Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration

Macintosh, Julia; Derksen, Alexa; Poulin, Chantal; Braverman, Nancy; Vanderver, Adeline; Thiffault, Isabelle; Albrecht, Steffen; Bernard, Geneviève

doi:10.1007/s10048-022-00683-8

Cited by 7 publications

(6 citation statements)

References 15 publications

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“…Macintosh et al described the latest case who had ultrastructural defect in the mitochondria when examined by electron microscopy. 6 In their brain MRIs, these patients had corpus callosal thinning, delayed myelination, hypomyelination, and periventricular leukomalacia with diffuse cerebral and cerebellar white matter T2 hyperintensities, but subsequent images on follow-up revealed progressive severe generalized cortical and subcortical atrophy with resultant ex vacuo ventricular dilatation—similar to our case, whom we saw late in his disease course.…”

Section: Discussionsupporting

confidence: 76%

“…►Table 1 gives a comprehensive account of the described variations of NRROS gene. 2,4,6 What Does This Article Add?…”

Section: Discussionmentioning

confidence: 99%

“…Two articles 2 4 describing nine cases in 2020 were followed by a recent case report in April 2022. 6 Ours is the 11th case reported worldwide and the first from India. Moreover, it is the first report to describe associated autoimmune encephalitis in a child with a NRROS variation.…”

Section: Introductionmentioning

confidence: 89%

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Anti–Gamma Aminobutyric Acid B Autoimmune Encephalitis in an Indian Child with Early-Onset Seizures, Neurodegeneration, and Brain Calcification due to NRROS Variation: The First Reported Case Worldwide

Kapat

Pandit

Das

et al. 2022

Journal of Pediatric Epilepsy

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A 1.5-year-old boy presented to us with a history of normal growth and developmental parameters until 6 months of age. However, at 7 months of age, he developed multiple types of seizures consisting initially of complex febrile seizures, followed by afebrile seizures. Multifocal clonic, generalized tonic–clonic, and myoclonic (multifocal and generalized) were the evolving seizure types. He had truncal hypotonia, but his appendicular hypotonia progressed to hypertonia over the next few months and further to decorticate posturing. Brain magnetic resonance imaging (MRI) showed generalized atrophy, predominantly frontotemporal, without any focal signal abnormalities or contrast enhancement. Computed tomography (CT) showed speckled calcification in subcortical white matter. Electroencephalogram showed bilateral frontotemporal epileptiform discharges with secondary generalization. His cerebrospinal fluid had normal cytology and biochemical results but was positive for anti–gamma aminobutyric acid B antibodies. Whole exome sequencing showed likely pathogenic, novel autosomal recessive homozygous variation of NRROS gene on chromosome 3 [c.1487G > A (p.Trp496Ter)], which impairs the functioning of anti-inflammatory cytokine transforming growth factor beta, resulting in a proinflammatory state within the central nervous system and thereby promoting autoimmune encephalitis. Parental Sanger sequencing validated the variation in both his parents. He was treated with both pulse methylprednisolone (30 mg/kg/day for 5 days) and intravenous immunoglobulin (2 g/kg), followed by slowly tapering of oral prednisolone and monthly intravenous immunoglobulin infusion (1 g/kg). There was significant reduction in seizure frequency and disappearance of epileptiform discharges from the electroencephalogram. However, the motor and cognitive improvement did not occur, and he had microcephaly and growth failure at the last follow-up. This is the 11th case report of neurodegeneration associated with NRROS gene variations, but the first report of autoimmune encephalitis being triggered by the variation in a child.

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Section: Discussionsupporting

confidence: 76%

“…►Table 1 gives a comprehensive account of the described variations of NRROS gene. 2,4,6 What Does This Article Add?…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anti–Gamma Aminobutyric Acid B Autoimmune Encephalitis in an Indian Child with Early-Onset Seizures, Neurodegeneration, and Brain Calcification due to NRROS Variation: The First Reported Case Worldwide

Kapat

Pandit

Das

et al. 2022

Journal of Pediatric Epilepsy

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“…As brain-resident immune cells, microglia also respond to central nervous system (CNS) injury and diverse neuropathologies ( Keren-Shaul et al, 2017 ; Salter and Stevens, 2017 ). The importance of microglia to human health is further highlighted by the high proportion of microglial genes that confer genetic risk in neurodegenerative disease ( McQuade and Blurton-Jones, 2019 ; Kim et al, 2020 ; Podleśny-Drabiniok et al, 2020 ; Amin et al, 2022 ) and “primary microgliopathies,” rare diseases arising from mutations that alter microglial function and survival ( Paloneva et al, 2002 ; Konno et al, 2018 ; Berdowski et al, 2021 ; Macintosh et al, 2022 ). These findings have inspired efforts to therapeutically target microglia.…”

Section: Introductionmentioning

confidence: 99%

Engineering an inhibitor-resistant human CSF1R variant for microglia replacement

Chadarevian

Lombroso

Peet

et al. 2022

Journal of Experimental Medicine

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Hematopoietic stem cell transplantation (HSCT) can replace endogenous microglia with circulation-derived macrophages but has high mortality. To mitigate the risks of HSCT and expand the potential for microglia replacement, we engineered an inhibitor-resistant CSF1R that enables robust microglia replacement. A glycine to alanine substitution at position 795 of human CSF1R (G795A) confers resistance to multiple CSF1R inhibitors, including PLX3397 and PLX5622. Biochemical and cell-based assays show no discernable gain or loss of function. G795A- but not wildtype-CSF1R expressing macrophages efficiently engraft the brain of PLX3397-treated mice and persist after cessation of inhibitor treatment. To gauge translational potential, we CRISPR engineered human-induced pluripotent stem cell–derived microglia (iMG) to express G795A. Xenotransplantation studies demonstrate that G795A-iMG exhibit nearly identical gene expression to wildtype iMG, respond to inflammatory stimuli, and progressively expand in the presence of PLX3397, replacing endogenous microglia to fully occupy the brain. In sum, we engineered a human CSF1R variant that enables nontoxic, cell type, and tissue-specific replacement of microglia.

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“…Postmortem pathological examination of the brain tissue of a 3-year-old female harboring NRROS mutations revealed severely reduced white matter with diffuse gliosis, dystrophic calcifications, and widespread infiltration of foamy macrophages [ 85 ].Globular mitochondria with concentrically arranged cristae were observed at the ultrastructural level [ 85 ]. Taken together, it is hypothesized that NRROS mutations result in increased ROS generation due to (I) deficient inhibition of NOX2 and (II) failure to release active TGF-β1, thus causing uncontrolled activation of microglia and inflammation-related ROS secretion from mitochondria [ 85 ].…”

Section: Mitochondrial Dysfunction and Oxidative Stress In Hereditary...mentioning

confidence: 99%

Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases

Nollet

Vanakker

2022

IJMS

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Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson–Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders.

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Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration

Cited by 7 publications

References 15 publications

Anti–Gamma Aminobutyric Acid B Autoimmune Encephalitis in an Indian Child with Early-Onset Seizures, Neurodegeneration, and Brain Calcification due to NRROS Variation: The First Reported Case Worldwide

Anti–Gamma Aminobutyric Acid B Autoimmune Encephalitis in an Indian Child with Early-Onset Seizures, Neurodegeneration, and Brain Calcification due to NRROS Variation: The First Reported Case Worldwide

Engineering an inhibitor-resistant human CSF1R variant for microglia replacement

Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases

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