Daniel Natera-de Benito

Bio: Daniel Natera-de Benito is an academic researcher from Hospital Sant Joan de Déu Barcelona. The author has contributed to research in topics: Muscular dystrophy & Exome. The author has an hindex of 5, co-authored 24 publications receiving 69 citations. Previous affiliations of Daniel Natera-de Benito include Carlos III Health Institute & University of Barcelona.

Longitudinal Study of Three microRNAs in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy.

Abstract: 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 droplet digital PCR. Over 4 years a minimum of two and a maximum of three measurements were performed at different time points in the same patient. Correlations between microRNA serum levels, age, and functional outcome measures were analyzed. We show the individual evolution of the levels of the three microRNAs in 12 patients and also the effect of corticosteroid treatment on microRNAs expression. We measure the expression of three microRNAs in the muscle of six DMD patients and also the expression of target genes for miR-30c. We found that levels of miR-30c and miR-206 remained significantly elevated in DMD patients relative to controls over the entire study length. The introduction of the corticosteroid treatment did not significantly influence the levels of these microRNAs. We report a trend for microRNA levels to decrease with age. Moreover, miR-206 expression levels are capable to distinguish DMD from BMD patients according to ROC analysis. We found miR-30c expression decreased in the muscle of DMD patients and marked upregulation of the target genes for this microRNA. MiR-30c and miR-206 represent sensitive biomarkers for DMD, while miR-206 may have an additional value to distinguish the DMD and BMD phenotype. This may be particularly relevant to assess the effectiveness of treatments aimed at converting the DMD to the less-severe BMD like phenotype.

Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain

Abstract: 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-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients' clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

Abstract: 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 causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement. In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient’s lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation. An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.

COVID-19 in children with neuromuscular disorders.

Abstract: 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 the clinical characteristics and outcome of COVID-19 in children with neuromuscular disorders. A registry of children with neuromuscular conditions and laboratory-confirmed-SARS-CoV-2 infection was set up by the Neuromuscular Working Group of the Spanish Pediatric Neurology Society (SENEP). Data to be collected were focused on the characteristics and baseline status of the neuromuscular condition and the course of COVID-19. Severe complications were not observed in our series of 29 children with neuromuscular disorders infected by SARS-CoV-2. Eighty-nine percent of patients were clinically categorized as asymptomatic or mild cases and 10% as moderate cases. Patients with a relatively more severe course of COVID-19 had SMA type 1 and were between 1 and 3 years. The course of COVID-19 in children with neuromuscular disorders may not be as severe as expected. The protective role of young age seems to outweigh the risk factors that are common in neuromuscular patients, such as a decreased respiratory capacity or a weak cough. Further studies are needed to know if this finding can be generalized to children with other chronic diseases.

Is this a practical approach

Abstract: 1. Health care is a human right. 2. The care of the individual is at the center of health care, but the whole system needs to work to improve the health of populations. 3. The health care system must treat illness, alleviate suffering and disability, and promote health. 4. Cooperation with each other, those served, and those in other sectors is essential for all who work in health care. 5. All who provide health care must work to improve it. 6. Do no harm.

Antibodies to Contactin-1 in Chronic Inflammatory Demyelinating Polyneuropathy (P01.150)

Abstract: OBJECTIVE: Discover novel autoantibodies in CIDP patients. BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disorder that includes patients with variable phenotypes and different responses to treatment. Its pathogenesis is autoimmune, with probable involvement of autoantibodies. Previous reports describe antibodies against myelin and axonal proteins, but their pathogenicity is controversial. Recent studies highlight the importance of the axo-glial junction in CIDP pathogenesis. Contactin-1 (CNTN1) and contactin associated protein 1 (CASPR1) are proteins of paranodes that play an essential role in myelination. We describe the presence of antibodies against CNTN1 and CNTN1/CASPR1 complex in a small subset of CIDP patients sharing specific clinical features. DESIGN/METHODS: We designed an unbiased approach for antigen unraveling using patients9 sera for hippocampal neuron immunoprecipitation. Mass spectrometry analysis revealed CNTN1-complex proteins in the precipitate. The presence of antibodies against CNTN1 complex was confirmed by immunocytochemistry in CNTN1-transfected cells, sciatic nerve immunohistochemistry and inhibition experiments. Patients9 clinical features and response to therapy were reviewed. RESULTS: Forty-six patients were included in the study. Two patients9 sera have antibodies against CNTN1 protein. Another patient precipitated both CNTN1 and CASPR1 proteins and had antibodies against the CNTN1/CASPR1 complex. All three patients shared clinical features including late and, aggressive onset, predominantly motor involvement with early axonal damage and poor response to intravenous immunoglobulins. CNTN1 antibodies were absent in 14 healthy controls and 90 patients with other neurological diseases, including 48 patients with Guillain-Barre syndrome. CONCLUSIONS: We describe the presence of antibodies against CNTN1-complex in a small subset of CIDP patients with homogeneous clinical features and response to therapy. Those antibodies could provide a diagnostic and prognostic biomarker. Studies with similar design can help discovering other autoantibodies and defining prognostic subgroups in CIDP. This work has been accepted for publication in Annals of Neurology. Supported by: Research grants from Fondo de Investigaciones Sanitarias (FIS intrasalud) 09/1964 (PI I Illa), Luis Querol by FIS CM 09/00017 and Gisela Nogales by FIS CD10/00027. Disclosure: Dr. Illa has received personal compensation for activities with Grifols. Dr. Nogales-Gadea has nothing to disclose. Dr. Querol has nothing to disclose. Dr. Gallardo has nothing to disclose. Dr. Rojas has nothing to disclose.

Congenital myasthenic syndromes.

Abstract: Congenital myasthenic syndromes (CMSs) are a genotypically and phenotypically heterogeneous group of neuromuscular disorders, which have in common an impaired neuromuscular transmission. Since the field of CMSs is steadily expanding, the present review aimed at summarizing and discussing current knowledge and recent advances concerning the etiology, clinical presentation, diagnosis, and treatment of CMSs. Systematic literature review. Currently, mutations in 32 genes are made responsible for autosomal dominant or autosomal recessive CMSs. These mutations concern 8 presynaptic, 4 synaptic, 15 post-synaptic, and 5 glycosilation proteins. These proteins function as ion-channels, enzymes, or structural, signalling, sensor, or transporter proteins. The most common causative genes are CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1. Phenotypically, these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay. Cognitive disability, dysmorphism, neuropathy, or epilepsy are rare. Low- or high-frequency repetitive nerve stimulation may show an abnormal increment or decrement, and SF-EMG an increased jitter or blockings. Most CMSs respond favourably to acetylcholine-esterase inhibitors, 3,4-diamino-pyridine, salbutamol, albuterol, ephedrine, fluoxetine, or atracurium. CMSs are an increasingly recognised group of genetically transmitted defects, which usually respond favorably to drugs enhancing the neuromuscular transmission. CMSs need to be differentiated from neuromuscular disorders due to muscle or nerve dysfunction.

Hereditary Spastic Paraplegia

Abstract: This chapter addresses diseases and disorders where spastic paraplegia develops in childhood, focusing on genetic etiologies. The primary clinical feature is bilateral leg spasticity when walking, emerging from progressive pathology within the axons in the corticospinal tracts and dorsal columns of the spinal cord. Spastic paraplegia may be relatively isolated or occur within a more diffuse neurodegenerative disorder. Updated diagnostic approaches, including genetics and neurophysiology, and treatment options are discussed.