Chronic Cough and Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS): Screening for Mutations in Replication Factor C Subunit 1 (RFC1).

Introduction: A common complaint in patients is chronic cough (CC), which may be refractory (RCC) or unexplained (UCC). Recent studies point, as a possible cause of CC, to the hereditary cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), with an estimated carrier prevalence of 1 in 20000.

Aim: In patients with CC, determine the prevalence of the biallelic (AAGGG)exp mutation in replication factor C subunit 1 (RFC1) responsible for CANVAS, test the usefulness of the Rydel-Seiffer fork test, and evaluate patient quality of life (QoL).

Distal myopathy due to digenic inheritance of TIA1 and SQSTM1 variants in two unrelated Spanish patients.

Welander distal myopathy typically manifests in late adulthood and is caused by the founder TIA1 c.1150G>A (p.Glu384Lys) variant in families of Swedish and Finnish descent.

Clinical and functional characteristics, possible causes, and impact of chronic cough in patients with cerebellar ataxia, neuropathy, and bilateral vestibular areflexia syndrome (CANVAS).

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is an hereditary autosomal recessive disease. Recent studies propose including chronic cough (CC) as a symptom of CANVAS. For 10 patients with CANVAS as genetically confirmed by biallelic expansion of the AAGG repeat motif (AAGGGexp) in intron 2 of replication factor C subunit 1 (RFC1), our aim was, as a multidisciplinary team, to describe clinical and functional characteristics and possible causes of CC following European Respiratory Society (ERS) recommendations, and to evaluate CC impact on quality of life (QoL) using self-administered questionnaires (Cough Severity Diary, Leicester Cough Questionnaire, Discrete Emotions Questionnaire, and EQ-5D-5L).

A new homozygous missense variant in LMOD3 gene causing mild nemaline myopathy with prominent facial weakness.

Nemaline myopathy (NEM) type 10, caused by biallelic mutations in LMOD3, is a severe congenital myopathy clinically characterized by generalized hypotonia and muscle weakness, respiratory insufficiency, joint contractures, and bulbar weakness. Here, we describe a family with two adult patients presenting mild nemaline myopathy due to a novel homozygous missense variant in LMOD3. Both patients presented mild delayed motor milestones, frequent falls during infancy, prominent facial weakness and mild muscle weakness in the four limbs.

Case report: pathogenic variant in causes Wolfram-like syndrome debuting with congenital bilateral deafness.

Congenital deafness could be the first manifestation of a syndrome such as in Usher, Pendred, and Wolfram syndromes. Therefore, a genetic study is crucial in this deficiency to significantly improve its diagnostic efficiency, to predict the prognosis, to select the most adequate treatment required, and to anticipate the development of other associated clinical manifestations. We describe a young girl with bilateral congenital profound deafness, who initially received a single cochlear implant.

Dystrophinopathy Phenotypes and Modifying Factors in DMD Exon 45-55 Deletion.

Objective: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset.

Methods: This cross-sectional, multicenter cohort study applied clinical and functional evaluation.

Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands.

Background: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset myopathy characterized by ptosis, dysphagia, and progressive proximal limb muscle weakness. The disease is produced by a short expansion of the (GCN) triplet in the PABPN1 gene. The size of expansion has been correlated to the disease onset and severity.

Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy.

Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease's severity.

Special Issue "Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy".

Since the gene responsible for Duchenne muscular dystrophy was first described in 1987 [...

The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort.

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: This is a retrospective cross-sectional data collection study conducted at a single center.

Novel PLEKHG5 mutations in a patient with childhood-onset lower motor neuron disease.

The PLEKHG5 gene encodes a protein that activates the nuclear factor kappa B (NFκB) signaling pathway. Mutations in this gene have been associated with distal spinal muscular atrophy IV and intermediate axonal neuropathy C, both with an autosomal recessive mode of inheritance. Two families with low motor neuron disease (LMND) caused by mutations in PLEKHG5 have been reported to date.

Publisher Correction: Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein.

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

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe.

Early and long-term effect of the treatment with pyridostigmine in patients with GMPPB-related congenital myasthenic syndrome.

GMPPB mutations cause congenital myasthenic syndromes (CMS) 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.

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients.

Background: About 40% of wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response.

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

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 , and 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.

Epilepsy in LAMA2-related muscular dystrophy: An electro-clinico-radiological characterization.

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 analyzed.

Results: Epilepsy occurred in 36% of patients with LAMA2-related MD.

Cylindrical spirals in two families: Clinical and genetic investigations.

Cylindrical spirals are a rare ultrastructural finding on muscle biopsy, with fewer than 20 reported cases since its first description in 1979. These structures are sometimes observed with tubular aggregates and are thought to comprise longitudinal sarcoplasmic reticulum. While mutations in genes encoding key components of Ca handling (ORAI1 and STIM1) underlie tubular aggregate myopathy, no causative genes have been associated with cylindrical spirals.

Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.

Purpose: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.

Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein.

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 spectrum of phenotypes and will reveal regions of the protein critical for its functions.