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ABSTRACT Objective Approximately half of patients with hereditary myopathies remain without a definitive genetic diagnosis after DNA next‐generation sequencing (NGS). Here, we implemented transcriptome analysis of muscle biopsies as a complementary diagnostic tool for patients with muscle disease but no definitive genetic diagnosis after exome sequencing. Methods In total, 70 undiagnosed cases with suspected genetic muscular dystrophies or congenital myopathies were included in the study. Muscle RNAseq comprised the analysis of aberrant splicing, aberrant expression, and monoallelic expression. In addition, existing NGS data or variant calling from RNAseq were reanalyzed, and genome sequencing was performed in selected cases. Four aberrant splicing open‐source tools were compared and assessed. Results RNAseq established a diagnosis in 10/70 patients (14.3%) by identifying aberrant transcripts produced by single nucleotide variants (7/10) or copy number variants (3/10). Reanalysis of NGS data allowed the diagnosis in 9/70 individuals (12.9%). Based on this cohort, FRASER was the tool that reported more splicing outlier events per sample while showing the highest accuracy (81.26%). Conclusions We demonstrate the utility of RNAseq in identifying causative variants in muscle diseases. Evaluation of four aberrant splicing tools allowed efficient identification of most pathogenic splicing events, obtaining a manageable number of candidate events for manual inspection, demonstrating feasibility for translation into a clinical setting. We also show how the integration of omic technologies reduces the turnaround time to identify causative variants.

Background The clinical status and treatment response of patients with peripheral neuropathies (PNs) rely on subjective and inaccurate clinical scales. Wearable sensors have been evaluated successfully in other neurological conditions to study gait and balance. Our aim was to explore the ability of biomechanical analysis using wearable technology to monitor disease activity in PN. Methods We conducted a single-center, longitudinal study to analyze gait parameters in PN patients and healthy controls using wearable biomechanical sensors. We used a novel technology that registers and integrates data from multiple wearable inertial sensors placed at different locations and plantar insoles. This system allows measuring kinematics, spatio-temporal parameters and plantar pressure. Patients wore the wearable system while performing the 2-min walking test (2MWT). Results We included 37 chronic inflammatory demyelinating polyneuropathy (CIDP) patients, 3 chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein (CANOMAD) patients, 21 monoclonal gammopathy patients of undetermined significance associated with IgM (IgM-MGUS) patients, 7 patients with autoimmune nodopathies, 11 patients with hereditary neuropathies, and 50 healthy controls. First, we analyzed the sensor's ability to detect changes in ataxia and steppage gait severity and found significant differences in spatiotemporal and angular variables of the gait cycle. Second, we found correlations between biomechanical features and clinical scales and with the specific gait phenotype they associated with. Finally, we demonstrated that this technology is able to capture clinically significant changes in gait features over time. Conclusions Our study provides proof-of-concept that wearable technology effectively detects and grades gait impairment, captures clinically relevant changes, and could enhance gait assessment in routine care and clinical research for patients with PN.

Blood tests showed hypokalaemia, evidence of renal failure, leucocytosis and abnormal liver function tests. [...]she was diagnosed with hyperemesis gravidarum causing electrolyte disturbances and thiamine deficiency leading to Wernicke’s encephalopathy. Pregnant women with severe vomiting and electrolyte imbalance may also develop osmotic demyelination syndrome, with similar extrapontine lesions.3 However, neuromyelitis optica spectrum disorder serum antibodies were negative and there had been no rapid shifts in serum osmolality.

Background and objectiveBetween 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing.MethodsWe detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.ResultsWe identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.ConclusionsWhile previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.

Background and purpose The purpose was to perform a nationwide epidemiological study of Guillain–Barré syndrome (GBS) in Spain, analysing background incidences and seasonal variation and trying to identify incidence changes during the coronavirus disease 2019 (COVID‐19) years. Methods This was an observational study collecting all GBS diagnoses from the National Epidemiological Surveillance Network collected by the Ministry of Health. Patients discharged with GBS as the main diagnosis and admitted during 2018–2021 were included. Data on the incidence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections were obtained from the National Epidemiology Centre. Results In total, 3147 cases were included, 832 in 2018, 861 in 2019, 670 in 2020 and 784 in 2021. Nationwide hospital incidence was 1.78 in 2018, 1.71 in 2019, 1.41 in 2020 and 1.66 in 2021, with an increased frequency in males, the elderly population and in the winter season. Eleven per cent of GBS patients needed ventilatory support. GBS and SARS‐CoV‐2 incidences did not correlate with one another (r = −0.29, p = 0.36). GBS incidence decreased during 2020 and during the COVID‐19 lockdown period in comparison to the same months of 2018–2019. Conclusions The incidence of GBS in Spain is similar to that of other countries. Despite prior reports describing a significant increase in COVID‐19‐associated GBS in Spain, a significant drop of GBS incidence during the SARS‐CoV‐2 pandemic was detected, probably due to prevention measures.

ABSTRACT Objective We aim to describe and characterize two unrelated Spanish families suffering from an autosomal dominant autophagic vacuolar myopathy caused by repeat expansions in PLIN4. Methods We evaluated the clinical phenotype and muscle imaging, and performed a genetic workup that included exome sequencing, muscle RNAseq, and long‐read genome sequencing. Muscle pathology was assessed by means of histochemistry, electron microscopy, PLIN4, p62, LC3, and NBR1 immunofluorescence and/or western blotting. Detailed characterization of autophagic vacuoles was performed. Results Patients presented around the age of 30 with mild proximal weakness followed by prominent distal weakness in lower legs, eventually spreading to other muscle groups. Muscle biopsies showed unique pathological features characterized by numerous rimmed vacuoles that displayed sarcolemmal features and were located beneath the sarcolemma and within the cytoplasm. Ultrastructural studies showed autophagic vacuoles, replications, and loops of the basal lamina and tubulofilamentous sarcoplasmic inclusions. p62 and NBR1 co‐localized with PLIN4 at the sarcolemma and vacuoles. LC3 immunoreactivity and other lysosomal markers were increased at the vacuoles. Targeted long‐read sequencing of PLIN4 in affected individuals revealed a single expanded allele of 39 × 99 bp repeats in family 1 and of 37 × 99 bp repeats in family 2. Interpretation We characterize two new families suffering from an autosomal dominant myopathy carrying repeat expansions in PLIN4. Subsarcolemmal p62 expression is a powerful although nonspecific marker of this disease. No correlation between the size of the expansion and clinical severity can be clearly established. PLIN4 expansions should be considered in the diagnosis of autosomal dominant vacuolar myopathies, especially when sarcolemmal features are present.

Castleman disease (CD) is a rare lymphoproliferative disorder. Two main variants have been described: unicentric or multicentric (UCD/MCD). MCD can be idiopathic or related to human herpesvirus 8 (HHV8) infection in the setting of immune deficiency. MCD is more severe than UCD and is usually accompanied by other systemic symptoms. Peripheral neuropathy can be associated with MCD in isolation or as part of a wider spectrum of symptoms, the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). Compared with POEMS-neuropathy, CD-neuropathy is often milder, sensory, and not painful. There are few reports of CD-neuropathy with cranial nerve involvement, only affecting the optic and trigeminal nerves. We present a 50-year-old patient who developed bilateral facial weakness, numbness of hands and feet, sensory ataxia, and progressive walking difficulties over 3 weeks. Nerve conduction studies showed sensory-motor axonal symmetric neuropathy with signs of demyelination in cranial segments. He had history of human immunodeficiency virus infection, well controlled under antiretroviral treatment. Upon admission, he developed fever and pancytopenia, and diffuse lymphadenopathies were detected. An axillary lymph node biopsy was performed showing HHV8-positive small follicles, lymphodepletion, and penetrating vessels with interfollicular polyclonal plasmocytosis, supporting the diagnosis of CD, and adjacent focus of HHV8+ Kaposi sarcoma. He was treated with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) chemoimmunotherapy regimen. The neuropathy progressively resolved, both clinically and electrophysiologically, over a period of 6 months in parallel with the remission of CD. CD-associated neuropathy may present as bifacial weakness and limb paraesthesia, mimicking the variant of Guillain-Barré syndrome. The neurological symptoms may have a subacute progression leading to important disability. The outcome is good with chemoimmunotherapy, with parallel recovery of the neuropathy and the CD.