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2. An Integrated Phenotypic and Genotypic Approach Reveals a High‐Risk Subtype Association for <scp> EBF3 </scp> Missense Variants Affecting the Zinc Finger Domain

Author

Cole A. Deisseroth, Vanesa C. Lerma, Christina L. Magyar, Jessica Mae Pfliger, Aarushi Nayak, Nathan D. Bliss, Ashley W. LeMaire, Vinodh Narayanan, Christopher Balak, Ginevra Zanni, Enza Maria Valente, Enrico Bertini, Paul J. Benke, Michael F. Wangler, and Hsiao‐Tuan Chao

Subjects
Neurology, Autism Spectrum Disorder, Neurodevelopmental Disorders, Mutation, Missense, Humans, Zinc Fingers, Neurology (clinical), Transcription Factors
Abstract

Collier/Olf/EBF (COE) transcription factors have distinct expression patterns in the developing and mature nervous system. To date, a neurological disease association has been conclusively established for only the Early B-cell Factor-3 (EBF3) COE family member through the identification of heterozygous loss-of-function variants in individuals with autism spectrum/neurodevelopmental disorders (NDD). Here, we identify a symptom severity risk association with missense variants primarily disrupting the zinc finger domain (ZNF) in EBF3-related NDD.A phenotypic assessment of 41 individuals was combined with a literature meta-analysis for a total of 83 individuals diagnosed with EBF3-related NDD. Quantitative diagnostic phenotypic and symptom severity scales were developed to compare EBF3 variant type and location to identify genotype-phenotype correlations. To stratify the effects of EBF3 variants disrupting either the DNA-binding domain (DBD) or the ZNF, we used in vivo fruit fly UAS-GAL4 expression and in vitro luciferase assays.We show that patient symptom severity correlates with EBF3 missense variants perturbing the ZNF, which is a key protein domain required for stabilizing the interaction between EBF3 and the target DNA sequence. We found that ZNF-associated variants failed to restore viability in the fruit fly and impaired transcriptional activation. However, the recurrent variant EBF3 p.Arg209Trp in the DBD is capable of partially rescuing viability in the fly and preserved transcriptional activation.We describe a symptom severity risk association with ZNF perturbations and EBF3 loss-of-function in the largest reported cohort to date of EBF3-related NDD patients. This analysis should have potential predictive clinical value for newly identified patients with EBF3 gene variants. ANN NEUROL 2022;92:138-153.

Published
2022

3. Clinical Variability in Spinal Muscular Atrophy Type <scp>III</scp>

Author

Claudio Bruno, Gian Luca Vita, Jacqueline Montes, Maria Sframeli, Tina Duong, Valeria Sansone, Annalia Frongia, Mariacristina Scoto, John W. Day, Francesco Muntoni, Giorgia Coratti, Enrico Bertini, Jessica Exposito Escudero, Simona Lucibello, Marika Pane, Sonia Messina, Allan M. Glanzman, Eugenio Mercuri, Roberto De Sanctis, Elena S. Mazzone, Anna Mayhew, Laura Antonaci, Francesca Bovis, Andrés Nascimento Osorio, Matthew Civitello, Sara Carnicella, Rachel Salazar, Richard S. Finkel, Chiara Marini Bettolo, Adele D'Amico, Nathalie Goemans, Robert Muni Lofra, Darryl C. De Vivo, Marleen Van den Hauwe, Maria Carmela Pera, Evelin Milev, Amy Pasternak, Sally Dunaway Young, Emilio Albamonte, and Basil T. Darras

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Longitudinal study, Adolescent, Models, Neurological, Gene Dosage, Spinal Muscular Atrophies of Childhood, Young Adult, 03 medical and health sciences, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, 0302 clinical medicine, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Humans, Survival of Motor Neuron 2 Protein, Models, Internal medicine, medicine, Preschool, business.industry, Repeated measures design, Retrospective cohort study, Spinal muscular atrophy, medicine.disease, SMA, 030104 developmental biology, Neurology, Neurological, Cohort, Neurology (clinical), sma, Age of onset, business, 030217 neurology & neurosurgery, Cohort study
Abstract

OBJECTIVE: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments. RESULTS: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (ß = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (ß = -1.15, p < 0.0001) and IIIB (ß = -0.69, p = 0.002). INTERPRETATION: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117.

Published
2020

4. De novoLMNAmutations cause a new form of congenital muscular dystrophy

Author

Pascale Guicheney, Nigel F. Clarke, L. Demay, Helen Roper, Norma B. Romero, Enrico Bertini, Carsten G. Bönnemann, Monique M. Ryan, Rabah Ben Yaou, Brigitte Estournet, Linda De Meirleir, Pierre Yves Jeannet, Caroline Sewry, Pascale Richard, B. Mbieleu, Susana Quijano-Roy, A. Barois, Andrés Nascimento, Ana Ferreiro, Francesco Muntoni, Gisèle Bonne, Adele D'Amico, Jaume Colomer, Jean Marie Cuisset, and Pediatrics

Subjects
Adult, Genetic Markers, Male, medicine.medical_specialty, Pathology, Cardiomyopathy, LMNA, Humans, Medicine, Muscular dystrophy, Child, Myopathy, Muscle contracture, congenital muscular dystrophy, biology, business.industry, Muscle weakness, Lamin Type A, medicine.disease, Surgery, Muscular Dystrophies, Limb-Girdle, Neurology, Child, Preschool, Mutation, Congenital muscular dystrophy, biology.protein, Female, Creatine kinase, Neurology (clinical), medicine.symptom, business
Abstract

Objective: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. Methods: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. Results: The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a “dropped head” syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers. Interpretation: The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD). Ann Neurol 2008;64:177–186

Published
2008

5. Subcomplexes of human ATP synthase mark mitochondrial biosynthesis disorders

Author

Sabine Hofmann, Rosalba Carrozzo, Ulrich Brandt, Enrico Bertini, Hermann Schägger, Ilka Wittig, and Filippo M. Santorelli

Subjects
Mitochondrial DNA, Mitochondrial Diseases, Protein Conformation, Mitochondrial disease, Submitochondrial Particles, macromolecular substances, Oxidative phosphorylation, Mitochondrion, Biology, DNA, Mitochondrial, Electron Transport Complex III, Neuroblastoma, Tumor Cells, Cultured, medicine, Humans, Electrophoresis, Gel, Two-Dimensional, Binding Sites, Electron Transport Complex I, ATP synthase, Inhibitor protein, Mitochondrial Proton-Translocating ATPases, medicine.disease, Mitochondria, Neurology, mitochondrial fusion, Biochemistry, biology.protein, Electrophoresis, Polyacrylamide Gel, Neurology (clinical), ATP–ADP translocase, Biomarkers
Abstract

Objective Methods: We describe biochemically and clinically relevant aspects of mitochondrial ATP synthase, the enzyme that supplies most ATP for the cells energy demand. Results Analyzing human Rho zero cells we could identify three subcomplexes of ATP synthase: F1 catalytic domain, F1 domain with bound natural IF1 inhibitor protein, and F1-c subcomplex, an assembly of F1 domain and a ring of FO-subunits c. Large amounts of F1 subcomplexes accumulated also in mitochondria of patients with specific mitochondrial disorders. By quantifying the F1 subcomplexes and other oxidative phosphorylation complexes in parallel, we were able to discriminate three classes of defects in mitochondrial biosynthesis, namely, mitochondrial DNA depletion, mitochondrial transfer RNA (tRNA) mutations, and mutations in the mitochondrial ATP6 gene. Interpretation The relatively simple electrophoretic assay used here is a straightforward approach to differentiate between various types of genetic alterations affecting the biosynthesis of oxidative phosphorylation complexes and will be useful to guide molecular genetic diagnostics in the field of mitochondrial neuromuscular disorders. Ann Neurol 2006

Published
2005

6. Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy

Author

Stefania Petrini, Haluk Topaloglu, Guglielmina Pepe, Enrico Bertini, Beril Talim, Patrizia Sabatelli, Brunella Bandinelli, Stefano Squarzoni, Luciano Merlini, Filip Roelens, Betti Giusti, C. Gartioux, Pascale Guicheney, Simona Lucioli, Valentina Pietroni, and Laura Lucarini

Subjects
Male, DNA, Complementary, Adolescent, Ullrich congenital muscular dystrophy, Blotting, Western, DNA Mutational Analysis, Nonsense mutation, Glycine, Fluorescent Antibody Technique, Genes, Recessive, Collagen Type VI, Biology, medicine.disease_cause, Muscular Dystrophies, White People, Exon, medicine, Humans, Missense mutation, RNA, Messenger, Allele, Child, Connective Tissue Diseases, Microscopy, Immunoelectron, Cytoskeleton, Genetics, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Bethlem myopathy, Exons, Fibroblasts, Blotting, Northern, medicine.disease, Phenotype, Molecular Weight, Neurology, Child, Preschool, Female, Neurology (clinical)
Abstract

In this study, we characterized five Ullrich scleroatonic muscular dystrophy patients (two Italians, one Belgian, and two Turks) with a clinical phenotype showing different degrees of severity, all carrying mutations localized in COL6A1. We sequenced the three entire COL6 complementary DNA. Three of five patients have recessive mutations: two patients (P1and P3) have homozygous single-nucleotide deletions, one in exon 9 and one in exon 22; one patient (P2) has a homozygous single-nucleotide substitution leading to a premature termination codon in exon 31. The nonsense mutation of P2 also causes a partial skipping of exon 31 with the formation of a premature termination codon in exon 32 in 15% of the total COL6A1 messenger RNA. The remaining two patients carry a heterozygous glycine substitution in exons 9 and 10 inside the triple-helix region; both are dominant mutations because the missense mutations are absent in the DNA of their respective parents. As for the three homozygous recessive mutations, the apparently healthy consanguineous parents all carry a heterozygous mutated allele. Here, for the first time, we report a genotype–phenotype correlation demonstrating that heterozygous glycine substitutions in the triple-helix domain of COL6A1 are dominant and responsible for a milder Ullrich scleroatonic muscular dystrophy phenotype, and that recessive mutations in COL6A1 correlate with more severe clinical and biochemical Ullrich scleroatonic muscular dystrophy phenotypes. Ann Neurol 2005;58:400 – 410

Published
2005

7. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Author

Christoph Hübner, Robert A. Ouvrier, Haluk Topaloglu, Heidemarie Neitzel, Nathalie Goemans, Christina Steglich, Carmen Navarro, Piroschka Stolz, Francesco Muntoni, Friedrich Bosch, Enrico Bertini, Kate Bushby, Ulf-Peter Guenther, Hanns Lochmüller, Katja Grohmann, Stephan Eichholz, Padraic Grattan-Smith, Sabine Rudnik-Schöneborn, Markus Schuelke, Raymonda Varon, Coleen Adams, Lionel Van Maldergem, Tilman Polster, Catrin Janetzki, and Klaus Zerres

Subjects
Pediatrics, medicine.medical_specialty, Pathology, Respiratory distress, business.industry, Respiratory disease, Muscle weakness, Prenatal diagnosis, Spinal muscular atrophy, Sudden infant death syndrome, medicine.disease, Central nervous system disease, Degenerative disease, Neurology, medicine, Neurology (clinical), medicine.symptom, business
Abstract

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) is the second anterior horn cell disease in infants in which the genetic defect has been defined. SMARD1 results from mutations in the gene encoding the immunoglobulin mu-binding protein 2 (IGHMBP2) on chromosome 11q13. Our aim was to review the clinical features of 29 infants affected with SMARD1 and report on 26 novel IGHMBP2 mutations. Intrauterine growth retardation, weak cry, and foot deformities were the earliest symptoms of SMARD1. Most patients presented at the age of 1 to 6 months with respiratory distress due to diaphragmatic paralysis and progressive muscle weakness with predominantly distal lower limb muscle involvement. Sensory and autonomic nerves are also affected. Because of the poor prognosis, there is a demand for prenatal diagnosis, and clear diagnostic criteria for infantile SMARD1 are needed. The diagnosis of SMARD1 should be considered in infants with non-5q spinal muscular atrophy, neuropathy, and muscle weakness and/or respiratory distress of unclear cause. Furthermore, consanguineous parents of a child with sudden infant death syndrome should be examined for IGHMBP2 mutations.

Published
2003

8. New familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy, and complex I deficiency

Author

Ron J. A. Wanders, Carlo Dionisi-Vici, C. Piantadosi, Cesare Bosman, Giuseppe Fariello, H.A.C.M. Bentlage, G. Sabetta, Enrico Bertini, Hermann Schägger, and Wim Ruitenbeek

Subjects
medicine.medical_specialty, business.industry, Cardiomyopathy, Hypertrophic cardiomyopathy, Macrocephaly, Skeletal muscle, medicine.disease, Central nervous system disease, medicine.anatomical_structure, Endocrinology, Mitochondrial respiratory chain, Neurology, Gliosis, Internal medicine, medicine, Neurology (clinical), medicine.symptom, business, Mitochondrial Encephalomyopathies
Abstract

Two siblings presented with a new phenotype consisting of fatal progressive macrocephaly and hypertrophic cardiomyopathy. Onset of symptoms started in both patients at the end of the first month of life with massive brain swelling causing macrocephaly and evolving to extensive brain destruction. Light microscopy of the lesions showed extensive small-vessel proliferation and gliosis. A distinct deficiency of complex I of mitochondrial respiratory chain was established in cultured fibroblasts, skeletal muscle, and heart muscle. Specific lack of complex I protein was demonstrated by two-dimensional gel electrophoresis.

Published
1997

9. RYR1 mutations are a common cause of congenital myopathies with central nuclei

Author

Wolfram Kress, Komala Pillay, Stephen Abbs, V cloke, Caroline Sewry, Haiyan Zhou, Howard E. Henderson, CG Boennemann, Clemens R. Müller, Enrico Bertini, Heinz Jungbluth, Francesco Muntoni, Jo M. Wilmshurst, Alvin Ndondo, James J. Dowling, S. Lillis, Susan Treves, Volker Straub, Ros Quinlivan, Adnan Y. Manzur, Thomas Cullup, and Safa Al-Sarraj

Subjects
Male, Pathology, medicine.medical_specialty, Heterozygote, Adolescent, Genotype, Biology, Compound heterozygosity, South Africa, medicine, Humans, Centronuclear myopathy, Myopathy, Child, Muscle, Skeletal, Genetics, RYR1, Muscle biopsy, medicine.diagnostic_test, Ryanodine Receptor Calcium Release Channel, medicine.disease, Congenital myopathy, Europe, DNM2, Phenotype, Neurology, Child, Preschool, Mutation, Neurology (clinical), medicine.symptom, Central core disease, Myopathies, Structural, Congenital
Abstract

Objective: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. Methods: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n ¼ 14) and Europe (n ¼ 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. Results: The high incidence in South African patients (n ¼ 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and t ype 1f iber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. Interpretation: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies. ANN NEUROL 2010;68:717–726

Published
2010

10. Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease

Author

Enrico Bertini, Patricia Combes, Céline Gonthier-Guéret, Geneviève Giraud, Aurélie Monnier, Faiza Fakhfakh, Nadège Kammoun, Triki Chahnez, Odile Boespflug-Tanguy, and Catherine Vaurs-Barrière

Subjects
Genetics, 0303 health sciences, Promoter mutation, Pelizaeus Merzbacher like disease, Pelizaeus-Merzbacher Disease, Transcription, Genetic, SOXE Transcription Factors, Biology, Connexins, 03 medical and health sciences, GJC2, 0302 clinical medicine, Neurology, Humans, Female, Neurology (clinical), 030217 neurology & neurosurgery, 030304 developmental biology
Published
2010

11. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Author

Katja, Grohmann, Raymonda, Varon, Piroschka, Stolz, Markus, Schuelke, Catrin, Janetzki, Enrico, Bertini, Kate, Bushby, Francesco, Muntoni, Robert, Ouvrier, Lionel, Van Maldergem, Nathalie M L A, Goemans, Hanns, Lochmüller, Stephan, Eichholz, Coleen, Adams, Friedrich, Bosch, Padraic, Grattan-Smith, Carmen, Navarro, Heidemarie, Neitzel, Tilman, Polster, Haluk, Topaloğlu, Christina, Steglich, Ulf P, Guenther, Klaus, Zerres, Sabine, Rudnik-Schöneborn, and Christoph, Hübner

Subjects
DNA-Binding Proteins, Male, Respiratory Distress Syndrome, Newborn, Mutation, Infant, Newborn, Humans, Infant, Female, Spinal Muscular Atrophies of Childhood, Carrier Proteins, Transcription Factors
Abstract

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) is the second anterior horn cell disease in infants in which the genetic defect has been defined. SMARD1 results from mutations in the gene encoding the immunoglobulin micro-binding protein 2 (IGHMBP2) on chromosome 11q13. Our aim was to review the clinical features of 29 infants affected with SMARD1 and report on 26 novel IGHMBP2 mutations. Intrauterine growth retardation, weak cry, and foot deformities were the earliest symptoms of SMARD1. Most patients presented at the age of 1 to 6 months with respiratory distress due to diaphragmatic paralysis and progressive muscle weakness with predominantly distal lower limb muscle involvement. Sensory and autonomic nerves are also affected. Because of the poor prognosis, there is a demand for prenatal diagnosis, and clear diagnostic criteria for infantile SMARD1 are needed. The diagnosis of SMARD1 should be considered in infants with non-5q spinal muscular atrophy, neuropathy, and muscle weakness and/or respiratory distress of unclear cause. Furthermore, consanguineous parents of a child with sudden infant death syndrome should be examined for IGHMBP2 mutations.

Published
2003

12. Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases

Author

Charles-Antoine Haenggeli, Ana Ferreiro, Daniel Fontan, Norma B. Romero, Michel Fardeau, Jon Andoni Urtizberea, Ana Cabello, Pascale Guicheney, Sylvie Odent, Heloisa G. Dos Santos, Annick Toutain, Cécile Laroche, Danielle Chateau, Enrico Bertini, and Brigitte Estournet

Subjects
Male, Weakness, Pathology, medicine.medical_specialty, Biopsy, Biology, Muscles/pathology, Muscular Diseases/genetics/pathology, Muscular Diseases, medicine, Humans, Myopathy, education, Retrospective Studies, Arthrogryposis, education.field_of_study, ddc:618, Selenoprotein N, Muscles, Muscle weakness, Anatomy, Amyotrophy, medicine.disease, Phenotype, Congenital myopathy, Neurology, Female, Neurology (clinical), medicine.symptom
Abstract

Multi-minicore disease (MmD) is a congenital myopathy morphologically defined by the presence of multiple small zones of sarcomeric disorganization and lack of oxidative activity ("minicores") in muscle fibers. The dinical expression of MmD is considered to be greatly variable, and the morphological lesions are nonspecific; therefore, its boundaries are poorly defined, and its molecular bases are not known. To better define the phenotypic characteristics of MmD, we analyzed a large series of 38 patients with multiple minicores in muscle fibers in the absence of any other potential cause. According to clinical features, 4 subgroups were identified. Most patients (30 cases) shared a common highly consistent phenotype marked by the axial predominance of muscle weakness and a high occurrence of severe respiratory insufficiency and scoliosis ("classical" form). Other forms were characterized by pharyngolaryngeal involvement and total lack of head control (2 cases), antenatal onset with arthrogryposis (3 cases), and slowly progressive weakness with marked hand amyotrophy (3 cases). Type 1 fiber predominance and hypotrophy as well as centrally located nuclei were found in every subgroup. MmD is thus phenotypically heterogeneous, but a typical recognizable phenotype does exist. This phenotype classification should be helpful when undertaking research into the molecular defects that cause MmD.

Published
2000

13. Correction

Author

Hülya Kayserili, Lihadh Al-Gazali, Asma A. Al-Tawari, László Sztriha, Bruno Dallapiccola, Enza Maria Valente, Joseph G. Gleeson, Enrico Bertini, Jean Messer, Clara Barbot, Carmelo Salpietro, Tracy Dixon-Salazar, C. Geoffrey Woods, Eugen Boltshauser, Moez Gribaa, Michel Koenig, Marco Castori, and Sarah E. Marsh

Subjects
Pediatrics, medicine.medical_specialty, Annals, Neurology, business.industry, Medicine, Neurology (clinical), business, Jouberts syndrome
Published
2005

14. AHI1 gene mutations cause specific forms of Joubert syndrome–related disorders.

Author

Enza Maria Valente, Francesco Brancati, Jennifer L. Silhavy, Marco Castori, Sarah E. Marsh, Giuseppe Barrano, Enrico Bertini, Eugen Boltshauser, Maha S. Zaki, Alice Abdel‐Aleem, Ghada M. H. Abdel‐Salam, Emanuele Bellacchio, Roberta Battini, Robert P. Cruse, William B. Dobyns, Kalpathy S. Krishnamoorthy, Clotilde Lagier‐Tourenne, Alex Magee, Ignacio Pascual‐Castroviejo, and Carmelo D. Salpietro

Published
2006

16. Distinguishing the four genetic causes of jouberts syndrome–related disorders.

Author

Enza Maria Valente, Sarah E. Marsh, Marco Castori, Tracy Dixon‐Salazar, Enrico Bertini, Lihadh Al‐Gazali, Jean Messer, Clara Barbot, C. Geoffrey Woods, Eugen Boltshauser, Asma A. Al‐Tawari, Carmelo D. Salpietro, Hulya Kayserili, László Sztriha, Moez Gribaa, Michel Koenig, Bruno Dallapiccola, and Joseph G. Gleeson

Published
2005

18. Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum.

Author

McCormick, Elizabeth M., Keller, Kierstin, Taylor, Julie P., Coffey, Alison J., Shen, Lishuang, Krotoski, Danuta, Harding, Brian, Alves, César Augusto Pinheiro Ferreira, Ardissone, Anna, Bai, Renkui, de Barcelos, Isabella Peixoto, Bertini, Enrico, Bluske, Krista, Christodoulou, John, Clause, Amanda R., Copeland, William C., Diaz, George A., Diodato, Daria, Dulik, Matthew C., and Enns, Greg

Subjects
MITOCHONDRIA, GENES, RECESSIVE genes, SCORING rubrics, INDIVIDUALIZED medicine, GENETIC disorder diagnosis
Abstract

Objective: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene–disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes. Methods: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene–Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS. Results: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31 of 114 GDRs curated (27%), moderate for 38 (33%), limited for 43 (38%), and disputed for 2 (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 were autosomal dominant, and 3 were X‐linked. Interpretation: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multisystem organ surveillance, recurrence risk counseling, reproductive choice, natural history studies, and determination of eligibility for interventional clinical trials. ANN NEUROL 2023;94:696–712 [ABSTRACT FROM AUTHOR]

Published
2023
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20. An Integrated Phenotypic and Genotypic Approach Reveals a High‐Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain.

Author

Deisseroth, Cole A., Lerma, Vanesa C., Magyar, Christina L., Pfliger, Jessica Mae, Nayak, Aarushi, Bliss, Nathan D., LeMaire, Ashley W., Narayanan, Vinodh, Balak, Christopher, Zanni, Ginevra, Valente, Enza Maria, Bertini, Enrico, Benke, Paul J., Wangler, Michael F., and Chao, Hsiao‐Tuan

Subjects
MISSENSE mutation, ZINC-finger proteins, GENOTYPES, PHENOTYPES, NEURAL development
Abstract

Objective: Collier/Olf/EBF (COE) transcription factors have distinct expression patterns in the developing and mature nervous system. To date, a neurological disease association has been conclusively established for only the Early B‐cell Factor‐3 (EBF3) COE family member through the identification of heterozygous loss‐of‐function variants in individuals with autism spectrum/neurodevelopmental disorders (NDD). Here, we identify a symptom severity risk association with missense variants primarily disrupting the zinc finger domain (ZNF) in EBF3‐related NDD. Methods: A phenotypic assessment of 41 individuals was combined with a literature meta‐analysis for a total of 83 individuals diagnosed with EBF3‐related NDD. Quantitative diagnostic phenotypic and symptom severity scales were developed to compare EBF3 variant type and location to identify genotype–phenotype correlations. To stratify the effects of EBF3 variants disrupting either the DNA‐binding domain (DBD) or the ZNF, we used in vivo fruit fly UAS‐GAL4 expression and in vitro luciferase assays. Results: We show that patient symptom severity correlates with EBF3 missense variants perturbing the ZNF, which is a key protein domain required for stabilizing the interaction between EBF3 and the target DNA sequence. We found that ZNF‐associated variants failed to restore viability in the fruit fly and impaired transcriptional activation. However, the recurrent variant EBF3 p.Arg209Trp in the DBD is capable of partially rescuing viability in the fly and preserved transcriptional activation. Interpretation: We describe a symptom severity risk association with ZNF perturbations and EBF3 loss‐of‐function in the largest reported cohort to date of EBF3‐related NDD patients. This analysis should have potential predictive clinical value for newly identified patients with EBF3 gene variants. ANN NEUROL 2022;92:138–153 [ABSTRACT FROM AUTHOR]

Published
2022
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21. Type I Interferon Signature in NOTCH1‐Related Leukoencephalopathy.

Author

Nicita, Francesco, Travaglini, Lorena, Matteo, Valentina, Aiello, Chiara, Longo, Daniela, Insalaco, Antonella, Bertini, Enrico, and Prencipe, Giusi

Subjects
TYPE I interferons, MEDICAL genetics, FUNDUS oculi, GENETIC variation, MAGNETIC resonance imaging, LEUKOENCEPHALOPATHIES
Abstract

PT = patient. gl Due to neuroimaging similarities with AGS, we investigated the peripheral blood type I interferon (IFN) score and levels of the IFN-inducible chemokines C-X-C motif chemokine ligand 10 (CXCL10; also known as IP-10) and CXCL9, and we found them significantly higher in the patient than in healthy controls (see Fig, 1I, J). This additional patient confirms the association between heterozygous I NOTCH1 i variants clustering in the heterodimerization domain of the NOTCH1 protein and a neuroimaging pattern of leukoencephalopathy with calcifications and cysts. (J) C-X-C motif chemokine ligand 9 (CXCL9) and CXCL10 plasma levels were measured by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN) in two different samples collected from the patient about 6 months apart and in controls (n = 15). [Extracted from the article]

Published
2023
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22. Clinical Variability in Spinal Muscular Atrophy Type III.

Author

Coratti, Giorgia, Messina, Sonia, Lucibello, Simona, Pera, Maria Carmela, Montes, Jacqueline, Pasternak, Amy, Bovis, Francesca, Exposito Escudero, Jessica, Mazzone, Elena Stacy, Mayhew, Anna, Glanzman, Allan M., Young, Sally Dunaway, Salazar, Rachel, Duong, Tina, Muni Lofra, Robert, De Sanctis, Roberto, Carnicella, Sara, Milev, Evelin, Civitello, Matthew, and Pane, Marika

Subjects
SPINAL muscular atrophy, NATURAL history, COVARIANCE matrices, AGE of onset
Abstract

Objective: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. Methods: HFMSE longitudinal changes were assessed using piecewise linear mixed‐effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12‐month assessments. Results: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (β = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (β = −1.15, p < 0.0001) and IIIB (β = −0.69, p = 0.002). Interpretation: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real‐world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109–1117 [ABSTRACT FROM AUTHOR]

Published
2020
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23. Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

Author

Traschütz, Andreas, Schirinzi, Tommaso, Laugwitz, Lucia, Murray, Nathan H., Bingman, Craig A., Reich, Selina, Kern, Jan, Heinzmann, Anna, Vasco, Gessica, Bertini, Enrico, Zanni, Ginevra, Durr, Alexandra, Magri, Stefania, Taroni, Franco, Malandrini, Alessandro, Baets, Jonathan, Jonghe, Peter, Ridder, Willem, Bereau, Matthieu, and Demuth, Stephanie

Subjects
MYOCLONUS, CEREBRAL atrophy, UBIQUINONES, CEREBELLAR ataxia, COGNITION disorders, MAGNETIC resonance imaging, PROTEINS, RESEARCH, GENETICS, GENETIC mutation, CROSS-sectional method, RESEARCH methodology, SELF-evaluation, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, RESEARCH funding, LONGITUDINAL method, HEALTH self-care
Abstract

Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10).Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data.Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%.Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263. [ABSTRACT FROM AUTHOR]

Published
2020
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24. Nusinersen in type 1 spinal muscular atrophy: Twelve-month real-world data.

Author

Pane, Marika, Coratti, Giorgia, Sansone, Valeria A., Messina, Sonia, Bruno, Claudio, Catteruccia, Michela, Sframeli, Maria, Albamonte, Emilio, Pedemonte, Marina, D'Amico, Adele, Bravetti, Chiara, Berti, Beatrice, Brigati, Giorgia, Tacchetti, Paola, Salmin, Francesca, de Sanctis, Roberto, Lucibello, Simona, Piastra, Marco, Genovese, Orazio, and Bertini, Enrico

Subjects
SPINAL muscular atrophy, NEUROMUSCULAR diseases, CHILDREN'S hospitals, DRUG efficacy
Abstract

Objective: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months.Methods: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2).Results: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = ±13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = ±1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2.Interpretation: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity. ANN NEUROL 2019;86:443-451. [ABSTRACT FROM AUTHOR]

Published
2019
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25. Passages 2018.

Author

Saper, Clifford B. and Saper, Clifford

Subjects
MEDICAL societies, NEUROLOGY, NEWSLETTERS
Published
2018
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29. Hypomyelinating leukodystrophies: Translational research progress and prospects.

Author

Pouwels, Petra J. W., Vanderver, Adeline, Bernard, Genevieve, Wolf, Nicole I., Dreha‐Kulczewksi, Steffi F., Deoni, Sean C. L., Bertini, Enrico, Kohlschütter, Alfried, Richardson, William, ffrench‐Constant, Charles, Köhler, Wolfgang, Rowitch, David, and Barkovich, A. James

Abstract

Hypomyelinating leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials. Ann Neurol 2014;76:5-19 [ABSTRACT FROM AUTHOR]

Published
2014
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31. DPM2-CDG: A muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy.

Author

Barone, Rita, Aiello, Chiara, Race, Valérie, Morava, Eva, Foulquier, Francois, Riemersma, Moniek, Passarelli, Chiara, Concolino, Daniela, Carella, Massimo, Santorelli, Filippo, Vleugels, Wendy, Mercuri, Eugenio, Garozzo, Domenico, Sturiale, Luisa, Messina, Sonia, Jaeken, Jaak, Fiumara, Agata, Wevers, Ron A., Bertini, Enrico, and Matthijs, Gert

Abstract

Objective: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases due to defects in protein and lipid glycosylation. We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome. There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry. Methods: Biochemical and molecular methods were combined to pinpoint the defect in the glycosylation pathway in the endoplasmic reticulum. Results: Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation in the endoplasmic reticulum. Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation of Dol-PP-GlcNAc2-Man5. DNA analysis revealed mutations in DPM2, 1 of the subunits of the dolichol-phosphate-mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in the second family are homozygous for the same missense mutation (c.68A>G, p.Y23C). Interpretation: We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to the congenital muscular dystrophies. ANN NEUROL 2012;72:550-558 [ABSTRACT FROM AUTHOR]

Published
2012
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32. De novo LMNA mutations cause a new form of congenital muscular dystrophy.

Author

Quijano-Roy, Susana, Mbieleu, Blaise, Bönnemann, Carsten G., Jeannet, Pierre-Yves, Colomer, Jaume, Clarke, Nigel F., Cuisset, Jean-Marie, Roper, Helen, De Meirleir, Linda, D'Amico, Adele, Ben Yaou, Rabah, Nascimento, Andrés, Barois, Annie, Demay, Laurence, Bertini, Enrico, Ferreiro, Ana, Sewry, Caroline A., Romero, Norma B., Ryan, Monique, and Muntoni, Francesco

Abstract

Objective To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. Methods Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. Results The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a 'dropped head' syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers. Interpretation The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy ( LMNA-related congenital muscular dystrophy, or L-CMD). Ann Neurol 2008. [ABSTRACT FROM AUTHOR]

Published
2008
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