Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model.

CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been linked to autophagy and lipid metabolism, but much remains to be learned, and there are no therapies acting on the molecular signatures in this disorder. The present study aims to characterize the molecular pathways involved in CLN8 disease and, by pinpointing altered ones, to identify potential therapies. To bridge the gap between cell and mammalian models, we generated a new zebrafish model of CLN8 deficiency, which recapitulates the pathological features of the disease. We observed, for the first time, that CLN8 dysfunction impairs autophagy. Using autophagy modulators, we showed that trehalose and SG2 are able to attenuate the pathological phenotype in mutant larvae, confirming autophagy impairment as a secondary event in disease progression. Overall, our successful modeling of CLN8 defects in zebrafish highlights this novel in vivo model's strong potential as an instrument for exploring the role of CLN8 dysfunction in cellular pathways, with a view to identifying small molecules to treat this rare disease.

Automatic speaking valve in tracheo-esophageal speech: treatment proposal for a widespread usage.

PURPOSE: Aim of this study was to calculate the percentage of the Automatic Speaking Valve (ASV) use in a large cohort of laryngectomized patients with voice prosthesis (VP) and to analyze the main reasons for non-use. Subsequently, a specific rehabilitation training was proposed. METHODS: One hundred-ten laryngectomized patients with VP were enrolled in the first phase of the study (census). Among them, 57 patients were included in the second phase (intervention), in which a training based on moving phonatory exercises was proposed. Structured questionnaires were used before and after training in order to investigate ASV use rate (days/week and hours/day; reasons for impeding the ASV use), average adhesive life-time during ASV use; hands-free speech duration; skin irritation. Patients also expressed their degree of on a VAS scale from 0 to 100. RESULTS: In the census phase the percentage of use of ASV (everyday, without problems) was equal to 17.27% (19/110 patients). The main causes of disuse concerned excessive fatigue and poor durability of the adhesives. The analysis of the results pre vs. post-training showed a statistically significant increase (p < 0.05) in all the investigated parameters. Patients reported a good level of treatment compliance (average frequency of performing exercises equal to 4.2 ± 2.5 days/week for 1.4 ± 1.01 h/day) and high degrees of satisfaction. After treatment, the percentage of use of AVS increased by 43% reaching a rate of 60% (66/110 patients). CONCLUSION: A specific and targeted approach that simulate the phonatory and breathing difficulties of everyday life can increase the ASV usage rate.

The involvement of Purkinje cells in progressive myoclonic epilepsy: Focus on neuronal ceroid lipofuscinosis.

The progressive myoclonic epilepsies (PMEs) are a group of rare neurodegenerative diseases characterized by myoclonus, epileptic seizures, and progressive neurological deterioration with cerebellar involvement. They include storage diseases like Gaucher disease, Lafora disease, and forms of neuronal ceroid lipofuscinosis (NCL). To date, 13 NCLs have been reported (CLN1-CLN8, CLN10-CLN14), associated with mutations in different genes. These forms, which affect both children and adults, are characterized by seizures, cognitive and motor impairments, and in most cases visual loss. In NCLs, as in other PMEs, central nervous system (CNS) neurodegeneration is widespread and involves different subpopulations of neurons. One of the most affected regions is the cerebellar cortex, where motor and non-motor information is processed and transmitted to deep cerebellar nuclei through the axons of Purkinje cells (PCs). PCs, being GABAergic, have an inhibitory effect on their target neurons, and provide the only inhibitory output of the cerebellum. Degeneration of PCs has been linked to motor impairments and epileptic seizures. Seizures occur when some insult upsets the normal balance in the CNS between excitatory and inhibitory impulses, causing hyperexcitability. Here we review the role of PCs in epilepsy onset and progression following their PME-related loss. In particular, we focus on the involvement of PCs in seizure phenotype in NCLs, highlighting findings from case reports and studies of animal models in which epilepsy can be linked to PC loss.

Is There Any Reliable Predictor of Functional Recovery Following Post-thyroidectomy Vocal Fold Paralysis?

BACKGROUND: Predicting definitive outcomes of post-thyroidectomy vocal fold paralysis (VFP) is challenging. We aimed to identify reliable predictors based on intraoperative neuromonitoring (IONM) and flexible fiberoptic laryngostroboscopy (FFL) findings. METHODS: Among 1172 thyroid operations performed from April to December 2021, all patients who exhibited vocal fold paralysis (VFP) at post-operative laryngoscopy were included. IONM data, including type of loss of signal (LOS), were collected. Patients underwent FFL, with arytenoid motility assessment, at 15, 45 and 120 days post-operatively. Patients were divided into two groups: those who recovered vocal fold motility (VFM) by the 120th post-operative day (recovery group) and those who did not (non-recovery group). RESULTS: Fifty-nine VFP cases (5.0% of total patients) met the inclusion criteria. Eight patients were lost at follow-up and were excluded. Overall, 9 patients were included in the non-recovery group (0.8% of total patients) and 42 in the recovery group. Among various predictive factors, only arytenoid fixation (AF) at the 15th post-operative day and Type I LOS were significant predictors for no VFM recovery (p = 0.007, RR = 9.739, CI:1.3-72.3 and p = 0.001, RR = 9.25, CI:2.2-39.3 for AF and Type I injury, respectively). The combination of type of LOS and arytenoid motility at the 15th post-op day yielded satisfactory predictive values for the progression of transient VFP to permanent. CONCLUSIONS: Arytenoid motility at the 15th post-op day and type II LOS are associated with recovery of VFM. Type of LOS and FFL could be included in the follow-up protocols of patients with VFP to reliably predict clinical outcomes.

Zebrafish as an Innovative Tool for Epilepsy Modeling: State of the Art and Potential Future Directions.

This article discusses the potential of Zebrafish (ZF) (Danio Rerio), as a model for epilepsy research. Epilepsy is a neurological disorder affecting both children and adults, and many aspects of this disease are still poorly understood. In vivo and in vitro models derived from rodents are the most widely used for studying both epilepsy pathophysiology and novel drug treatments. However, researchers have recently obtained several valuable insights into these two fields of investigation by studying ZF. Despite the relatively simple brain structure of these animals, researchers can collect large amounts of data in a much shorter period and at lower costs compared to classical rodent models. This is particularly useful when a large number of candidate antiseizure drugs need to be screened, and ethical issues are minimized. In ZF, seizures have been induced through a variety of chemoconvulsants, primarily pentylenetetrazol (PTZ), kainic acid (KA), and pilocarpine. Furthermore, ZF can be easily genetically modified to test specific aspects of monogenic forms of human epilepsy, as well as to discover potential convulsive phenotypes in monogenic mutants. The article reports on the state-of-the-art and potential new fields of application of ZF research, including its potential role in revealing epileptogenic mechanisms, rather than merely assessing iatrogenic acute seizure modulation.

Converging Role for REEP1/SPG31 in Oxidative Stress.

Mutations in the receptor expression-enhancing protein 1 gene (REEP1) are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in REEP1, suggesting a key role of bioenergetics in disease-related manifestations. Nevertheless, the regulation of mitochondrial function in SPG31 remains unclear. To elucidate the pathophysiology underlying REEP1 deficiency, we analyzed in vitro the impact of two different mutations on mitochondrial metabolism. Together with mitochondrial morphology abnormalities, loss-of-REEP1 expression highlighted a reduced ATP production with increased susceptibility to oxidative stress. Furthermore, to translate these findings from in vitro to preclinical models, we knocked down REEP1 in zebrafish. Zebrafish larvae showed a significant defect in motor axon outgrowth leading to motor impairment, mitochondrial dysfunction, and reactive oxygen species accumulation. Protective antioxidant agents such as resveratrol rescued free radical overproduction and ameliorated the SPG31 phenotype both in vitro and in vivo. Together, our findings offer new opportunities to counteract neurodegeneration in SPG31.

Short-Term Effects of Human versus Bovine Sialylated Milk Oligosaccharide Microinjection on Zebrafish Larvae Survival, Locomotor Behavior and Gene Expression.

Milk oligosaccharides are a complex class of carbohydrates that act as bioactive factors in numerous defensive and physiological functions, including brain development. Early nutrition can modulate nervous system development and can lead to epigenetic imprinting. We attempted to increase the sialylated oligosaccharide content of zebrafish yolk reserves, with the aim of evaluating any short-term effects of the treatment on mortality, locomotor behavior, and gene expression. Wild-type embryos were microinjected with saline solution or solutions containing sialylated milk oligosaccharides extracted from human and bovine milk. The results suggest that burst activity and larval survival rates were unaffected by the treatments. Locomotion parameters were found to be similar during the light phase between control and treated larvae; in the dark, however, milk oligosaccharide-treated larvae showed increased test plate exploration. Thigmotaxis results did not reveal significant differences in either the light or the dark conditions. The RNA-seq analysis indicated that both treatments exert an antioxidant effect in developing fish. Moreover, sialylated human milk oligosaccharides seemed to increase the expression of genes related to cell cycle control and chromosomal replication, while bovine-derived oligosaccharides caused an increase in the expression of genes involved in synaptogenesis and neuronal signaling. These data shed some light on this poorly explored research field, showing that both human and bovine oligosaccharides support brain proliferation and maturation.

Oropharyngeal Dysphagia After Hospitalization for COVID-19 Disease: Our Screening Results.

A high percentage of patients suffered symptoms also after recovery from the Coronavirus Disease-2019 (COVID-19) infection. It is not well clear what are the specific long-term sequelae (complications and symptoms). During the acute phase the patients may develop a multi-organ system pathology including aerodigestive tract. As the pathophysiology of COVID-19 emerges, the aim of our study was to describe the prevalence of oropharyngeal dysphagia after COVID-19 disease. From March to July 2020 we enrolled patients recovered from SARS-CoV-2 infection who had been previously hospitalized for the disease. They were screened for dysphagia by mean of the Eating Assessment Tool-10 (EAT-10). The cases with EAT-10 score > 3 were graded for the aspiration risk by applying the Gugging Swallowing Screen (GUSS) and were submitted to the Swal-QoL questionnaire. The cases with a GUSS score > 19 were subjected to FEES. 8/117 (7%) patients had positive screening result. 4/8 (50%) revealed an abnormal health related quality of life in oropharyngeal dysphagia with a mean Swal-QoL score of 69.73. The most affected domain was the "time of meals" (mean score 65) following by the "sleep" (mean score 66) and "eating desire" (mean score 72). 1/8 cases showed increased risk for aspiration and did not showed endoscopic signs of oropharyngeal dysphagia. Our results showed that the prevalence of upper dysphagia after hospitalization for SARS-CoV-2 is not anecdotal and that probably this long-lasting sequela has a psychogenic etiology.

Trehalose Treatment in Zebrafish Model of Lafora Disease.

Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a-/- zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities.

Long-term voice outcomes and quality of life after open partial horizontal laryngectomy type II vs. total laryngectomy: A cross-sectional study.

OBJECTIVES: We aim to analyse long-term voice outcomes and quality of life (QoL) in patients undergoing open partial horizontal laryngectomy type II (OPHL type II) and to compare them to those obtained by patients undergoing total laryngectomy (TL) with voice prosthesis (VP). DESIGN: Cross-sectional cohort study. SETTING: Patients undergoing surgery for advanced laryngeal cancer, assessed during the usual follow-up consultations at the Phoniatric Unit (February 2020-December 2020). PARTICIPANTS: Forty-five patients were enrolled and divided into two groups: OPHL group and TL group. MAIN OUTCOMES MEASURES: Acoustic analysis, maximum phonation time, INFV0  scale, I-SECEL, UW-QoL-V4 and MDADI questionnaires were used to assess the long-term outcomes. RESULTS: Voices of patients undergoing OPHL Type II were worse than those of laryngectomised patients with VP. Nevertheless, scores in voice and dysphagia-related QoL were comparable and scores in the social domain of QoL were higher in OPHL group. CONCLUSIONS: Open partial horizontal laryngectomy Type II allows an acceptable voice recovery and a satisfactory QoL.

Development of a process map for the delivery of virtual clinical pharmacy services at Odette Cancer Centre during the COVID-19 pandemic.

Virtual methods have been innovatively utilized to provide clinical and supportive care to patients with cancer. Oncology pharmacists have been actively involved in this movement, in order to minimize patient contact and decrease the risk of viral transmission for this high-risk group. In response to COVID-19 restrictions, the Odette Cancer Centre pharmacy modified the delivery of clinical pharmacy services (CPS), including medication histories and patient education/counseling, to a remote telephone-based model. Process maps were created to visualize workflow before and after the pandemic. Process metrics were tracked over a 6-week period. From March 25th to May 1st, 2020, 202 best-possible medication histories and baseline assessments were completed; 149 of these (74%) were completed remotely. For medication therapy counsels, 72 of 199 were completed remotely (36%). Despite workflow disruptions caused by the pandemic, these results demonstrate that clinical pharmacy service levels could be maintained by incorporating remote delivery approaches without significant investment in resources. Challenges included acceptance by patients and lack of technology to support system-level processes. Further research to develop, refine, and individualize virtual clinical pharmacy care models will help to consolidate the role of these approaches in the post-COVID-19 era.

Impact of Tracheal Tube on Swallowing in Post-Operative Head and Neck Cancer Patients: Scintigraphic Analysis.

Dysphagia is common in tracheostomized patients who underwent head and neck surgery for cancer treatment. The objective of this study was to evaluate, by means of oropharyngoesophageal scintigraphy (OPES), the impact of an occluded tracheal tube (TT) on swallowing in patients treated for head and neck cancer before hospital discharge, to provide further information to the benefit of out-patient care management. From October 2018 to November 2019, we enrolled 19 tracheostomized patients (6 females and 13 males; mean age 61 years) who underwent primary surgical resection of head and neck tumor and swallowing rehabilitation during hospitalization. All subjects underwent a double-standard OPES, one with occluded tracheal tube and the other without TT, with their tracheal stoma being closed directly by a plaster. For each study, we assessed and compared the following quantitative parameters: oral transit time (OTTsec), pharyngeal transit time (PTTsec), esophageal transit time (ETTsec), oral retention index (ORI%), pharyngeal retention index (PRI%), esophageal retention index (ERI%), and aspiration percentage (AP%). The mean values of OTT, PTT, ORI%, PRI%, and ERI% were abnormal during OPES both with TT and without TT and did not statistically differ between the two tests (p > 0.05). Aspiration was detected in 4 cases out of 19 (21.05%) cases during OPES with TT and in 4/19 (21.05%) cases without TT who showed a mean AP% of 11.4% and 11.5% respectively (p > 0.05). Patients with abnormal AP% (> 0%) during OPES with TT showed aspiration signs without TT. Our study showed that the mere presence of a closed tracheal tube does not impact significantly the oropharyngeal transit of bolus during swallowing. This result suggests the possibility to maintain a small-diameter occluded tracheal tube in place for the postsurgical management of head and neck cancer patients.

Efficient Neuroprotective Rescue of Sacsin-Related Disease Phenotypes in Zebrafish.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a multisystem hereditary ataxia associated with mutations in SACS, which encodes sacsin, a protein of still only partially understood function. Although mouse models of ARSACS mimic largely the disease progression seen in humans, their use in the validation of effective therapies has not yet been proposed. Recently, the teleost Danio rerio has attracted increasing attention as a vertebrate model that allows rapid and economical screening, of candidate molecules, and thus combines the advantages of whole-organism phenotypic assays and in vitro high-throughput screening assays. Through CRISPR/Cas9-based mutagenesis, we generated and characterized a zebrafish sacs-null mutant line that replicates the main features of ARSACS. The sacs-null fish showed motor impairment, hindbrain atrophy, mitochondrial dysfunction, and reactive oxygen species accumulation. As proof of principle for using these mutant fish in high-throughput screening studies, we showed that both acetyl-DL-leucine and tauroursodeoxycholic acid improved locomotor and biochemical phenotypes in sacs-/- larvae treated with these neuroprotective agents, by mediating significant rescue of the molecular functions altered by sacsin loss. Taken together, the evidence here reported shows the zebrafish to be a valuable model organism for the identification of novel molecular mechanisms and for efficient and rapid in vivo optimization and screening of potential therapeutic compounds. These findings may pave the way for new interventions targeting the earliest phases of Purkinje cell degeneration in ARSACS.

A homozygous MRPL24 mutation causes a complex movement disorder and affects the mitoribosome assembly.

Mitochondrial ribosomal protein large 24 (MRPL24) is 1 of the 82 protein components of mitochondrial ribosomes, playing an essential role in the mitochondrial translation process. We report here on a baby girl with cerebellar atrophy, choreoathetosis of limbs and face, intellectual disability and a combined defect of complexes I and IV in muscle biopsy, caused by a homozygous missense mutation identified in MRPL24. The variant predicts a Leu91Pro substitution at an evolutionarily conserved site. Using human mutant cells and the zebrafish model, we demonstrated the pathological role of the identified variant. In fact, in fibroblasts we observed a significant reduction of MRPL24 protein and of mitochondrial respiratory chain complex I and IV subunits, as well a markedly reduced synthesis of the mtDNA-encoded peptides. In zebrafish we demonstrated that the orthologue gene is expressed in metabolically active tissues, and that gene knockdown induced locomotion impairment, structural defects and low ATP production. The motor phenotype was complemented by human WT but not mutant cRNA. Moreover, sucrose density gradient fractionation showed perturbed assembly of large subunit mitoribosomal proteins, suggesting that the mutation leads to a conformational change in MRPL24, which is expected to cause an aberrant interaction of the protein with other components of the 39S mitoribosomal subunit.

Distal motor neuropathy associated with novel EMILIN1 mutation.

Elastin microfibril interface-located proteins (EMILINs) are extracellular matrix glycoproteins implicated in elastogenesis and cell proliferation. Recently, a missense mutation in the EMILIN1 gene has been associated with autosomal dominant connective tissue disorder and motor-sensory neuropathy in a single family. We identified by whole exome sequencing a novel heterozygous EMILIN1 mutation c.748C>T [p.R250C] located in the coiled coil forming region of the protein, in four affected members of an autosomal dominant family presenting a distal motor neuropathy phenotype. In affected patient a sensory nerve biopsy showed slight and unspecific changes in the number and morphology of myelinated fibers. Immunofluorescence study of a motor nerve within a muscle biopsy documented the presence of EMILIN-1 in nerve structures. Skin section and skin derived fibroblasts displayed a reduced extracellular deposition of EMILIN-1 protein with a disorganized network of poorly ramified fibers in comparison with controls. Downregulation of emilin1a in zebrafish displayed developmental delay, locomotion defects, and abnormal axonal arborization from spinal cord motor neurons. The phenotype was complemented by wild-type zebrafish emilin1a, and partially the human wild-type EMILIN1 cRNA, but not by the cRNA harboring the novel c.748C>T [p.R250C]. These data suggest a role of EMILIN-1 in the pathogenesis of diseases affecting the peripheral nervous system.

The prevalence of signs and symptoms of laryngopharyngeal reflux and laryngeal precancerous lesions in urban taxi drivers.

PURPOSE: Taxi drivers represent a large group of workers employed in the service sector of transport. Many studies found an increased risk of a range of health disorders in relation to their irregular work shifts, inappropriate diet, drinking and smoking habits and their high exposure to gasoline- and diesel-engine exhaust fumes. The aim of the present study was to assess the sample of a larynx from taxi drivers, considering symptoms and endoscopic signs of laryngopharyngeal reflux (LPR) and precancerous lesions. METHODS: Taxi drivers enrolled (n = 74) were questioned about their nicotine dependence using the Fagerstrom scale. The Reflux Symptom Index (RSI) was administered to screen LPR symptoms. Each subject underwent videolaryngoscopy with Reflux Finding Score (RFS) calculation. Data were compared with those obtained from the control group (n = 102). RESULTS: Taxi drivers' group did not show a significantly greater dependence on cigarette smoking (p < 0.05) based on the Fagerstrom scale. RSI resulted greater or equal to 13 (cut-off for reflux disease) for 28/74 (37.3%) taxi drivers and 14/102 (13.7%) controls, with a statistically significant difference between the two groups (p = 0.0015; OR = 3.14). RFS was greater or equal to 7 (95% certainty of having LPR) in 40/74 (53%) cases and 30/102 (29.4%) controls (p = 0.0010, OR = 2.82). Three taxi drivers (4%) had leucoplastic lesions of the vocal cords worthy of biopsy, which turned out to be infiltrating squamous cell carcinoma on histological examination. CONCLUSIONS: Taxi drivers resulted at risk of LPR and presented high-prevalence laryngeal precancerous lesions and carcinoma.

Fishing in the Cell Powerhouse: Zebrafish as A Tool for Exploration of Mitochondrial Defects Affecting the Nervous System.

The zebrafish (Danio rerio) is a small vertebrate ideally suited to the modeling of human diseases. Large numbers of genetic alterations have now been modeled and could be used to study organ development by means of a genetic approach. To date, limited attention has been paid to the possible use of the zebrafish toolbox in studying human mitochondrial disorders affecting the nervous system. Here, we review the pertinent scientific literature discussing the use of zebrafish in modeling gene mutations involved in mitochondria-related neurological human diseases. A critical analysis of the literature suggests that the zebrafish not only lends itself to exploration of the pathological consequences of mitochondrial energy output on the nervous system but could also serve as an attractive platform for future drugs in an as yet untreatable category of human disorders.

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype.

Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism-epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin-proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management.

Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan.

Defective dolichol-phosphate mannose synthase (DPMS) complex is a rare cause of congenital muscular dystrophy associated with hypoglycosylation of alpha-dystroglycan (α-DG) in skeletal muscle. We used the zebrafish (Danio rerio) to model muscle abnormalities due to defects in the subunits of DPMS. The three zebrafish ortholog subunits (encoded by the dpm1, dpm2 and dpm3 genes, respectively) showed high similarity to the human proteins, and their expression displayed localization in the midbrain/hindbrain area and somites. Antisense morpholino oligonucleotides targeting each subunit were used to transiently deplete the dpm genes. The resulting morphant embryos showed early death, muscle disorganization, low DPMS complex activity, and increased levels of apoptotic nuclei, together with hypoglycosylated α-DG in muscle fibers, thus recapitulating most of the characteristics seen in patients with mutations in DPMS. Our results in zebrafish suggest that DPMS plays a role in stabilizing muscle structures and in apoptotic cell death.