoli, Gaetano Cantalupo, Stefania Bigoni, Giorgia Mancano, Simona Pellacani,et al.
Wiley
AbstractCOL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2‐related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2‐related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2‐related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.
Rodolfo Tonin, Federica Feo, Silvia Falliano, Lorenzo Ferri, Laura Giunti, Martino Calamai, Elena Procopio, Francesco Mari, Valerio Conti, Ilaria Fanelli,et al.
Elsevier BV
Annalisa Vetro, Cristiana Pelorosso, Simona Balestrini, Alessio Masi, Sophie Hambleton, Emanuela Argilli, Valerio Conti, Simone Giubbolini, Rebekah Barrick, Gaber Bergant,et al.
Elsevier BV
Sarah E. Sheppard, Laura Bryant, Rochelle N. Wickramasekara, Courtney Vaccaro, Brynn Robertson, Jodi Hallgren, Jason Hulen, Cynthia J. Watson, Victor Faundes, Yannis Duffourd,et al.
American Association for the Advancement of Science (AAAS)
Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.
Gemma Marinella, Guja Astrea, Bianca Buchignani, Denise Cassandrini, Stefano Doccini, Massimiliano Filosto, Daniele Galatolo, Salvatore Gallone, Fabio Giannini, Diego Lopergolo,et al.
MDPI AG
Objective: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants. Methods: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression. Results: In Step I, we identified variants in COLVI-related genes in 48 patients, of which three were homozygous variants (Group 1). Then, we sorted variants according to their CADD score, clinical data and complementary studies (such as muscle and skin biopsy, study of expression of COLVI on fibroblast or muscle and muscle magnetic resonance). We finally assessed how potentially pathogenic variants (two biallelic and 12 monoallelic) destabilize COL6A1-A2-A3 subunits. Overall, 15 out of 512 patients were prioritized according to this pipeline. In seven of them, we confirmed reduced or absent immunocytochemical expression of collagen VI in cultured skin fibroblasts or in muscle tissue. Conclusions: In a real-world diagnostic scenario applied to heterogeneous neuromuscular conditions, a multistep integration of clinical and molecular data allowed the identification of about 3% of those patients harboring pathogenetic collagen VI variants.
Michela Taiana, Alessandra Govoni, Sabrina Salani, Nicole Kleinschmidt, Noemi Galli, Matteo Saladini, Stefano Bruno Ghezzi, Valentina Melzi, Margherita Bersani, Roberto Del Bo,et al.
BMJ
peroxidase–conjugated antibody (Molecular Probes/Invitrogen) in saturating solution. The western
Beatrice Berti, Giovanna Longo, Francesco Mari, Stefano Doccini, Ilaria Piccolo, Maria Alice Donati, Francesca Moro, Renzo Guerrini, Filippo M. Santorelli, and Vittoria Petruzzella
Springer Science and Business Media LLC
Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.
Francesca Peluso, V. Palazzo, G. Indolfi, F. Mari, Roberta Pasqualetti, E. Procopio, C. Nesti, R. Guerrini, F. Santorelli and S. Giglio
Background Mutations in lysyl-tRNA synthetase ( KARS1 ), an enzyme that charges tRNA with the amino acid lysine in both the cytoplasm and mitochondria, have been associated thus far with autosomal recessive Charcot–Marie–Tooth type CMTRIB, hearing loss type DFNB89, and mitochondrial encephalohepatopathy (MEH) featuring neurodevelopmental disorders with microcephaly, white matter changes, and cardiac and hepatic failure in less than 30 patients. Case presentation We report the clinical, biochemical and molecular findings of a 14-month-old girl with severe MEH compatible clinical features, profound sensorineural hearing loss, leopard spot retinopathy, pancytopenia, and advanced liver disease with portal hypertension leading to death at the age of 30 months. Conclusions Whole exome sequencing identified two rare variants in KARS1 gene. Our report expands the allelic and clinical features of tRNA synthase disorders. Moreover, with our report we confirm the usefulness of WES as first tier diagnostic method in infants with complex multisystem phenotypes.
Giacomo M. Bacci, Silvio Polizzi, Francesco Mari, Valerio Conti, Roberto Caputo, and Renzo Guerrini
Ovid Technologies (Wolters Kluwer Health)
Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by mutations in either TSC1 or TSC2 genes and is characterized by hamartomas in multiple organs. The most frequent and best-known ocular manifestation in TSC is the retinal hamartoma. Less frequent ocular manifestations include punched out areas of retinal depigmentation, eyelid angiofibromas, uveal colobomas, papilledema, and sector iris depigmentation. In this article, we report 2 patients carrying known pathogenic variants in the TSC2 gene who exhibited an atypical, unilateral, iris coloboma associated with localized areas of retinal dysembryogenesis.
C. Vannicola, L. Tassi, C. Barba, C. Boniver, M. Cossu, M. de Curtis, L. De Palma, I. D'Errico, G. Didato, R. Guerrini,et al.
Elsevier BV
Epilepsy surgery is recommended in selected patients with Tuberous Sclerosis Complex (TSC). However, reports on predictive factors of seizure outcome are variable. Here we report on seizure and cognitive outcome of 35 TSC patients who received surgery for refractory epilepsy in 7 Italian centers over a period of 22 years (1997-2019). The rate of seizure-free individuals at last follow-up (mean 7.5 years, range 1-21 years) was 51%. Patients with longer follow-up (≥10 years) had a lower rate of Engel I outcome (11.1%) than those who received surgery in the last 10 years (65.4%, p = 0.003). Factors associated with Engel II, III, IV outcome in our cohort included: high number of cortical tubers (≥5); presence of subependymal nodules (SENs); seizure onset before age 1 year; and multifocal interictal epileptic discharges (IEDs) on electroencephalogram (EEG). A subset of patients evaluated with Vineland Adaptive Behaviour Scales (VABS) showed developmental gains, in line with their developmental trajectories, but no improvement in standard scores after surgery was noted. Our study demonstrates that the rates of successful seizure outcome of epilepsy surgery in TSC have improved in the last 10 years. More than half of the patients achieved seizure freedom, and a high proportion of affected individuals experienced a reduction in seizure burden and in antiseizure medications. A comprehensive assessment after surgery should be performed in TSC patients to evaluate the overall neurodevelopmental outcome, as measures that are based only on seizure control do not adequately identify the benefits of surgery on global functioning in these patients.
Deborah Tolomeo, Daniele Orsucci, Claudia Nesti, Jacopo Baldacci, Roberta Battini, Claudio Bruno, Giorgia Bruno, Denise Cassandrini, Stefano Doccini, M. Alice Donati,et al.
MDPI AG
Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity. For this reason, the diagnosis of MDs continues to be difficult, with the new “genotype first” approach still failing to diagnose a large group of patients. With the aim of investigating possible relationships between clinical and/or biochemical phenotypes and definitive molecular diagnoses, we performed a retrospective multicenter study of 111 pediatric patients with clinical suspicion of MD. In this cohort, the strongest predictor of a molecular (in particular an mtDNA-related) diagnosis of MD was neuroimaging evidence of basal ganglia (BG) involvement. Regression analysis confirmed that normal BG imaging predicted negative genetic studies for MD. Psychomotor regression was confirmed as an independent predictor of a definitive diagnosis of MD. The findings of this study corroborate previous data supporting a role for neuroimaging in the diagnostic approach to MDs and reinforce the idea that mtDNA sequencing should be considered for first-line testing, at least in specific groups of children.
Annalisa Vetro, Hang N Nielsen, Rikke Holm, Robert F Hevner, Elena Parrini, Zoe Powis, Rikke S Møller, Cristina Bellan, Alessandro Simonati, Gaétan Lesca,et al.
Oxford University Press (OUP)
Abstract Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations’ effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, ‘profound’ phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, ‘profound’ and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.
Carmen Barba, Domenico Montanaro, Laura Grisotto, Francesca Frijia, Simona Pellacani, Anna Cavalli, Susanna Rizzi, Matteo Lenge, Gayane Aghakhanyan, Valentina Sibilia,et al.
Public Library of Science (PLoS)
Flavio Giordano, Carla Moscheo, Matteo Lenge, Roberto Biagiotti, Francesco Mari, Iacopo Sardi, Anna Maria Buccoliero, Lorenzo Mongardi, Eleonora Aronica, Renzo Guerrini,et al.
Springer Science and Business Media LLC
L. Vignatelli, E. Antelmi, I. Ceretelli, M. Bellini, C. Carta, P. Cortelli, L. Ferini-Strambi, R. Ferri, R. Guerrini, F. Ingravallo,et al.
Springer Science and Business Media LLC
Angelica D'Amore, Alessandra Tessa, Carlo Casali, Maria Teresa Dotti, Alessandro Filla, Gabriella Silvestri, Antonella Antenora, Guja Astrea, Melissa Barghigiani, Roberta Battini,et al.
Frontiers Media SA
Roberta Vasta, Antonio Cerasa, Alessia Sarica, Emanuele Bartolini, Iolanda Martino, Francesco Mari, Tiziana Metitieri, Aldo Quattrone, Antonio Gambardella, Renzo Guerrini,et al.
Elsevier BV
Maurizio Lucchesi, Enrico Chiappa, Flavio Giordano, Francesco Mari, Lorenzo Genitori, and Iacopo Sardi
S. Karger AG
Introduction: Cardiac rhabdomyomas represent a frequent manifestation of tuberous sclerosis. Tumor growth, mainly prenatally, can result in intrauterine fetal or neonatal deaths in almost 10% of patients. Case Report: We treated 3 consecutive infants aged less than 12 months with sirolimus, an oral mTOR inhibitor. All patients achieved significant reductions in cardiac rhabdomyomas. A complete response was documented in 2 patients, while a partial response with tumor debulking greater than 50% was seen in the other one. The median time to best cardiac response was 1.9 months in all patients, and 3.3 months in those with complete response. The side effects profile was acceptable. Conclusion: Sirolimus may have a significant role in promoting natural regression of cardiac rhabdomyomas. Prospective clinical trials are needed.
Francesco Mari, Beatrice Berti, Alessandro Romano, Jacopo Baldacci, Riccardo Rizzi, M. Grazia Alessandrì, Alessandra Tessa, Elena Procopio, Anna Rubegni, Charles Marques Lourenḉo,et al.
Springer Science and Business Media LLC
Guja Astrea, , Alessandro Romano, Corrado Angelini, Carlo Giuseppe Antozzi, Rita Barresi, Roberta Battini, Carla Battisti, Enrico Bertini, Claudio Bruno,et al.
Springer Science and Business Media LLC
Denise Cassandrini, , Rosanna Trovato, Anna Rubegni, Sara Lenzi, Chiara Fiorillo, Jacopo Baldacci, Carlo Minetti, Guja Astrea, Claudio Bruno,et al.
Springer Science and Business Media LLC
Steffen Syrbe, Frederike L Harms, Elena Parrini, Martino Montomoli, Ulrike Mütze, Katherine L Helbig, Tilman Polster, Beate Albrecht, Ulrich Bernbeck, Ellen van Binsbergen,et al.
Oxford University Press (OUP)
Mario Mascalchi, Francesco Mari, Beatrice Berti, Emanuele Bartolini, Matteo Lenge, Andrea Bianchi, Laura Antonucci, Filippo M. Santorelli, Barbara Garavaglia, and Renzo Guerrini
Springer Science and Business Media LLC