Early-onset dysphagia and severe neurodevelopmental disorder as early signs in a patient with two novel variants in NARS1: a case report and brief review of the literature.

Aminoacyl-tRNA synthetases (ARSs) aminoacylate tRNA molecules with their cognate amino acid, enabling information transmission and providing substrates for protein biosynthesis. They also take part in nontranslational functions, mediated by the presence of other proteins domains. Mutations in ARS genes have been described as responsive to numerous factors, including neurological, autoimmune, and oncological. Variants of the ARS genes, both in heterozygosity and homozygosity, have been reported to be responsible for different pathological pictures in humankind. We present the case of a patient referred in infancy for failure to thrive and acquired microcephaly (head circumference: -5 SD). During follow-up we highlighted: dysphagia (which became increasingly severe until it became incompatible with oral feeding, with gastrostomy implantation, resulting in resolution of feeding difficulties), strabismus, hypotonia. NCV (Nerve Conduction Velocity) showed four limbs neuropathy, neurophysiological examination performed at 2 years of age mainly sensory and demyelinating. Exome sequencing (ES) was performed, detecting two novel compound heterozygous variants in the NARS1 gene (OMIM *108410): NM_004539:c.[662 A > G]; [1155dup], p.[(Asn221Ser)]; [(Arg386Thrfs*19)], inherited from mother and father respectively. In this article, we would like to focus on the presence of progressive dysphagia and severe neurodevelopmental disorder, associated with two novel variants in the NARS1 gene.

The Effect of Genetic Taste Status on Swallowing: A Literature Review.

PURPOSE: Swallowing and taste share innervation pathways and are crucial to nutritive intake. Individuals vary in their perception of taste due to factors such as genetics; however, it is unclear to what extent genetic taste status influences swallowing physiology and function. The purpose of this review article is to provide background on genetic taste status, review the evidence on the association between genetic taste status and swallowing, and discuss research and clinical implications. METHOD: A comprehensive literature review was conducted using search terms related to swallowing and genetic taste status. Studies were included if they investigated the main effect of genetic taste status on swallowing or the interaction of genetic taste status with other variables. Studies were grouped by participant population (healthy participants or persons with a swallowing disorder), swallowing-related outcome measure, and method of genetic taste status measurement. RESULTS: The results were mixed, with five of 10 reviewed studies reporting a statistically significant main or interaction effect on swallowing. Most studies included healthy participants, with only one study investigating participants with dysphagia. Additionally, swallowing-related outcome measures and methods of determining genetic taste status varied greatly between studies conducted on separate cohorts. CONCLUSIONS: Few studies have incorporated genetic taste status as a variable in swallowing research, and results are mixed. Future research on sensation and swallowing should consider the potential effect of genetic taste status and follow standardized procedures for its determination. Despite the limited evidence, clinicians may consider how individual differences in perception shape swallowing outcomes.

A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma.

BACKGROUND: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. RESULTS: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10- 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). CONCLUSIONS: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

Assessment of gene expressions from squamous cell carcinoma of the head and neck to predict radiochemotherapy-related xerostomia and dysphagia.

PURPOSE: We tested the hypothesis that gene expressions from biopsies of locally advanced head and neck squamous cell carcinoma (HNSCC) patients can supplement dose-volume parameters to predict dysphagia and xerostomia following primary radiochemotherapy (RCTx). MATERIAL AND METHODS: A panel of 178 genes previously related to radiochemosensitivity of HNSCC was considered for nanoString analysis based on tumour biopsies of 90 patients with locally advanced HNSCC treated by primary RCTx. Dose-volume parameters were extracted from the parotid, submandibular glands, oral cavity, larynx, buccal mucosa, and lips. Normal tissue complication probability (NTCP) models were developed for acute, late, and for the improvement of xerostomia grade ≥2 and dysphagia grade ≥3 using a cross-validation-based least absolute shrinkage and selection operator (LASSO) approach combined with stepwise logistic regression for feature selection. The final signatures were included in a logistic regression model with optimism correction. Performance was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: NTCP models for acute and late xerostomia and the improvement of dysphagia resulted in optimism-corrected AUC values of 0.84, 0.76, and 0.70, respectively. The minimum dose to the contralateral parotid was selected for both acute and late xerostomia and the minimum dose to the larynx was selected for dysphagia improvement. For the xerostomia endpoints, the following gene expressions were selected: RPA2 (cellular response to DNA damage), TCF3 (salivary gland cells development), GBE1 (glycogen storage and regulation), and MAPK3 (regulation of cellular processes). No gene expression features were selected for the prediction of dysphagia. CONCLUSION: This hypothesis-generating study showed the potential of improving NTCP models using gene expression data for HNSCC patients. The presented models require independent validation before potential application in clinical practice.

Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS.

Current treatments for dysphagia in ALS do not target the underlying tongue weakness and denervation atrophy that is prevalent in spinal and bulbar ALS cases. To address this clinical gap, we studied the low copy number SOD1-G93A (LCN-SOD1) mouse model of ALS to quantify the impact of limb phenotype on tongue denervation atrophy, dysphagia penetrance, and survival time in preparation for future treatment-based studies. Two male LCN-SOD1 breeders and 125 offspring were followed for limb phenotype inheritance, of which 52 (30 LCN-SOD1 and 22 wild-type/WT, both sexes) underwent characterization of dysphagia penetrance (via videofluoroscopic swallow study; VFSS) and survival time at disease end-stage (15-20% body weight loss). From these, 16 mice (8/genotype) underwent postmortem histological analysis of the genioglossus for evidence of denervation atrophy. Results revealed that both breeders displayed a mixed (hindlimb and forelimb) ALS phenotype and sired equal proportions of hindlimb vs. mixed phenotype offspring. Dysphagia penetrance was complete for mixed (100%) versus incomplete for hindlimb (64%) phenotype mice; yet survival times were similar. Regardless of limb phenotype, LCN-SOD1 mice had significantly smaller genioglossus myofibers and more centralized myonuclei compared to WT mice (p < 0.05). These biomarkers of denervation atrophy were significantly correlated with VFSS metrics (lick and swallow rates, p < 0.05) but not survival time. In conclusion, both LCN-SOD1 phenotypes had significant tongue denervation atrophy, even hindlimb phenotype mice without dysphagia. This finding recapitulates human ALS, providing robust rationale for using this preclinical model to explore targeted treatments for tongue denervation atrophy and ensuing dysphagia.

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)n triplet in the PABPN1 gene. The size of expansion has been correlated to the disease onset and severity. We report the clinical features of a large cohort of OPMD patients harboring the (GCN)15 allele from the Canary Islands. METHODS: A retrospective observational study was performed analyzing the clinical, demographic, and genetic data of 123 OPMD patients. Clinical data from this cohort were compared with clinical data collected in a large European study including 139 OPMD patients. RESULTS: A total of 113 patients (94.2%) carried the (GCN)15 expanded PABN1 allele. Age of symptoms' onset was 45.1 years. The most frequent symptom at onset was ptosis (85.2%) followed by dysphagia (12%). The severity of the disease was milder in the Canary cohort compared to European patients as limb weakness (35.1% vs. 50.4%), the proportion of patients that require assistance for walking or use a wheelchair (9.3% vs. 27.4%), and needed of surgery because of severe dysphagia (4.6% vs. 22.8%) was higher in the European cohort. CONCLUSIONS: Nearly 95% of patients with OPMD from the Canary Islands harbored the (GCN)15 expanded allele supporting a potential founder effect. Disease progression seemed to be milder in the (GCN)15 OPMD Canary cohort than in other cohorts with shorter expansions suggesting that other factors, apart from the expansion size, could be involved in the progression of the disease.

The molecular mechanism of the transcriptional activator SWI regulating gene ARID1B affecting swallowing dysfunction after stroke in rats.

Background: After a stroke, more than 50% of patients are suffering from dysphagia. Because the swallowing dysfunction is closely related to some neural pathways, the probing of the neuro-molecular mechanism of dysphagia is very important for future diagnosis and treatment. Methods: Our study is a typical causal study with the purpose of exploring molecular mechanisms. In this study, a rat model of dysphagia after stroke was constructed, and ARID1B overexpression plasmid was injected into the rat body through tail vein injection. The number of swallows and the swallowing response time induced by distilled water in each group of rats on the 7 th and 14 th day after modeling were detected. After 14 days of successful model establishment, the rat brain tissues were collected, part of the brainstem nucleus tractus solitarius and nucleus suspicious tissues were analyzed with a Ca2+ fluorescent indicator to analyze the intracellular concentration of Ca2+. For a part of the brainstem nucleus tractus solitarius and suspected nucleus tissues, immunohistochemistry was used to analyze the expression characteristics of genes ARID1B and TACR1 related proteins. The cerebrospinal fluid of brain tissue was collected, and the expression of gene TAC1 related protein in cerebrospinal fluid was analyzed by ELISA. For a part of the brainstem nucleus tractus solitarius and suspicious nucleus tissues, western blot was used to analyze the expression of gene SMARCA1 related protein, protein UNC80 and NALCN. Results: The detection of swallowing characteristics and the detection of intracellular Ca2+ concentration indicate the serious impact of stroke on swallowing function. The protein expression showed a consistent trend, which also showed that the overexpression of gene ARID1B can improve swallowing function to a certain extent. Conclusion: Due to our experiments, the molecular mechanism related to dysphagia was explored to a certain extent. At the same time, we found that the overexpression of the gene ARID1B can improve the swallowing function.

An examination into the effect of genetic taste status and intensity of carbonation on swallowing and palatability in healthy young adults.

BACKGROUND: Dysphagia is a highly prevalent condition and affects a wide range of cohorts. A common compensatory strategy to manage dysphagia is diet modification. However, this technique is often associated with poor patient quality of life and adverse long-term effects. Carbonated liquids have shown promise as an alternative compensatory strategy for the management of dysphagia. AIMS: To examine the effect of genetic taste status and intensity of carbonation on swallowing and palatability in a healthy young adult population. To examine the palatability of carbonated liquids over time. METHODS & PROCEDURES: A total of 35 healthy young adults were recruited for this prospective, quantitative cohort study. They each drank 150 ml of still water (SW), lightly carbonated water (LCW) and highly carbonated water (HCW). Swallow function, palatability and genetic taste status were assessed using the timed water swallow test, the hedonic general labelled magnitude scale and participant ratings of the bitterness of propylthiouracil strips, respectively. Participants were divided into groups of supertasters, moderate tasters and non-tasters. OUTCOMES & RESULTS: A significant difference was found between SW and HCW on three tests of swallow function. Average time per swallow increased (p = 0.03), average swallow velocity decreased (p = 0.001) and average volume per swallow decreased (p = 0.017) on HCW compared with SW. HCW had a greater impact on swallow function than LCW. A significant mean difference in palatability ratings was found across intensity levels of carbonated fluids (p = 0.002), specifically between SW and HCW (p = 0.001). HCW was less palatable than SW. The palatability of carbonated liquids, investigated within a subgroup of five participants, did not decrease after a 24-h period during which participants only drank carbonated liquids (p = 0.102). A significant difference was found between supertasters' (n = 9) (mean = 13.33) and non-tasters' (n = 20) (mean = -24.5) palatability ratings of HCW (p = 0.03). Despite differences in swallow function between SW and HCW, no differences were detected between supertasters' and non-tasters' swallow function on SW, LCW or HCW. CONCLUSIONS & IMPLICATIONS: Carbonated liquids have the ability to alter swallow function in a healthy young adult population; however, liquids must be highly carbonated in order to have an effect. Additionally, highly carbonated liquids are less palatable than SW, but the palatability of carbonated liquids does not decrease over time. Furthermore, supertasters find HCW more palatable than non-tasters. These findings suggest that carbonated liquids alter swallowing in a healthy population. Further research in a clinical population is needed to better understand the potential role of sensory stimulation as a dysphagia intervention. WHAT THIS PAPER ADDS: What is already known on the subject Several studies have found that carbonated liquids have the ability to alter swallow function in both healthy and clinical populations. However, there is a lack of evidence around the optimum intensity of CO2 in carbonated liquids and the palatability of carbonated liquids as well as the palatability of carbonated fluids over time. What this paper adds to existing knowledge The findings from this study suggest that carbonated liquids can alter swallow function in a healthy young adult population, but liquids must be highly carbonated in order to have an effect. HCW is less palatable than SW, but the palatability of carbonated liquids does not decrease over time. Additionally, supertasters find HCW more palatable than non-supertasters (non-tasters). What are the potential or actual clinical implications of this work? The findings from this study suggest that carbonated liquids may be suitable for use as a sensory stimulation technique for people with dysphagia, as their palatability does not decrease over time; however, further research in a clinical population is needed in order to determine this. Additionally, intensity of stimulus is an important factor to consider during dysphagia evaluation to identify what intensity is required to optimize swallowing.

Homozygous frameshift mutation of SPG11 as a cause of progressive flaccid paralysis, ataxia and dysphagia.

Hereditary spastic paraplegias (HSP) are phenotypically and genotypically diverse. We describe a unique case of autosomal recessive HSP (ARHSP) diagnosed at age 44 in a patient previously described as having "spinal muscular ataxia" [sic]. Predominant lower motor neuron findings and lack of clinical spasticity reduced suspicion for HSP in early life. The identified SPG11 mutation was novel and the presentation was atypical for HSP in general and SPG11 disease specifically.

Novel de novo ARCN1 intronic variant causes rhizomelic short stature with microretrognathia and developmental delay.

The archain 1 (ARCN1) gene encodes the coatomer subunit delta protein and is a component of the COPI coatomer complex, which is involved in retrograde vesical trafficking from the Golgi complex to the endoplasmic reticulum. Variants in ARCN1 have recently been associated with rhizomelic short stature with microcephaly, microretrognathia, and developmental delay. Here we report a 3.5-yr-old boy with microcephaly, global developmental delay, and multiple congenital abnormalities and the ARCN1-related syndrome caused by a novel de novo intronic variant. Whole-exome sequencing of the proband and his parents was utilized to determine the genetic origin of the patient's disorder and identified a de novo variant, NM_001655.5:c.654-15A > G, in the ARCN1 gene. Follow-up functional characterization of mRNA from the patient demonstrated that this variant creates a splicing defect of the ARCN1 mRNA. ARCN1-related syndrome represents an emerging disorder of developmental delay, and this report represents the sixth described patient. Despite the few instances reported in literature, the phenotype is consistent between our patient and previously reported individuals.

Polyhydramnios is associated with postnatal dysphagia determining short-term prognosis of the newborn with 22q11.2 deletion syndrome - A case series analysis.

OBJECTIVE: We experienced a case of 22q11.2 deletion syndrome (22qDS), with severe polyhydramnios, and dysphagia, which prompted us to review prognosis in neonates with 22qDS, with a focus on dysphagia. CASE REPORT: A patient was referred to our hospital at 35 gestational weeks because of polyhydramnios. After amniotic fluid reduction, labor was induced at 38 weeks. The neonate had serious dysphagia, and 22qDS was diagnosed postnatally by fluorescent in situ hybridization analysis. This prompted a retrospective analysis of 9 cases with 22qDS experienced in our facility. Three out of these nine cases showed polyhydramnios, and had severe dysphagia postnatally. In total, 4 cases had dysphagia, while mortality was observed in 2 of these 4 cases. Additionally, 5 cases without dysphagia had normal development and no major complications. CONCLUSION: Polyhydramnios associated with postnatal dysphagia might be a risk factor related to short-term prognostic outcomes in newborns with 22qDS.

Age-Associated Salivary MicroRNA Biomarkers for Oculopharyngeal Muscular Dystrophy.

Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR < 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association (p < 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age (p < 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMD.

Novel compound heterozygous mutation in NPC1 gene cause Niemann-Pick disease type C with juvenile onset.

Niemann-Pick disease type C (NPC) is a progressive lysosomal storage disorder caused by mutations in the NPC1 (in 95% of cases) or NPC2 (in ~5% of cases) genes, inherited in an autosomal recessive manner. We report the case of a 38-year-old woman with learning disorder from her first year of schooling, and could notice slow progressed cognitive impairment, social withdrawal, apathy, handwriting alterations, deterioration of language skills and dysphagia. Brain magnetic resonance imaging showed severe cerebellar atrophy, hypoplasia of the corpus callosum, asymmetric lateral ventricular enlargement, and severe enlargement of frontal and parietal subarachnoid spaces. Next generation sequencing for NPC genes (NPC1 and NPC2) detected compound heterozygous mutations in NPC1 gene, including c.1553G[A (p.Arg518Gln), paternally inherited, and c.1270C[T (p.Pro424Ser) maternally inherited. The first mutation has been already described in literature and correlated to NPC, while the second mutation is still unknown. Moreover, filipin test and quantification of plasma oxysterols confirmed NPC diagnosis. We can suggest the missense mutation c.1270C[T (p.Pro424Ser) as a new causative mutation of NPC.

Familial dysphagia: eosinophilic esophagitis.

We present a family with several cases of eosinophilic esophagitis. Some cases of eosinophilic esophagitis in the same family have been previously described. Patients with eosinophilic esophagitis present frequently atopy, and atopy has a strong family association due to complex interactions between genetic and environment. However, eosinophilic esophagitis has a stronger genetic component than other atopic diseases. Eosinophilic esophagitis has been linked to variations in genes like eotaxin-3, TSLP and its receptor and CAPN14, although the inheritance pattern has not yet well defined.

Disfagia de etiología familiar: esofagitis eosinofílica / No disponible

No disponible

Optimizing the Translational Value of Mouse Models of ALS for Dysphagia Therapeutic Discovery.

The goal of this study was to compare dysphagia phenotypes in low and high copy number (LCN and HCN) transgenic superoxide dismutase 1 (SOD1) mouse models of ALS to accelerate the discovery of novel and effective treatments for dysphagia and early amyotrophic lateral sclerosis (ALS) diagnosis. Clinicopathological features of dysphagia were characterized in individual transgenic mice and age-matched controls utilizing videofluoroscopy in conjunction with postmortem assays of the tongue and hypoglossal nucleus. Quantitative PCR accurately differentiated HCN-SOD1 and LCN-SOD1 mice and nontransgenic controls. All HCN-SOD1 mice developed stereotypical paralysis in both hindlimbs. In contrast, LCN-SOD1 mice displayed wide variability in fore- and hindlimb involvement. Lick rate, swallow rate, inter-swallow interval, and pharyngeal transit time were significantly altered in both HCN-SOD1 and LCN-SOD1 mice compared to controls. Tongue weight, tongue dorsum surface area, total tongue length, and caudal tongue length were significantly reduced only in the LCN-SOD1 mice compared to age-matched controls. LCN-SOD1 mice with lower body weights had smaller/lighter weight tongues, and those with forelimb paralysis and slower lick rates died at a younger age. LCN-SOD1 mice had a 32% loss of hypoglossal neurons, which differed significantly when compared to age-matched control mice. These novel findings for LCN-SOD1 mice are congruent with reported dysphagia and associated tongue atrophy and hypoglossal nucleus pathology in human ALS patients, thus highlighting the translational potential of this mouse model in ALS research.

Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration.

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

Mutations in both SAMD9 and SLC19A2 genes caused complex phenotypes characterized by recurrent infection, dysphagia and profound deafness - a case report for dual diagnosis.

BACKGROUND: Phenotypic difference is general in Mendelian disease. Due to the extremely low incidence for a single disease, phenotype spectrum needs to be expanded. Meanwhile, earlier knowledge says patients who suffered from two kinds of different Mendelian disease are very rare. CASE PRESENTATION: We describe a case of neonatal male with genital anomalies, growth delay, skin hyperpigmentation, chronic lung disease with recurrent infection, anemia, and severe deafness. Without any clear etiology after routine workflow, whole exome sequencing was carried on. A pathogenic de novo SAMD9 mutation and compound heterozygous likely-pathogenic variants in SLC19A2 were identified. Some symptoms were improved after the patient was treated with vitamin B1. Unfortunately, the boy died from sepsis and multiple organ failure before 1 year old. CONCLUSION: Combining the phenotype and clinical progress of treatment, we report that it is the first case of a patient with both MIRAGE syndrome and TRMA syndrome.

VCP myopathy: A family with unusual clinical manifestations.

INTRODUCTION: Valosin-containing protein (VCP) variants that affect muscle, bone, and the nervous system are termed multisystem proteinopathy. VCP myopathy is manifested as limb-girdle weakness, distal weakness and scapuloperoneal weakness. METHODS: We reviewed clinical, genetic, and muscle biopsy data from 6 members of a family with VCP myopathy. RESULTS: Clinical features of family members were complex and included dementia, myopathy, and hearing impairment. Ophthalmoplegia, ptosis, and dysphagia were present in 3 siblings. Rimmed vacuoles were observed in muscle biopsies, consistent with the pathological changes of VCP myopathy. A heterozygous VCP c.463C>A (p.R155S) that segregated in an autosomal-dominant pattern was identified by genetic analysis. CONCLUSIONS: VCP myopathy can cause unusual manifestations that include ophthalmoplegia, ptosis, and dysphagia. This study increased our understanding of the clinical manifestations of VCP myopathy. Muscle Nerve 59:365-369, 2019.