Daniel Natera-de Benito

Hospital Sant Joan de Déu · Neuromuscular Unit

Objective To delineate the epileptic phenotype of LAMA2‐related muscular dystrophy (MD) and correlate it with the neuroradiological and muscle biopsy findings, as well as the functional motor phenotype. Methods Clinical, electrophysiological, neuroradiological, and histopathological data of 25 patients with diagnosis of LAMA2‐related MD were analy...

Objective Children with neuromuscular disorders have been assumed to be a particularly vulnerable population since the beginning of COVID-19. Although this is a plausible hypothesis, there is no evidence that complications or mortality rates in neuromuscular patients are higher than in the general population. The aim of this study is to describe th...

Objective: To accurately categorize the phenotypes of individuals with collagen VI-related dystrophies (COL6-RDs) during the first years of life in order to predict long-term motor function and pulmonary function, provide phenotype-specific anticipatory care and improve clinical trial readiness. Methods: This retrospective, multicenter, internat...

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases σ and δ (PTP σ/δ) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital crani...

The cellular and molecular consequences of lack of dystrophin in humans are only partially known, which is crucial for the development of new therapies aiming to slow or stop the progression Duchenne and Becker muscular dystrophies. We analyzed muscle biopsies of DMD patients and controls using single nuclei RNA sequencing (snRNAseq) and correlated...

Introduction: LMNA-related muscular dystrophy is a rare entity that produce “laminopathies” such as Emery–Dreifuss muscular dystrophy (EDMD), limb–girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). Heart failure, malignant arrhythmias, and sudden death may occur. No consensus exists on cardiovascular...

DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin–glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unr...

Objective: Mutations in ANXA11 cause amyotrophic lateral sclerosis (ALS) and have recently been identified as a cause of multisystem proteinopathy and adult-onset muscular dystrophy. These conditions are adult-onset diseases and result from the substitution of Aspartate 40 (Asp40) for an apolar residue in the intrinsically disordered domain (IDD)...

Background Up to 7% of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) remain genetically undiagnosed after routine genetic testing. These patients are thought to carry deep intronic variants, structural variants or splicing alterations not detected through multiplex ligation-dependent probe amplification or exome...

Primary acetylcholine receptor deficiency is the most common subtype of congenital myasthenic syndrome, resulting in reduced amount of acetylcholine receptors expressed at the muscle endplate and impaired neuromuscular transmission. AChR deficiency is caused mainly by pathogenic variants in the ε-subunit of the acetylcholine receptor encoded by CHR...

DTNA encodes for α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex that binds to dystrophin/utrophin and α-syntrophin. Absence of α-dystrobrevin causes muscular dystrophy in mice but variants in DTNA in humans have not been associated with muscle disease. Here, we present nine individuals from two unrelated families...

Fibroadipogenic progenitor cells (FAPS) are mesenchymal stem cells key in the expansion of the fibro-adipogenic tissue in Duchenne muscular dystrophy (DMD). Human FAPs are just starting to be characterized and it is not known if there are different subtypes of FAPs in the muscle and their potential role in the pathophysiology of DMD. We cultured FA...

ANXA11 mutations have been associated with two different adult-onset conditions: amyotrophic lateral sclerosis and inclusion body myopathy/multisystem proteinopathy. The pathogenic variant p.Asp40Gly has been identified in individuals with ALS and, more recently, p.Asp40Tyr in patients with multisystem proteinopathy. The pathophysiological mechanis...

Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The TK2 genes were seque...

Objective: To assess in adult spinal muscular atrophy (SMA) patients the construct validity and responsiveness of several outcome measures. Methods: Patients older than 15 years and followed-up in five referral centres for at least 6 months, between October 2015 and August 2020, with one motor function scale (Hammersmith Functional Motor Scale E...

Guillain-Barré syndrome (GBS) is characterized by rapidly progressive and generally ascending symmetrical muscle weakness, accompanied by decreased or absent osteotendinous reflexes. The inflammatory process may affect the myelin or the axon. There are 4 clinical forms of GBS: 1) acute inflammatory demyelinating polyradiculoneuropathy, 2) acute mot...

Background and purpose: The aim was to assess the safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients. Methods: Patients older than 15 years and followed for at least 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM) in five referral centers were i...

Myotonic dystrophy type 1 (DM1) is a progressive, non-treatable, multi-systemic disorder. To investigate the contribution of epigenetics to the complexity of DM1, we compared DNA methylation profiles of four annotated CpG islands (CpGis) in the DMPK locus and neighbouring genes, in distinct DM1 tissues and derived cells, representing six DM1 subtyp...

Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Cata...

Collagen VI-related disorders are the second most common congenital muscular dystrophies for which no treatments are presently available. They are mostly caused by dominant-negative pathogenic variants in the genes encoding α chains of collagen VI, a heteromeric network forming collagen; for example, the c.877G>A; p.Gly293Arg COL6A1 variant, which...

Collagen VI-related dystrophies (COL6-RDs) are a group of rare congenital neuromuscular dystrophies that represent a continuum of overlapping clinical phenotypes that go from the milder Bethlem myopathy (BM) to the severe Ullrich congenital muscular dystrophy, for which there is no effective treatment. Mutations in one of the three Collagen VI gene...

Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To b...

Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and...

Objectives The study is aimed to analyze both sleep architecture and prevalence of sleep-disordered breathing (SDB), in a group of patients with type 2 spinal muscular atrophy (SMA), considering motor dysfunction, and compare them with age-matched controls. Methods Eighteen SMA type 2 patients, (nine males median age 9.5 (4-17) years) and eighteen...

Objective To assess safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients. Methods Patients older than 15 years and followed at least for 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Clinical and patients glo...

Introduction: Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. As new treatment strategies become available, reliable biomarkers and o...

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we...

The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for est...

The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can b...

Background The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS) and, less frequently, ATP7A -related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly af...

Background: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as c...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts and the relationship between phenotypes and genotypes is only partially understood. Methods Retrospective cross-sectional data col...

Diagnosis is essential for the management and treatment of patients with rare diseases. In a group of patients, the genetic study identifies variants of uncertain significance or inconsistent with the phenotype; therefore, it is urgent to develop novel strategies to reach the definitive diagnosis. Herein, we develop the in-house Translational Diagn...

GMPPB mutations cause congenital myasthenic syndromes overlapping with muscular dystrophy. Treatment with pyridostigmine has been reported to be effective in those patients. Nevertheless, results of functional motor assessments to determine its precise impact on the short and long term were not available. We describe the response to treatment with...

The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-pheno...

Our objective was to investigate the potential of three microRNAs, miR-181a-5p, miR-30c-5p, and miR-206 as prognostic biomarkers for long-term follow up of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients. We analyzed the expression of three microRNAs in serum of 18 patients (DMD 13, BMD 5) and 13 controls using drople...

Important advances have been made in the field of congenital myopathies in recent years, forcing clinicians to constantly review and update this group of diseases. The increasing identification of new genes and phenotypes associated with already known genes has been possible to a great extent thanks to the development accomplished in next generatio...

Duchenne muscular dystrophy is a genetically determined disease, linked to the X chromosome, c haracterized clinically by producing progressive muscle weakness, with an incidence of 1 per 3500-6000 males born. It is caused by the mutation of the DMD gene, which encodes dystrophin, a sub-sarcolemmal protein essential for structural muscle stability....

INTRODUCTION The recent advances in the therapies for some neuromuscular disorders imply a better prognosis. As a consequence, health-related quality of life has emerged as a core outcome. It is particularly important to know both the self-perceived health-related quality of life by children, as soon as possible, as well as the parental perception....

TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. Variants in TRAPPC11 have been reported to be associated with a broad spectrum of phenotypes but all affected individuals display muscular pathology. Identifying additional variants will further our understanding of the clinical spe...

To the Editor We read with interest the article by Elrick et al¹ defining clinical subpopulations of children diagnosed as having acute flaccid myelitis (AFM). Among 45 patients who met the US Centers for Disease Control and Prevention case definition of AFM, the clinical presentation of 1 in 4 was consistent with an alternative diagnosis such as m...

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by homozygous deletions or loss-of-function mutations in SMN1, which result in a degeneration of motor neurons in the spinal cord and brain stem. Even without a randomized placebo-controlled trial, salbutamol has been offered to patients with SMA in the neuromuscular clinics of...

Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long‐term follow‐up of seven patients with CHRNG‐related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics,...