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SNAREs play an important role in the process of membrane trafficking. In the present research, we investigated subcellular localization of an uncharacterized Arabidopsis thaliana protein reported to interact with a trans-Golgi network-localized Qa-SNARE, SYNTAXIN OF PLANTS 43. Based on the similarity of its amino acid sequence to metazoan fucosyltransferases, we have named this novel protein AtGTLP (Arabidopsis thaliana GlycosylTransferase-Like Protein) and predicted that it should be a member of yet uncharacterized family of Arabidopsis fucosyltransferases, as it shows no significant sequence similarity to fucosyltransferases previously identified in Arabidopsis. AtGTLP is a membrane-anchored protein, which exhibits a type II-like topology, with a single transmembrane helix and a globular domain in the C-terminal part of its amino acid sequence. Colocalization data we collected suggest that AtGTLP should localize mainly to Golgi apparatus, especially to certain zones of trans-Golgi. As single atgtlp-/- mutants showed no obvious difference in phenotype (primary root length and fresh mass), AtGTLP and proteins related to AtGTLP with high similarity in amino acid sequences may have redundant functions.
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BACKGROUND: Childhood neurodegenerative diseases often pose a challenge to clinicians to diagnose because of the degree of genetic heterogeneity and variable presentations. Here, we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia in which postmortem pathological analysis led to the diagnosis of interferon regulatory factor 2 binding protein like (IRF2BPL)-related disorder. METHODS: Detailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral-pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions. Follow up testing for the CAG repeat expansion at ATN1 was non-diagnostic. RESULTS: Subsequent exome sequencing reanalysis of the research exome identified a pathogenic de novo IRF2BPL variant. The IRF2BPL c.562C>T, p.(Arg188Ter) variant, distal to the polyQ repeat tract, results in variable mRNA levels depending on the cell type examined with decreased mRNA in the brain, as well as destabilization of the protein product and corresponding downstream molecular abnormalities in patient derived cells. CONCLUSION: We provide the first detailed pathological description for IRF2BPL-related disorder, termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures; Mendelian Inheritance in Man, 618088) and evidence for the inclusion of this condition in the differential diagnosis of spastic-ataxic neurodegenerative conditions, reminiscent of DRPLA. Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats. © 2024 International Parkinson and Movement Disorder Society.
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Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.
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Taquicardia Ventricular , Ratones , Animales , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Arritmias Cardíacas/genética , Flecainida , Mutación Missense , Muerte Súbita Cardíaca , MutaciónRESUMEN
BACKGROUND: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT. METHODS: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateâ , moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated. RESULTS: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity. CONCLUSION: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan.
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COVID-19 , Pulmón , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Cohortes , COVID-19/complicaciones , COVID-19/diagnóstico por imagen , COVID-19/epidemiología , Disnea/etiología , Pueblos del Este de Asia , Japón/epidemiología , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Alta del Paciente , Estudios Prospectivos , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Sociedades Médicas , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
We report a case of chronic infection with Pasteurella multocida in the lower respiratory tract in a man with a cat. A 77-year-old man presented with recurrent hemoptysis accompanied by bronchiectasis and an opacity in the left lung on chest computed tomography. Although the patient was seropositive for Mycobacterium avium complex, repeated sputum cultures were negative for any specific pathogen. Three years later, he was referred to our hospital for hemoptysis with enhanced opacity in the lower lobe of the left lung. Culture of bronchial lavage fluid obtained via bronchoscopy was positive for P. multocida. The patient was treated with amoxicillin-clavulanic acid for 14 days and was instructed to avoid close contact with his cat. His symptoms and chest imaging findings improved and have not recurred during more than 1 1/2 years of follow up. P. multocida can cause chronic lower respiratory infections.
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Bronquitis , Pasteurella multocida , Infecciones del Sistema Respiratorio , Masculino , Humanos , Anciano , Hemoptisis/etiología , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Pulmón , Bronquitis/diagnóstico , Bronquitis/complicacionesRESUMEN
A 75-year-old male visited our hospital with bilateral hilar lymph node swelling detected on chest radiography during an annual medical checkup. Chest computed tomography revealed swelling of multiple hilar mediastinal lymph nodes. Histopathological and immunohistochemical examinations of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens from the hilar lymph nodes revealed amyloid deposition. Bilateral hilar and mediastinal lymphadenopathies can be the first manifestations of amyloidosis diagnosed using EBUS-TBNA.
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Amiloidosis , Neoplasias Pulmonares , Linfadenopatía , Masculino , Humanos , Anciano , Neoplasias Pulmonares/diagnóstico , Linfadenopatía/etiología , Linfadenopatía/patología , Mediastino/patología , Ganglios Linfáticos/patología , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Broncoscopía/métodosRESUMEN
AIM: To evaluate the use of donor-derived cell-free DNA (dd-cfDNA) in diagnosing graft injuries in Japanese liver transplantation (LTx), including family-related living donors. METHODS: A total of 321 samples from 10 newly operated LTx recipients were collected to monitor the early dynamics of dd-cfDNA levels after LTx. Fifty-five samples from 55 recipients were collected during protocol biopsies (PB), whereas 36 samples from 27 recipients were collected during event biopsies, consisting of 11 biopsy-proven acute rejection (AR), 20 acute dysfunctions without rejection (ADWR), and 5 chronic rejections. The levels of dd-cfDNA were quantified using a next-generation sequencer based on single nucleotide polymorphisms. RESULTS: The dd-cfDNA levels were elevated significantly after LTx, followed by a rapid decline to the baseline in patients without graft injury within 30 days post-LTx. The dd-cfDNA levels were significantly higher in the 11 samples obtained during AR than those obtained during PB (p < 0.0001), which decreased promptly after treatment. The receiver operator characteristic curve analysis of diagnostic ability yielded areas under the curve of 0.975 and 0.897 for AR (rejection activity index [RAI] ≥3) versus PB and versus non-AR (ADWR + PB). The dd-cfDNA levels during AR were elevated earlier and correlated more strongly with the RAI (r = 0.740) than aspartate aminotransferase/alanine aminotransferase. The dd-cfDNA levels were neither associated with graft fibrosis based on histology nor the status of donor-specific antibodies in PB samples. CONCLUSIONS: Donor-derived cell-free DNA serves as a sensitive biomarker for detecting graft injuries in LTx. Further large-scale cohort studies are warranted to optimize its use in differentiating various post-LTx etiologies.
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Alveolar barrier dysfunction is one of the major pathophysiological changes in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In ALI/ARDS, tumor necrosis factor-alpha (TNFα) disrupts the barriers of alveolar epithelium and endothelium. Glucocorticoids (GCs) exert anti-inflammatory effects and ameliorate pulmonary edema in ALI/ARDS. However, the involvement of GCs in the restoration of alveolar epithelial barrier dysfunction has not been extensively studied. Here, we elucidated that dexamethasone (Dex) restored TNFα-induced alveolar epithelial barrier dysfunction in vitro using primary rat alveolar epithelial cells isolated from Sprague-Dawley rats. Moreover, Dex promoted the alveolar epithelial cell barrier integrity by initiating GC receptor-mediated signaling via the downregulation of myosin light chain kinase (MLCK) expression and the dephosphorylation of myosin light chain (MLC) 2. Further investigation revealed that Dex enhanced the expression of zonula occludens-1 (ZO-1), a tight junction-related protein, at intercellular junction sites. These findings suggest that GCs strengthen the integrity of the alveolar epithelial barrier in ALI/ARDS via the GR-MLCK-pMLC2 axis.
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Células Epiteliales Alveolares , Síndrome de Dificultad Respiratoria , Ratas , Animales , Células Epiteliales Alveolares/metabolismo , Factor de Necrosis Tumoral alfa , Ratas Sprague-Dawley , Proteínas de Uniones Estrechas/metabolismo , Dexametasona/farmacología , Células Epiteliales/metabolismoRESUMEN
BACKGROUND: Magnetic resonance (MR)-plaque imaging reflects the characteristics of carotid plaque. We evaluated the relationship between MR-plaque images and ischemic change after carotid artery stenting (CAS). METHODS: MR-plaque images were acquired from patients with carotid artery stenosis before CAS treatment. We calculated the relative signal intensity of plaque components compared with that of the sternocleidomastoid muscle and evaluated the presence/absence of T1-T2 mismatch and match sign. We then assessed the appearance of new ischemic lesions after CAS on diffusion-weighted imaging (DWI). Factors associated with the appearance of a high-intensity lesion on DWI were retrospectively analyzed. RESULTS: A total of 64 patients with carotid artery stenoses treated with CAS were included in this study. In univariate analysis, T1-T2 mismatch sign was associated with the appearance of high-intensity lesions on DWI after CAS (odds ratio [OR], 12.00; 95% confidence interval [CI], 3.593-40.072; P < 0.0001), whereas T1-T2 match sign and high intensity on T2-weighted imaging were negatively associated (OR, 0.061, 95% CI, 0.007-0.502, P = 0.009 and OR, 0.085; 95% CI, 0.022-0.334, P = 0.0004, respectively). In multivariate logistic regression analysis, T1-T2 mismatch sign was independently associated with the appearance of a high-intensity lesion on DWI after CAS (OR, 16.695; 95% CI, 1.324-210.52; P = 0.0295). CONCLUSIONS: T1-T2 mismatch sign on MR-plaque imaging is significantly associated with the appearance of new ischemic lesions after CAS. T1-T2 mismatch sign may be useful in considering treatment strategies for carotid artery stenosis.
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Estenosis Carotídea , Humanos , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/cirugía , Estenosis Carotídea/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Stents/efectos adversos , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/cirugía , Arterias Carótidas/patología , Imagen de Difusión por Resonancia MagnéticaRESUMEN
Nodular pulmonary amyloidosis, a subtype of pulmonary amyloidosis, is a unique disease that can mimic lung cancer on radiographic imaging and is related to lymphoproliferative disorders. In this report, we describe a case of a 76-year-old male who presented with a solitary nodule in his left lower lung lobe on computed tomography that increased from 6 mm to 13 mm in diameter over 40 months. Lung cancer was suspected; however, transbronchial lung biopsy revealed deposition of an eosinophilic and homogeneous amorphous substance, which showed apple-green birefringence under polarized light after Congo red staining, and immunohistochemistry analysis returned positive results for immunoglobulin lambda light-chain. Upper gastrointestinal endoscopy revealed a gastric mucosa-associated lymphoid tissue (MALT) lymphoma. These findings indicated that this was a case of nodular pulmonary amyloidosis that preceded a diagnosis of MALT lymphoma.
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Amiloidosis , Neoplasias Pulmonares , Linfoma de Células B de la Zona Marginal , Masculino , Humanos , Anciano , Linfoma de Células B de la Zona Marginal/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Amiloidosis/diagnóstico , Amiloidosis/etiología , Pulmón/diagnóstico por imagenRESUMEN
We report a case of retroperitoneal hematoma during prophylactic heparin therapy for coronavirus disease 2019 (COVID-19). A 79-year-old man was diagnosed with COVID-19 pneumonia with possible exacerbation of fibrotic hypersensitivity pneumonia. He received a prophylactic dose of subcutaneous heparin therapy, methylprednisolone pulse therapy and Intravenous remdesivir but developed a spontaneous iliopsoas muscle hematoma, and transcatheter arterial embolization was performed. Even with a prophylactic dose of subcutaneous heparin therapy, the course should be carefully monitored, especially in patients with preexisting risk factors for hemorrhagic complications. Once retroperitoneal hematoma develops, aggressive procedures, such as transcatheter arterial embolization, should be considered to avoid fatal outcomes.
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COVID-19 , Masculino , Humanos , Anciano , Anticoagulantes/efectos adversos , Heparina/efectos adversos , Hematoma/inducido químicamente , Hematoma/tratamiento farmacológico , Hemorragia GastrointestinalRESUMEN
BACKGROUND AND OBJECTIVES: The prognosis of idiopathic chronic fibrotic interstitial pneumonitis (CFIP) in patients with acute exacerbation (AE) is variable. We examined whether the imaging pattern on thoracic computed tomography (CT) or the severity of respiratory failure with AE-CFIP is associated with short-term prognosis. METHODS: Patients admitted to two university hospitals were retrospectively analyzed and divided into derivation and validation cohorts. The distribution of newly appearing parenchymal abnormalities on thoracic CT was classified into peripheral, multifocal, and diffuse patterns. Respiratory failure was defined as severe if a fraction of inspired oxygen ≥ 0.5 was required to maintain percutaneous oxygen saturation ≥ 90% on admission. Factors associated with 90 day-mortality were analyzed using univariate and Cox proportional hazard regression. RESULTS: In 59 patients with AE-CFIP of the derivation cohort, diffuse pattern on CT was associated with higher mortality within 90 days (43%) than peripheral/multifocal pattern (17%, p = 0.03). Additionally, compared with non-severe failure, severe respiratory failure was associated with higher mortality (47% vs. 21%, p = 0.06). Cox proportional hazard regression analysis demonstrated that a combination of diffuse pattern on CT and severe respiratory failure was associated with the poorest prognosis (hazard ratio [HR] 3.51 [interquartile range 1.26-9.80], p = 0.016) in the derivation cohort, which was confirmed in the validation cohort (n = 31, HR 4.30 [interquartile range 1.51-12.2], p = 0.006). CONCLUSION: The combination of imaging pattern on thoracic CT and severity of respiratory failure was associated with the prognosis of idiopathic AE-CFIP.
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Neumonías Intersticiales Idiopáticas , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Insuficiencia Respiratoria , Humanos , Estudios Retrospectivos , Pronóstico , Tomografía Computarizada por Rayos X/métodos , Progresión de la EnfermedadRESUMEN
We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses.
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Pruebas Genéticas , Humanos , Pruebas Genéticas/métodos , Ontario/epidemiología , Secuenciación del ExomaRESUMEN
BACKGROUND: Febrile neutropenia (FN) during cancer chemotherapy can lead to morbidity and mortality. The Multinational Association of Supportive Care in Cancer (MASCC) and clinical index of stable febrile neutropenia (CISNE) scores have been widely used to predict the risk of severe medical complications in patients with FN; however, there are few tools for predicting chemotherapy delays or discontinuation after FN. METHODS: Patients admitted to two university hospitals between 2014 and 2018 with a FN diagnosis during the first cycle of chemotherapy for lung cancer were reviewed retrospectively. RESULTS: Among 539 patients who received 813 courses of chemotherapy for lung cancer, 49 (9%) developed FN during the first treatment cycle. Although all the patients recovered from their primary infection, 19 patients (38.8%) developed serious medical complications, 11 (22.4%) were unable to resume chemotherapy and one (2.0%) declined to resume chemotherapy, and nine (18.4%) died within 90 days. Patients who failed to resume chemotherapy had a lower MASCC score (median 8.5 vs. 17, p < 0.01) and a higher CISNE score (median 3 vs. 1, p < 0.01) at the onset of FN. The specificity to predict the patient who failed to resume chemotherapy was 90% or more with MASCC score ≤9 or CISNE score ≥3, with the sensitivity of 61%. MASCC score ≤ 16 can also be a sensitive indicator with the sensitivity and specificity of 89 and 52%, respectively. CONCLUSION: The MASCC and CISNE scores are useful in identifying lung cancer patients who are unable to resume chemotherapy as scheduled after the onset of FN.
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Antineoplásicos , Neutropenia Febril , Neoplasias Pulmonares , Humanos , Neutropenia Febril/inducido químicamente , Antineoplásicos/uso terapéutico , Estudios Retrospectivos , Valor Predictivo de las Pruebas , Medición de Riesgo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inducido químicamenteRESUMEN
OBJECTIVES: To analyse the clinical characteristics and prognosis of acute exacerbation (AE) in patients with idiopathic pulmonary fibrosis (IPF) and pulmonary emphysema. DESIGN: A multicentre retrospective cohort study SETTING: Two university hospitals in Japan PARTICIPANTS: Patients admitted to hospitals due to AE of IPF diagnosed based on a multidisciplinary discussion. INTERVENTIONS: None PRIMARY AND SECONDARY OUTCOME MEASURES: 90-day mortality rate METHODS: We retrospectively analysed consecutive patients with AE of IPF, with or without pulmonary emphysema, admitted to two university hospitals between 2007 and 2018. RESULTS: Among 62 patients (median age, 75 years; 48 men) admitted for AE of IPF, 29 patients (46%) presented with concomitant pulmonary emphysema. There was no significant difference in the arterial partial oxygen pressure/fraction of inhaled oxygen (P/F) ratio or other laboratory and radiographic data between patients with and without emphysema. The 90-day mortality rate was significantly lower in patients with emphysema than in those with IPF alone (23% vs 52%, p=0.03). The median survival time was significantly longer in patients with emphysema than in those with IPF alone (405 vs 242 days, p=0.02). CONCLUSION: Patients with IPF and emphysema had better short-term survival after AE than those with non-emphysematous IPF.
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Fibrosis Pulmonar Idiopática , Enfisema Pulmonar , Anciano , Estudios de Cohortes , Humanos , Fibrosis Pulmonar Idiopática/complicaciones , Japón , Masculino , Oxígeno , Pronóstico , Enfisema Pulmonar/complicaciones , Estudios RetrospectivosRESUMEN
OBJECTIVE: Post-bronchoscopy pneumonia can affect the prognosis of lung cancer patients. This prospective study examined the efficacy of prophylactic antibiotics for lung cancer patients at high-risk of post-bronchoscopy pneumonia, determined by our prediction score, using three risk factors: age 70 years or older, current smoking, and central tumors visualized on CT. METHODS: Patients with lung cancer who underwent diagnostic bronchoscopy between June 2018 and March 2020 with a score of 2 points or higher were enrolled. Sulbactam/ampicillin was administered intravenously within one hour prior to bronchoscopy, followed by oral clavulanate/amoxicillin for three days. We used the data of lung cancer patients who underwent diagnostic bronchoscopy between April 2012 and July 2014 and exhibited a score of 2 or higher as the historical control. RESULTS: Post-bronchoscopy pneumonia occurred in none of the 24 patients in the prophylaxis group and in 17 of 144 patients in the control group, with no significant difference in the incidence of pneumonia between the two groups. CONCLUSIONS: Antibiotic prophylaxis can be effective and safe for the patients high-risk of post-bronchoscopy pneumonia. A multicenter prospective study to examine the effects of prophylactic antibiotics in high-risk patients is feasible with a modest number of participants.
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Neoplasias Pulmonares , Neumonía , Anciano , Antibacterianos/uso terapéutico , Broncoscopía/efectos adversos , Humanos , Neoplasias Pulmonares/complicaciones , Neumonía/etiología , Neumonía/prevención & control , Estudios ProspectivosRESUMEN
An 82-year-old woman with a history of chronic thromboembolic pulmonary hypertension (CTEPH) presented with malaise, left facial nerve paralysis and the positive seroconversion of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA). She was diagnosed with ANCA-associated vasculitis (AAV). Administration of corticosteroids significantly improved her symptoms, with a decline in the serum MPOANCA level. Ten months later than the initial presentation, she developed an AAV exacerbation with lung infiltration and pericardial effusion, which improved with high-dose corticosteroid therapy. To date, a limited number of AAV cases concomitant with pulmonary hypertension have been reported. The case report presented herein suggests a potential role for CTEPH in the development of AAV.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Hipertensión Pulmonar , Anciano de 80 o más Años , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Anticuerpos Anticitoplasma de Neutrófilos , Femenino , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiologíaRESUMEN
OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. INTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304-321.
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Apirasa , Discapacidad Intelectual , Paraplejía Espástica Hereditaria , Sustancia Blanca , Apirasa/genética , Disartria , Humanos , Discapacidad Intelectual/genética , Mutación/genética , Paraplejía/genética , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/genética , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull's eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.