Soledad Monges

Garrahan Hospital

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Fabiana Lubieniecki

Garrahan Hospital

Norma B. Romero

Assistance Publique – Hôpitaux de Paris

A.L. Taratuto

Instituto de Neurología Cognitiva

Jocelyn Laporte

Institut de génétique et de biologie moléculaire et cellulaire

Johann Böhm

Institut de génétique et de biologie moléculaire et cellulaire

A. Madelaine

Sorbonne Université

Guy Brochier

Institut de Myologie

Gisèle Bonne

Centre de Recherche en Myologie

Ana Lía Taratuto

Instituto de Neurología de Buenos Aires

Emmanuelle Lacène

Institut de Myologie

Cooperative Institutions

Inserm

134

Erasmus MC

132

Aarhus University Hospital

104

Assistance Publique – Hôpitaux de Paris

Garrahan Hospital

Sorbonne Université

Erasmus University Rotterdam

University of Michigan–Ann Arbor

Institut de Myologie

Centre National de la Recherche Scientifique

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Genotype–phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina

European Journal of Paediatric Neurology (2016)

Sofía Medrano Soledad Monges Luis Pablo Gravina Laura Alías J. Mozzoni

SMN1

10.1016/j.ejpn.2016.07.017

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Citations (24)

International retrospective natural history study of LMNA-related congenital muscular dystrophy

Brain Communications (2021)

Rabah Ben Yaou Pomi Yun Ivana Dabaj Gina Norato Sandra Donkervoort

Abstract Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0–2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8–4.0) and age of ambulation loss (median: 7 years, range: 1.2–38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype–phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

LMNA

Natural history study

10.1093/braincomms/fcab075

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Citations (25)

G.P.5.01 Inflammatory or ‘congenital myopathy’ type findings in muscle biopsies of patients with LMNA mutations

Neuromuscular Disorders (2007)

Fabiana Lubieniecki Soledad Monges Alberto Dubrovsky Alejandro Stewart-Harris Víctor Ruggieri

LMNA

Dilated Cardiomyopathy

Muscle contracture

Muscle weakness

Proximal muscle weakness

Muscle Atrophy

10.1016/j.nmd.2007.06.124

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Citations (3)

Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype

Acta Neuropathologica Communications (2014)

Edoardo Malfatti Vilma‐Lotta Lehtokari Johann Böhm Josine M. de Winter Ursula Schäffer

Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3. In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation between clinical severity on the one hand and the degree of sarcomeric dissociation and contractility efficiency on the other. By contrast the percentage of fibres occupied by rods, as well as the quantity and the sub sarcolemmal position of rods, appears to inversely correlate with severity. Based on our observations, we propose myofibrillar dissociation and changes in contractility as an important cause of muscle weakness in NEB-mutated NM patients.

Nemaline myopathy

Nebulin

Muscle Hypotonia

Myofibril

Muscle weakness

Actinin

Congenital myopathy

10.1186/2051-5960-2-44

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Citations (80)

APPLICATION OF NEXT GENERATION TECHNOLOGIES

Neuromuscular Disorders (2021)

E. Foncuberta Fabiana Lubieniecki E. Cavassa Francisco Javier Ruescas García N. Piergrossi

Amplicon

LMNA

10.1016/j.nmd.2021.07.343

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Citations (0)

G.P.8 12 Centronuclear myopathy: clinical and morphological phenotype/genotype correlations

Neuromuscular Disorders (2006)

Jorge A. Bevilacqua Marc Bitoun Anders Oldfors Fabiana Lubieniecki Soledad Monges

Genotype-phenotype distinction

10.1016/j.nmd.2006.05.214

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Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

PLoS ONE (2013)

Jonàs Juan‐Mateu Lídia González-Quereda Maria José Rodríguez Edgard Verdura Kira Lázaro

DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.

Exon skipping

Splice site mutation

Minigene

Nonsense mutation

Nonsense-Mediated Decay

Exonic splicing enhancer

splice

10.1371/journal.pone.0059916

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Citations (50)

Series de Pediatría Garrahan. El niño con problemas neurológicos

H Arroyo Fernanda De Castro Pérez Soraya Anis El Kik Jorge Agrimbau Celeste Buompadre

Source

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The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia

Human Mutation (2013)

Catherine L. Bladen Karen Rafferty Volker Straub Soledad Monges Angélica Moresco

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

Neuromuscular disease

10.1002/humu.22390

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Citations (100)

Características de los pacientes con atrofia muscular espinal en seguimiento en un hospital público pediátrico. Estudio descriptivo

Neurología Argentina (2024)

Ana Corina López Soledad Monges Camila Ailín Aleu Maylén Cingolani Agostina Gerardi

10.1016/j.neuarg.2024.03.005

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Citations (0)