Sujet(s)
Astrocytes , Tronc cérébral , Protéine gliofibrillaire acide , Imagerie par résonance magnétique , Humains , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Protéine gliofibrillaire acide/immunologie , Protéine gliofibrillaire acide/métabolisme , Astrocytes/anatomopathologie , Astrocytes/métabolisme , Femelle , MâleSujet(s)
Astrocytes , Tronc cérébral , Protéine gliofibrillaire acide , Imagerie par résonance magnétique , Humains , Protéine gliofibrillaire acide/immunologie , Protéine gliofibrillaire acide/métabolisme , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Astrocytes/anatomopathologie , Astrocytes/métabolismeSujet(s)
Astrocytes , Tronc cérébral , Protéine gliofibrillaire acide , Humains , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Protéine gliofibrillaire acide/immunologie , Protéine gliofibrillaire acide/métabolisme , Astrocytes/anatomopathologie , Astrocytes/métabolisme , Imagerie par résonance magnétiqueRÉSUMÉ
Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1-/- mice. Further, we show that A1-reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV-infected IFNAR1-/- mice also induced neuronal cell death through the activation of A1-reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach.
Sujet(s)
Astrocytes , Infections à Bunyaviridae , Souris knockout , Phlebovirus , Récepteur à l'interféron alpha-bêta , Animaux , Astrocytes/virologie , Astrocytes/anatomopathologie , Souris , Récepteur à l'interféron alpha-bêta/génétique , Récepteur à l'interféron alpha-bêta/déficit , Phlebovirus/génétique , Phlebovirus/physiologie , Phlebovirus/pathogénicité , Infections à Bunyaviridae/virologie , Infections à Bunyaviridae/anatomopathologie , Infections à Bunyaviridae/immunologie , Encéphale/virologie , Encéphale/anatomopathologie , Encéphale/immunologie , Moelle spinale/virologie , Moelle spinale/anatomopathologie , Modèles animaux de maladie humaine , Neurones/virologie , Neurones/anatomopathologie , Souris de lignée C57BL , Tronc cérébral/virologie , Tronc cérébral/anatomopathologie , Mort cellulaireRÉSUMÉ
Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level. We utilized the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and constructed the ASD PRS in an independent cohort, the UK Biobank. Regression analyses controlled for multiple comparisons with the false-discovery rate (FDR) at 5% were performed to investigate the association between ASD PRS and forty-four brain magnetic resonance imaging (MRI) phenotypes among ~ 31,000 participants. Primary analyses included sixteen MRI phenotypes: total volumes of the brain, cerebrospinal fluid (CSF), grey matter (GM), white matter (WM), GM of whole cerebellum, brainstem, and ten regions of the cerebellum (I_IV, V, VI, VIIb, VIIIa, VIIIb, IX, X, CrusI and CrusII). Secondary analyses included twenty-eight MRI phenotypes: the sub-regional volumes of cerebellum including the GM of the vermis and both left and right lobules of each cerebellar region. ASD PRS were significantly associated with the volumes of seven brain areas, whereby higher PRS were associated to reduced volumes of the whole brain, WM, brainstem, and cerebellar regions I-IV, IX, and X, and an increased volume of the CSF. Three sub-regional volumes including the left cerebellar lobule I-IV, cerebellar vermes VIIIb, and X were significantly and negatively associated with ASD PRS. The study highlights a substantial connection between susceptibility to ASD, its underlying genetic etiology, and neuroanatomical alterations of the adult brain.
Sujet(s)
Tronc cérébral , Cervelet , Imagerie par résonance magnétique , Hérédité multifactorielle , Phénotype , Humains , Cervelet/imagerie diagnostique , Cervelet/anatomopathologie , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Mâle , Femelle , Adulte , Prédisposition génétique à une maladie , Taille d'organe , Adulte d'âge moyen , Trouble autistique/génétique , Trouble autistique/imagerie diagnostique , Étude d'association pangénomique , Trouble du spectre autistique/génétique , Trouble du spectre autistique/imagerie diagnostique , Substance grise/imagerie diagnostique , Substance grise/anatomopathologie , Études cas-témoinsRÉSUMÉ
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder attributed to ABCD1 mutations. Case reports with predominant brainstem involvement are rare. CASE PRESENTATION: In this study, we reported a plateau male worker of X-ALD characterized by progressive weakness accompanied by gait instability, mild nystagmus, and constipation. After 2 years of onset, a brain Magnetic Resonance Image (MRI) scan showed no abnormality but genetic analysis revealed a heterozygous mutation (c.1534G>A) in the ABCD1 gene. After 7 years of onset, although the patient was given aggressive dietary and symptomatic treatment in the course of the disease, a brain MRI scan showed predominantly brainstem damage, but serum concentrations of very long-chain fatty acids were normal, and he had been bedridden for almost 2 years with severe bladder dysfunction, forcing him to undergo cystostomy. The patient was discharged with improved urinary retention and renal function. CONCLUSIONS: We reported an X-ALD patient with a novel ABCD1 variation characterized by brainstem damage and retrospectively summarized the clinical manifestation, MRI features, and genetic features of X-ALD patients with brainstem damage.
Sujet(s)
Membre-1 de la sous-famille D de transporteurs à cassette liant l'ATP , Adrénoleucodystrophie , Tronc cérébral , Mutation faux-sens , Humains , Adrénoleucodystrophie/génétique , Adrénoleucodystrophie/anatomopathologie , Adrénoleucodystrophie/diagnostic , Membre-1 de la sous-famille D de transporteurs à cassette liant l'ATP/génétique , Mâle , Tronc cérébral/anatomopathologie , Tronc cérébral/imagerie diagnostique , Adulte , Imagerie par résonance magnétiqueRÉSUMÉ
Leptomeningeal metastasis (LM) is a devastating complication of malignancy. Diagnosis relies on both contrast enhancement on imaging and malignant cells in cerebral spinal fluid cytology. Though early detection and prompt intervention improves survival, the detection of LM is limited by false negatives. A rare brainstem imaging finding uncovered specifically in EGFR mutation-positive lung cancer patients may represent an early sign of LM. This sign demonstrates high signal on T2 fluid-attenuated inversion recovery and diffusion-weighted imaging sequences, but paradoxically lacks correlative contrast enhancement. Here we report a case of a 72-year-old female EGFR-positive lung cancer patient who developed this lesion following treatment with two first-generation EGFR tyrosine kinase inhibitors then showed subsequent response to osimertinib, an irreversible third-generation EGFR tyrosine kinase inhibitor.
A non-enhancing, T2 FLAIR hyperintense, diffusion-restricting brainstem lesion in an EGFR-positive lung cancer patient may represent an early indicator of leptomeningeal metastases.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Récepteurs ErbB , Tumeurs du poumon , Inhibiteurs de protéines kinases , Humains , Femelle , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/imagerie diagnostique , Carcinome pulmonaire non à petites cellules/métabolisme , Sujet âgé , Inhibiteurs de protéines kinases/usage thérapeutique , Récepteurs ErbB/antagonistes et inhibiteurs , Récepteurs ErbB/génétique , Récepteurs ErbB/métabolisme , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/imagerie diagnostique , Tronc cérébral/anatomopathologie , Tronc cérébral/imagerie diagnostique , Tronc cérébral/métabolisme , Dérivés de l'aniline/usage thérapeutique , Acrylamides/usage thérapeutique , Imagerie par résonance magnétique de diffusion , Indoles , PyrimidinesRÉSUMÉ
We presented a case of a 34-year-old male with postoperative brainstem cavernous malformations complicated with LGI1 encephalitis and secondary hypertrophic olivary degeneration (HOD). Due to recurrent dizziness and headache, the patient was diagnosed as brainstem cavernous malformations with recurrent hemorrhage and underwent resection. He subsequently developed unexplained abnormal mental behavior 1 month after the surgery, and diagnosed with LGI1 encephalitis. Six months later, cranial MRI showed HOD. This condition is rare in clinical practice,and a complex mechanism underlies the occurrence.
Sujet(s)
Protéines et peptides de signalisation intracellulaire , Humains , Mâle , Adulte , Encéphalite/complications , Encéphalite/imagerie diagnostique , Noyau olivaire/anatomopathologie , Noyau olivaire/imagerie diagnostique , Protéines , Hémangiome caverneux du système nerveux central/complications , Hémangiome caverneux du système nerveux central/chirurgie , Hémangiome caverneux du système nerveux central/imagerie diagnostique , Complications postopératoires/étiologie , Complications postopératoires/imagerie diagnostique , Imagerie par résonance magnétique , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Hypertrophie ,RÉSUMÉ
Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
Sujet(s)
Tronc cérébral , COVID-19 , Neurones , SARS-CoV-2 , Humains , Mâle , SARS-CoV-2/génétique , COVID-19/génétique , COVID-19/virologie , Tronc cérébral/anatomopathologie , Tronc cérébral/virologie , Tronc cérébral/métabolisme , Adolescent , Neurones/métabolisme , Neurones/anatomopathologie , Encéphalite virale/génétique , Encéphalite virale/anatomopathologie , Encéphalite virale/virologie , Fibroblastes/métabolisme , Rhombencéphale/métabolismeRÉSUMÉ
Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
Sujet(s)
Évolution de la maladie , Corps de Lewy , Maladie à corps de Lewy , alpha-Synucléine , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Humains , Mâle , Adulte d'âge moyen , alpha-Synucléine/métabolisme , Maladie d'Alzheimer/anatomopathologie , Maladie d'Alzheimer/métabolisme , Encéphale/anatomopathologie , Encéphale/métabolisme , Tronc cérébral/anatomopathologie , Tronc cérébral/métabolisme , Corps de Lewy/anatomopathologie , Corps de Lewy/métabolisme , Maladie à corps de Lewy/anatomopathologie , Maladie à corps de Lewy/métabolisme , Bulbe olfactif/anatomopathologie , Bulbe olfactif/métabolismeRÉSUMÉ
Human alphaherpesvirus 1 (HSV-1) establishes life-long latency in sensory neurons in trigeminal ganglia (TG), brainstem neurons, and other CNS neurons. Two important segments of the brainstem were examined in this study: principal sensory nucleus of the spinal trigeminal tract (Pr5) because it receives direct afferent inputs from TG, and locus coeruleus (LC) because it is indirectly connected to Pr5 and LC sends axonal projections to cortical structures, which may facilitate viral spread from brainstem to the brain. The only viral gene abundantly expressed during latency is the latency associated transcript (LAT). Previous studies revealed 8-week old female C57Bl/6 mice infected with a LAT null mutant (dLAT2903) versus wild-type (wt) HSV-1 exhibit higher levels of senescence markers and inflammation in LC of females. New studies revealed 1-year old mice latently infected with wt HSV-1 or dLAT2903 contained differences in neuroinflammation and senescence in Pr5 and LC versus young mice. In summary, these studies confirm HSV-1 promotes neuro-inflammation in the brainstem, which may accelerate neurodegenerative disease.
Sujet(s)
Tronc cérébral , Herpèsvirus humain de type 1 , Souris de lignée C57BL , Maladies neuro-inflammatoires , Latence virale , Animaux , Herpèsvirus humain de type 1/physiologie , Herpèsvirus humain de type 1/génétique , Tronc cérébral/virologie , Tronc cérébral/anatomopathologie , Souris , Femelle , Maladies neuro-inflammatoires/virologie , Maladies neuro-inflammatoires/anatomopathologie , Herpès/virologie , Herpès/anatomopathologie , Vieillissement , Humains , Infection latente/virologie , Ganglion trigéminal/virologie , Modèles animaux de maladie humaineSujet(s)
Tronc cérébral , Encéphalite , Immunoglobuline G , Imagerie par résonance magnétique , Glycoprotéine MOG , Humains , Glycoprotéine MOG/immunologie , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Encéphalite/imagerie diagnostique , Encéphalite/immunologie , Encéphalite/anatomopathologie , Femelle , Autoanticorps/immunologie , Mâle , AdulteRÉSUMÉ
Respiratory infections are one of the most common causes of illness and morbidity in neonates worldwide. In the acute phase infections are known to cause wide-spread peripheral inflammation. However, the inflammatory consequences to the critical neural control centres for respiration have not been explored. Utilising a well characterised model of neonatal respiratory infection, we investigated acute responses within the medulla oblongata which contains key respiratory regions. Neonatal mice were intranasally inoculated within 24 h of birth, with either Chlamydia muridarum or sham-infected, and tissue collected on postnatal day 15, the peak of peripheral inflammation. A key finding of this study is that, while the periphery appeared to show no sex-specific effects of a neonatal respiratory infection, sex had a significant impact on the inflammatory response of the medulla oblongata. There was a distinct sex-specific response in the medulla coincident with peak of peripheral inflammation, with females demonstrating an upregulation of anti-inflammatory cytokines and males showing very few changes. Microglia also demonstrated sex-specificity with the morphology of females and males differing based upon the nuclei. Astrocytes showed limited changes during the acute response to neonatal infection. These data highlight the strong sex-specific impact of a respiratory infection can have on the medulla in the acute inflammatory phase.
Sujet(s)
Animaux nouveau-nés , Infections à Chlamydia , Chlamydia muridarum , Animaux , Souris , Femelle , Infections à Chlamydia/microbiologie , Infections à Chlamydia/anatomopathologie , Mâle , Infections de l'appareil respiratoire/microbiologie , Infections de l'appareil respiratoire/anatomopathologie , Tronc cérébral/anatomopathologie , Maladies neuro-inflammatoires/microbiologie , Maladies neuro-inflammatoires/anatomopathologie , Maladies neuro-inflammatoires/immunologie , Caractères sexuels , Souris de lignée C57BL , Cytokines/métabolismeSujet(s)
Tronc cérébral , COVID-19 , Humains , COVID-19/complications , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Moelle spinale/imagerie diagnostique , Moelle spinale/vascularisation , SARS-CoV-2 , Mâle , Infarctus/étiologie , Infarctus/imagerie diagnostique , Infarctus du tronc cérébral/étiologie , Infarctus du tronc cérébral/imagerie diagnostique , Adulte d'âge moyen , Imagerie par résonance magnétiqueRÉSUMÉ
BACKGROUND AND PURPOSE: While classic brain MR imaging features of Alexander disease have been well-documented, lesional patterns can overlap with other leukodystrophies, especially in the early stages of the disease or in milder phenotypes. We aimed to assess the utility of a new neuroimaging sign to help increase the diagnostic specificity of Alexander disease. MATERIALS AND METHODS: A peculiar bilateral symmetric hyperintense signal on T2-weighted images affecting the medulla oblongata was identified in an index patient with type I Alexander disease. Subsequently, 5 observers performed a systematic MR imaging review for this pattern by examining 55 subjects with Alexander disease and 74 subjects with other leukodystrophies. Interobserver agreement was assessed by the κ index. Sensitivity, specificity, and receiver operating characteristic curves were determined. RESULTS: The identified pattern was present in 87% of subjects with Alexander disease and 14% of those without Alexander disease leukodystrophy (P < .001), 3 with vanishing white matter, 4 with adult polyglucosan body disease, and 3 others. It was found equally in both type I and type II Alexander disease (28/32, 88% versus 18/21, 86%; P = .851) and in subjects with unusual disease features (2/2). Sensitivity (87.3%; 95% CI, 76.0%-93.7%), specificity (86.5%; 95% CI, 76.9%-92.5%), and interobserver agreement (κ index = 0.82) were high. CONCLUSIONS: The identified pattern in the medulla oblongata, called the chipmunk sign due to its resemblance to the face of this rodent, is extremely common in subjects with Alexander disease and represents a diagnostic tool that can aid in early diagnosis, especially in subjects with otherwise atypical MR imaging findings and/or clinical features.
Sujet(s)
Maladie d'Alexander , Imagerie par résonance magnétique , Sensibilité et spécificité , Humains , Maladie d'Alexander/imagerie diagnostique , Mâle , Femelle , Adulte , Imagerie par résonance magnétique/méthodes , Adulte d'âge moyen , Jeune adulte , Adolescent , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Enfant , Sujet âgé , Moelle allongée/imagerie diagnostique , Moelle allongée/anatomopathologie , Enfant d'âge préscolaireRÉSUMÉ
Cerebellar ataxia is an uncommon and atypical manifestation of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, often accompanied by seizures, psychiatric symptoms, and cognitive deficits. Previous cases of isolated brainstem-cerebellar symptoms in patients with anti-NMDAR encephalitis have not been documented. This report presents a case of anti-NMDAR encephalitis in which the patient exhibited cerebellar ataxia, nystagmus, diplopia, positive bilateral pathological signs, and hemiparesthesia with no other accompanying symptoms or signs. The presence of positive CSF anti-NMDAR antibodies further supports the diagnosis. Other autoantibodies were excluded through the use of cell-based assays. Immunotherapy was subsequently administered, leading to a gradual recovery of the patient.
Sujet(s)
Encéphalite à anticorps anti-récepteur N-méthyl-D-aspartate , Autoanticorps , Tronc cérébral , Humains , Encéphalite à anticorps anti-récepteur N-méthyl-D-aspartate/diagnostic , Tronc cérébral/anatomopathologie , Autoanticorps/immunologie , Autoanticorps/liquide cérébrospinal , Autoanticorps/sang , Femelle , Ataxie cérébelleuse/étiologie , Ataxie cérébelleuse/diagnostic , Ataxie cérébelleuse/immunologie , Cervelet/anatomopathologie , Cervelet/imagerie diagnostique , Récepteurs du N-méthyl-D-aspartate/immunologie , Adulte , Immunothérapie , Mâle , Imagerie par résonance magnétiqueRÉSUMÉ
Post-acute COVID syndrome (PACS) is a global health concern and is often associated with debilitating symptoms. Post-COVID fatigue is a particularly frequent and troubling issue, and its underlying mechanisms remain incompletely understood. One potential contributor is micropathological injury of subcortical and brainstem structures, as has been identified in other patient populations. Texture-based analysis (TA) may be used to measure such changes in anatomical MRI data. The present study develops a methodology of voxel-wise TA mapping in subcortical and brainstem regions, which is then applied to T1-weighted MRI data from a cohort of 48 individuals who had PACS (32 with and 16 without ongoing fatigue symptoms) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19. Both groups were assessed an average of 4-5 months post-infection. There were no significant differences between PACS and control groups, but significant differences were observed within the PACS groups, between those with and without fatigue symptoms. This included reduced texture energy and increased entropy, along with reduced texture correlation, cluster shade and profile in the putamen, pallidum, thalamus and brainstem. These findings provide new insights into the neurophysiological mechanisms that underlie PACS, with altered tissue texture as a potential biomarker of this debilitating condition.
Sujet(s)
Tronc cérébral , COVID-19 , Fatigue , Imagerie par résonance magnétique , Syndrome de post-COVID-19 , Humains , COVID-19/complications , COVID-19/imagerie diagnostique , Mâle , Femelle , Fatigue/imagerie diagnostique , Fatigue/étiologie , Fatigue/anatomopathologie , Adulte d'âge moyen , Adulte , Tronc cérébral/imagerie diagnostique , Tronc cérébral/anatomopathologie , Encéphale/imagerie diagnostique , Encéphale/anatomopathologie , Thalamus/imagerie diagnostique , Thalamus/anatomopathologie , Sujet âgé , Putamen/imagerie diagnostique , Putamen/anatomopathologie , SARS-CoV-2RÉSUMÉ
BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. CASE PRESENTATION: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.
Sujet(s)
Aspartate-tRNA ligase , Mutation de type INDEL , Leucoencéphalopathies , Humains , Aspartate-tRNA ligase/génétique , Aspartate-tRNA ligase/déficit , Mâle , Leucoencéphalopathies/génétique , Leucoencéphalopathies/anatomopathologie , Femelle , Tronc cérébral/anatomopathologie , Tronc cérébral/imagerie diagnostique , Enfant , Acide lactique/sang , Russie , Adulte , Moelle spinale/anatomopathologie , Moelle spinale/imagerie diagnostique , Adolescent , Maladies mitochondrialesRÉSUMÉ
AIM: Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi-system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the Ndufs4(-/-) mouse model of LS: treatment of Ndufs4(-/-) mice with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon-gamma (IFNγ) and interferon gamma-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS. METHODS: To establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout animals, as well as IFNγ and IP10 heterozygous, Ndufs4(-/-)/Ifng(+/-) and Ndufs4(-/-)/IP10(+/-), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS. RESULTS: Loss of IP10 does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage-dependent manner, though the benefits are modest compared to Csf1r inhibition. CONCLUSIONS: IFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.