NRROS-Related Microgliopathy

Mendelian MONDO:0030033 Pathograph 18 Show in embeddings browser microgliopathy neurodegenerative disease

NRROS-related microgliopathy (seizures, early-onset, with neurodegeneration and brain calcifications; SENEBAC, MIM 618875) is an autosomal recessive, usually lethal infantile neurodegenerative disorder caused by biallelic loss-of-function variants in NRROS (negative regulator of reactive oxygen species, also called LRRC33). NRROS is a leucine-rich repeat transmembrane protein expressed by microglia and CNS perivascular macrophages that binds latent TGF-beta1 and presents it at the cell surface, where integrin alpha-v beta-8 releases the active cytokine to signal locally on the presenting microglial cell. Without NRROS, microglia lose this autocrine TGF-beta1 signal and do not acquire or maintain their homeostatic identity. Development is usually normal or mildly delayed until seizures begin in the first two years of life. Seizures are drug-resistant, and children then lose developmental skills, develop acquired microcephaly, and show progressive cerebral atrophy, white matter loss and punctate or serpiginous calcification at the grey-white matter junction. Most reported children have died by about three years of age.

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Inheritance

1
Autosomal recessive HP:0000007
Affected children carry biallelic NRROS variants, homozygous in consanguineous families and compound heterozygous otherwise.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:32197075 SUPPORT Human clinical
"We report six individuals from four families with bi-allelic variants in NRROS."
Biallelic variants in all affected individuals.
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Discussions and Knowledge Gaps

2
Could haematopoietic cell transplantation or another microglial replacement strategy halt disease in children with NRROS-related microgliopathy if given before neurodegeneration is advanced?
KNOWLEDGE GAP OPEN nrros_microglial_replacement
Attached to
pathophysiology#Failure of Homeostatic Microglial Identity animal_models#Lrrc33 knockout mouse
In Lrrc33-deficient mice, wild-type bone marrow repopulates the brain with wild-type microglia and halts progression. Because the defect is cell autonomous to NRROS-deficient myeloid cells, replacement is a mechanistic rationale for transplantation, but no human outcome has been reported and the children in published series were diagnosed after regression had begun.
Show evidence (1 reference)
PMID:29909984 SUPPORT Model organism
"Whole bone marrow transplantation results in selective repopulation of Lrrc33-/- brains with WT microglia and halts disease progression."
Preclinical rescue that motivates the question.
Does the human disease follow from loss of microglial TGF-beta1 activation alone, or does loss of NRROS-mediated restraint of NOX2 and reactive oxygen species production also contribute?
KNOWLEDGE GAP OPEN nrros_tgfb_versus_nox2
Attached to
pathophysiology#NRROS Loss of Function pathophysiology#Perivascular Foamy Macrophage Accumulation
NRROS was first described as a negative regulator of NOX2 in phagocytes, and the foamy macrophages in patient brain are p22phox-positive. The phenotype of the knockouts, rescue by wild-type marrow, and the overlap with human TGF-beta1 deficiency point to the TGF-beta axis, but no study has separated the two functions in the CNS disease.
Show evidence (3 references)
PMID:24739962 SUPPORT Model organism
"NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known as gp91(phox) and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the..."
Establishes the second, NOX2-regulating function of NRROS.
PMID:32197075 SUPPORT Human clinical
"The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency."
Clinical overlap with TGF-beta1 deficiency favours the TGF-beta axis.
PMID:29483653 SUPPORT Human clinical
"biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy"
Human TGF-beta1 deficiency produces epilepsy, brain atrophy and leukoencephalopathy, the CNS features shared with NRROS deficiency.
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Pathophysiology

7
NRROS Loss of Function
Biallelic truncating or destabilising variants in NRROS abolish the protein's ability to anchor latent TGF-beta1 at the surface of microglia and perivascular macrophages.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
NRROS hgnc:24613 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NRROS (hgnc:24613). hgnc:24613 is a gene from the HUGO Gene Nomenclature Committee.
latent TGF-beta1 binding GO:0050431 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased latent TGF-beta1 binding, annotated with transforming growth factor beta binding (GO:0050431). GO:0050431 is a molecular function from the Gene Ontology.
Downstream
Loss of Microglial Autocrine TGF-beta1 Activation
Show evidence (2 references)
PMID:32197075 SUPPORT BACKGROUND In vitro / ex vivo
"Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface"
States the molecular function lost with NRROS, binding and surface anchoring of latent TGF-beta1, which is what the GO binding term records.
PMID:32197075 SUPPORT In vitro / ex vivo
"we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS"
Disease-associated NRROS variants lose the latent TGF-beta1 anchoring function in a cell assay.
Loss of Microglial Autocrine TGF-beta1 Activation
NRROS is the milieu molecule that presents latent TGF-beta1 on the microglial surface for integrin alpha-v beta-8-dependent activation. The activated cytokine acts on the presenting cell and its immediate neighbours, so loss of NRROS removes TGF-beta signalling from microglia.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
TGF-beta receptor signaling in microglia GO:0007179 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased TGF-beta receptor signaling in microglia, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology.
Animal models
Lrrc33 knockout mouse Mouse recapitulates Microglia lacking LRRC33 lose TGF-beta signalling.
Downstream
Failure of Homeostatic Microglial Identity
Show evidence (1 reference)
PMID:29909984 SUPPORT Model organism
"LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation"
Establishes NRROS/LRRC33 as the microglial surface presenter of latent TGF-beta for local integrin-dependent activation.
Failure of Homeostatic Microglial Identity
Without NRROS-dependent TGF-beta1 signalling, microglia do not express the homeostatic microglial signature (Sall1 in the mouse; P2Y12 and TMEM119 in human brain) and adopt a reactive phenotype. In the one autopsied child with truncating variants, the accumulating foamy myeloid cells lacked the homeostatic microglial markers P2Y12 and TMEM119.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
microglia development GO:0014005 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased microglia development (GO:0014005). GO:0014005 is a biological process from the Gene Ontology. microglial cell activation GO:0001774 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased microglial cell activation (GO:0001774). GO:0001774 is a biological process from the Gene Ontology.
Animal models
Nrros knockout mouse Mouse recapitulates Loss of the microglial identity programme in the absence of NRROS.
Lrrc33 knockout mouse Mouse rescues Whole bone marrow transplantation replaces Lrrc33-deficient microglia with wild-type cells and halts disease progression.
Downstream
Perivascular Foamy Macrophage Accumulation
Neuronal Loss and Reactive Gliosis
Deep White Matter Myelin Loss
Show evidence (3 references)
PMID:28459434 SUPPORT Model organism
"NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function."
Nrros-deficient mice fail to express the microglial identity genes.
PMID:29909984 SUPPORT Model organism
"GSEA thus provided independent, hypothesis-free support for the requirement of LRRC33 for TGF-β signaling in microglia and for the reactive phenotype of Lrrc33−/− microglia."
Links the loss of microglial TGF-beta signalling to the reactive microglial state in Lrrc33-deficient mice.
PMID:32100099 SUPPORT Human clinical
"did not immunoreact with CD163, Iba1, NRROS, CD3, P2Y12, or TMEM119"
In patient post-mortem brain the accumulating myeloid cells lacked the homeostatic microglial markers P2Y12 and TMEM119.
Perivascular Foamy Macrophage Accumulation
CD68-positive, MHC class II-positive foamy macrophages accumulate, mostly around vessels, throughout the cerebral and cerebellar white matter and the descending corticospinal tracts. In Nrros-deficient mice, perivascular macrophage-like myeloid cells take the place of normal microglia. The foamy cells are p22phox-positive, which is relevant to the separate NRROS role as a negative regulator of NOX2.
perivascular macrophage CL:0000881 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves perivascular macrophage (CL:0000881). CL:0000881 is a cell type from the Cell Ontology. foamy macrophage CL:0000517 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves foamy macrophage, annotated with macrophage derived foam cell (CL:0000517). CL:0000517 is a cell type from the Cell Ontology.
Show evidence (3 references)
PMID:32100099 SUPPORT Human clinical
"The most striking pathological finding was the accumulation of foamy macrophages, predominantly in a perivascular distribution, throughout the white matter"
Post-mortem neuropathology of an affected child.
PMID:35099671 SUPPORT Human clinical
"Pathological examination revealed both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages."
Independent autopsy finding of foamy macrophage infiltration.
PMID:28459434 SUPPORT Model organism
"Instead, perivascular macrophage-like myeloid cells populate the Nrros-/- CNS."
Mouse knockout shows the replacement of microglia by perivascular macrophage-like cells.
Neuronal Loss and Reactive Gliosis
Widespread neuronal loss with reactive gliosis in cortical and deep grey matter, cerebellum and brainstem, producing the progressive cerebral atrophy seen on serial imaging. One autopsy also found abnormal mitochondrial ultrastructure on electron microscopy.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
astrocyte activation GO:0048143 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased astrocyte activation (GO:0048143). GO:0048143 is a biological process from the Gene Ontology.
Animal models
Nrros knockout mouse Mouse partially recapitulates Astrogliosis is present, but this knockout showed no neuronal loss.
Downstream
Drug-resistant epilepsy
Developmental regression
Cerebral atrophy
Dystrophic Brain Calcification
Show evidence (3 references)
PMID:32100099 SUPPORT Human clinical
"There was widespread neuronal loss with reactive gliosis throughout the grey matter"
Post-mortem neuropathology of an affected child.
PMID:29909984 SUPPORT Model organism
"Losses of neurons, myelin and axons in Lrrc33−/− mice provide a cellular mechanistic basis for impaired motor coordination and ascending paraparesis."
Neuronal loss in the Lrrc33-deficient mouse.
PMID:35099671 SUPPORT Human clinical
"This is the first reported case of NRROS variants with a mitochondrial ultrastructure abnormality noted on electron microscopy analysis of post-mortem tissue."
Records a mitochondrial ultrastructural abnormality in degenerating brain tissue; reported in one child and not yet replicated.
Deep White Matter Myelin Loss
Reduced myelin in the deep cerebral white matter, with relative preservation of subcortical U fibres, and loss of myelinated axons in the corticospinal tracts.
oligodendrocyte CL:0000128 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oligodendrocyte (CL:0000128). CL:0000128 is a cell type from the Cell Ontology.
myelination GO:0042552 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myelination (GO:0042552). GO:0042552 is a biological process from the Gene Ontology.
Animal models
Lrrc33 knockout mouse Mouse partially recapitulates Myelin and axon loss in the spinal cord, brainstem and corticospinal tract.
Downstream
Reduced cerebral white matter volume
Delayed myelination
Show evidence (2 references)
PMID:32100099 SUPPORT Human clinical
"There was reduced myelin basic protein (MBP) expression in the white matter (Fig. 2g) compared to age-matched controls, although there was preservation of U fibers."
Post-mortem white matter findings in an affected child.
PMID:29909984 SUPPORT Model organism
"Progressive paraparesis was associated with loss of myelin and axons in the spinal cord and brainstem."
Myelin and axon loss in the Lrrc33-deficient mouse.
Dystrophic Brain Calcification
Punctate and linear calcification of the neuropil, typically in the deep and subcortical white matter and at the grey-white junction, which increases as the disease progresses. Neuropathology describes it as dystrophic, i.e. secondary to tissue damage; how loss of NRROS leads to calcification has not been directly studied.
Downstream
Intracranial calcification
Show evidence (2 references)
PMID:32100099 SUPPORT Human clinical
"Focal calcification was noted in the neuropil."
Post-mortem confirmation of parenchymal calcification.
PMID:35099671 SUPPORT Human clinical
"Pathological examination revealed both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages."
The calcification is characterized as dystrophic at autopsy.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for NRROS-Related Microgliopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Head and Neck 1
Acquired microcephaly Progressive microcephaly HP:0000253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acquired microcephaly, annotated with Progressive microcephaly (HP:0000253). HP:0000253 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35716448 SUPPORT Human clinical
"Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis."
Acquired microcephaly is listed as a diagnostic clue.
PMID:35099671 SUPPORT Human clinical
"There were concerns of regression and decelerating head growth and at 12 months she was diagnosed with hypotonia and failure-to-thrive."
Decelerating head growth after normal early development.
Musculoskeletal 2
Intracranial calcification FREQUENT HP:0430048 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial calcification (HP:0430048). HP:0430048 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35716448 SUPPORT Human clinical
"Intracranial calcifications were described in eight of eleven children."
Frequency (8/11) in a systematic review.
PMID:35716448 SUPPORT Human clinical
"Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis."
Characteristic distribution of the calcification.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39422130 SUPPORT Human clinical
"normal early development followed by regression of milestones, dysmorphism, microcephaly, refractory seizures, absent deep tendon reflexes, and hypotonia"
Hypotonia in a case report.
PMID:35099671 SUPPORT Human clinical
"There were concerns of regression and decelerating head growth and at 12 months she was diagnosed with hypotonia and failure-to-thrive."
Hypotonia in a second case report.
Nervous System 11
Drug-resistant epilepsy VERY_FREQUENT Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Drug-resistant epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Bound to HP:0001250 Seizure because HPO has no drug-resistant or refractory epilepsy term: ols:hp searches for l~drug-resistant and l~refractory return no epilepsy term.
Show evidence (2 references)
PMID:35716448 SUPPORT Human clinical
"All had a history of drug-resistant epilepsy, with 3 having epileptic spasms."
Systematic review of 11 patients.
PMID:32197075 SUPPORT Human clinical
"the onset of seizures occurred within the first year of life, followed by developmental regression"
Seizure onset in infancy across six individuals.
Epileptic spasms OCCASIONAL HP:0011097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic spasms, annotated with Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35716448 SUPPORT Human clinical
"All had a history of drug-resistant epilepsy, with 3 having epileptic spasms."
Three of eleven reviewed children had epileptic spasms.
Myoclonic seizures HP:0032794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonic seizures, annotated with Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35099671 SUPPORT Human clinical
"At 16 months she developed myoclonic epilepsy that proved to be refractory."
Single case report; frequency not established.
Developmental regression VERY_FREQUENT HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32197075 SUPPORT Human clinical
"All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination."
Six affected individuals from four families.
PMID:35716448 SUPPORT Human clinical
"The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months."
Timing of regression in a systematic review.
Cerebral atrophy VERY_FREQUENT HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebral atrophy, annotated with Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35716448 SUPPORT Human clinical
"Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children."
Neuroimaging in all reviewed patients.
Reduced cerebral white matter volume VERY_FREQUENT HP:0034295 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced cerebral white matter volume (HP:0034295). HP:0034295 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35716448 SUPPORT Human clinical
"Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children."
White matter loss on imaging in all reviewed patients.
Delayed myelination HP:0012448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed myelination (HP:0012448). HP:0012448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32197075 SUPPORT Human clinical
"All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination."
Delayed myelination in six affected individuals.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular dilatation, annotated with Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32100099 SUPPORT Human clinical
"As disease progressed, repeat imaging revealed increased calcification, severe generalized atrophy with ventricular dilatation, and diffuse signal changes in cerebral and cerebellar white matter."
Ventricular dilatation accompanies the progressive atrophy.
Thin corpus callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39422130 SUPPORT Human clinical
"Neuroimaging features included cerebral atrophy, thin corpus callosum, and white matter calcifications."
Imaging finding in a case report.
PMID:35099671 SUPPORT Human clinical
"Repeat MRI at 20 months showed a thin corpus callosum"
Imaging finding in a second case report.
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent deep tendon reflexes, annotated with Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39422130 SUPPORT Human clinical
"areflexia and dysmorphic features have not been reported before with this entity"
Reported in a single child and explicitly described by the authors as new to the phenotype.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40463927 SUPPORT Human clinical
"presenting with drug-resistant epilepsy, rapid developmental regression, microcephaly, dystonia, and intracranial calcifications"
Dystonia in a single case report.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35099671 SUPPORT Human clinical
"There were concerns of regression and decelerating head growth and at 12 months she was diagnosed with hypotonia and failure-to-thrive."
Single case report; frequency not established.
🧬

Genetic Associations

1
NRROS (Causative)
Gene: NRROS hgnc:24613 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NRROS (hgnc:24613). hgnc:24613 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:32100099 SUPPORT Human clinical
"Exome sequencing identified homozygous NRROS variants in the affected children from both families"
Homozygous NRROS variants in affected children.
PMID:42806633 SUPPORT Human clinical
"The mutational spectrum of NRROS disorder is characterized primarily by loss-of-function variants, with only four missense variants identified in affected individuals to date p.(Leu10Pro), p.(Leu62Pro), p.(Leu86Pro), and p.(Asn408His)."
Summarizes the mutational spectrum across reported families.
PMID:35716448 SUPPORT Human clinical
"The most common reported genetic variation was c.1981delC; (p.Leu661Serfs*97) observed in two families (likely due to a founder effect)."
Identifies the recurrent, probably founder, frameshift allele.
💊

Medical Actions

3
Antiseizure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest. valproic acid CHEBI:39867 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valproic acid (CHEBI:39867). CHEBI:39867 is a therapeutic agent from Chemical Entities of Biological Interest. clobazam CHEBI:31413 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clobazam (CHEBI:31413). CHEBI:31413 is a therapeutic agent from Chemical Entities of Biological Interest. topiramate CHEBI:63631 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses topiramate (CHEBI:63631). CHEBI:63631 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Seizures are treated with standard antiseizure medications, but they are drug-resistant in every reported child. In one case focal seizures were initially controlled with levetiracetam, then failed to respond to valproic acid, clobazam and topiramate. No disease-modifying therapy has been reported; care is otherwise supportive.
Mechanism Target:
INHIBITS Drug-resistant epilepsy — Symptomatic seizure suppression; response is at best transient because the epilepsy is drug-resistant.
Show evidence (3 references)
PMID:40463927 SUPPORT Human clinical
"She was diagnosed with focal epilepsy that was initially well-controlled with levetiracetam."
Transient seizure control with levetiracetam in one child.
PMID:40463927 REFUTE Human clinical
"Seizures failed to be controlled with valproic acid, clobazam and topiramate and the patient was started on a ketogenic diet."
Several antiseizure medications failed in the same child.
PMID:35716448 REFUTE Human clinical
"All had a history of drug-resistant epilepsy, with 3 having epileptic spasms."
Every reviewed child had epilepsy that medication did not control.
Ketogenic Diet
Action: ketogenic dietNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is ketogenic diet, annotated with Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
Tried in one child after medications failed; seizure control was partial, and the diet was stopped because of a suboptimal response and resistant metabolic acidosis.
Mechanism Target:
INHIBITS Drug-resistant epilepsy — Partial and unsustained seizure reduction in a single case.
Show evidence (1 reference)
PMID:40463927 SUPPORT Human clinical
"She showed partial seizure control on the ketogenic diet; however, it was discontinued due to suboptimal response and resistant metabolic acidosis."
Single-case report of partial benefit and intolerance.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Autosomal recessive inheritance gives carrier parents a 25% recurrence risk in each pregnancy; carrier testing of parents and siblings is possible once the familial variants are known.
Show evidence (1 reference)
PMID:40463927 SUPPORT Human clinical
"Early recognition of this disorder is essential for accurate diagnosis and genetic counseling, particularly given its autosomal recessive inheritance and a 25% recurrence risk in future pregnancies."
States the counseling rationale and recurrence risk.
🔬

Diagnosis

2
Exome Sequencing for Biallelic NRROS Variants (Biallelic (homozygous or compound heterozygous) pathogenic NRROS variants)
The diagnosis is molecular: every reported family was ascertained by exome sequencing, which identified biallelic NRROS variants. Testing is suggested by infantile drug-resistant epilepsy with regression and the imaging signature below.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:32100099 SUPPORT Human clinical
"Exome sequencing identified homozygous NRROS variants in the affected children from both families"
The founding families were diagnosed by exome sequencing.
PMID:40463927 SUPPORT Human clinical
"This case underscores the importance of considering NRROS-related microgliopathy in children with early-onset neurodegeneration, drug-resistant epilepsy, and intracranial calcifications, enabling targeted genetic testing, diagnosis, and counseling."
States the clinical triad that should prompt NRROS testing.
Neuroimaging Signature of Calcification and Atrophy
CT shows punctate or linear calcification in the deep and subcortical white matter and at the grey-white matter junction; serial MRI shows progressive cerebral atrophy, white matter volume loss and delayed myelination. Together with acquired microcephaly, the pattern is a diagnostic clue.
computed tomography of the head NCIT:C17204 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:35716448 SUPPORT Human clinical
"Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis."
Names the diagnostic imaging and growth clues.
PMID:35099671 SUPPORT Human clinical
"Computed tomography (CT) at 18 months confirmed calcifications in the subcortical and deep white matter"
CT is the modality that confirms the calcification.
📈

Progression

3
Presymptomatic infancy
Age: Birth to about 8-12 months
Pregnancy, delivery and early development are usually unremarkable; some children have mild early delay.
Show evidence (1 reference)
PMID:35716448 SUPPORT Human clinical
"Early development was normal in seven of these eleven children."
Early development was normal in most reviewed children.
Seizure onset and regression
Age: First two years of life (median 12 months)
Drug-resistant seizures begin, followed by loss of acquired skills, deceleration of head growth and progressive calcification and atrophy on imaging.
Show evidence (1 reference)
PMID:35716448 SUPPORT Human clinical
"The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months."
Timing of seizure onset and regression.
Terminal neurodegeneration
Age: Death typically between 2 and 4 years (median 36 months)
Neurological decline is progressive; reported deaths occurred in early childhood, sometimes precipitated by infection and respiratory complications.
Show evidence (2 references)
PMID:32100099 SUPPORT Human clinical
"in the second year of life, they experienced the onset of refractory seizures and neurodegeneration, leading to death between the ages of 27 and 36 months"
Age at death in the original three children.
PMID:35099671 SUPPORT Human clinical
"Neurological regression was exacerbated by repeat infections and respiratory distress and the child died at 3 years and 10 months."
Course to death in a further child.
🐁

Animal Models

2
Nrros knockout mouse
Germline Nrros-deficient mice develop motor defects and die before 6 months of age; normal microglia are absent and perivascular macrophage-like myeloid cells populate the CNS.
Species
Mouse
Genotype
Nrros-/-
Publication
PMID:28459434
Pathograph links
Failure of Homeostatic Microglial Identity recapitulates fidelity: high observes: cellular Loss of the microglial identity programme in the absence of NRROS.
Readouts
Microglial identity gene expression (Sall1)
Direction: DECREASED
Interpretation: Microglia fail to express the identity transcription factor Sall1.
Show evidence (1 reference)
PMID:28459434 SUPPORT Model organism
"NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function."
Reports the loss of microglial identity gene expression.
Show evidence (1 reference)
PMID:28459434 SUPPORT Model organism
"Nrros-/- mice display astrogliosis and lack normal CD11bhiCD45lo microglia"
The knockout lacks normal microglia.
Neuronal Loss and Reactive Gliosis partially recapitulates fidelity: moderate observes: tissue Astrogliosis is present, but this knockout showed no neuronal loss.
Limitations: The original Nrros-/- report found astrogliosis without detectable demyelination or neuronal loss, whereas patients show widespread neuronal loss; the mice also do not develop seizures or brain calcification as described in that report.
Show evidence (1 reference)
PMID:28459434 SUPPORT Model organism
"Nrros-/- mice display astrogliosis and lack normal CD11bhiCD45lo microglia, but they show no detectable demyelination or neuronal loss."
Astrogliosis without neuronal loss in this model.
Lrrc33 knockout mouse
Lrrc33-deficient mice have reactive microglia, develop ascending paraparesis after 2 months with loss of neurons, myelin and axons, and die by 5 months. Whole bone marrow transplantation repopulates the brain with wild-type microglia and halts progression.
Species
Mouse
Genotype
Lrrc33-/-
Publication
PMID:29909984
Pathograph links
Loss of Microglial Autocrine TGF-beta1 Activation recapitulates fidelity: high observes: cellular Microglia lacking LRRC33 lose TGF-beta signalling.
Show evidence (1 reference)
PMID:29909984 SUPPORT Model organism
"GSEA thus provided independent, hypothesis-free support for the requirement of LRRC33 for TGF-β signaling in microglia and for the reactive phenotype of Lrrc33−/− microglia."
Transcriptomic evidence of lost TGF-beta signalling in microglia.
Deep White Matter Myelin Loss partially recapitulates fidelity: moderate observes: tissue Myelin and axon loss in the spinal cord, brainstem and corticospinal tract.
Limitations: The mouse presents as an ascending paraparesis with spinal cord involvement, whereas children present with drug-resistant epilepsy, regression and cerebral calcification.
Readouts
Spinal cord and brainstem myelin and axon content
Direction: DECREASED
Interpretation: Histological correlate of the white matter degeneration node.
Show evidence (1 reference)
PMID:29909984 SUPPORT Model organism
"Progressive paraparesis was associated with loss of myelin and axons in the spinal cord and brainstem."
Reports myelin and axon loss.
Show evidence (1 reference)
PMID:29909984 SUPPORT Model organism
"Lrrc33−/− mice appear normal up to 2 months of age, but then develop ascending paraparesis that is characterized by demyelination, loss of axons, loss of neurons in the somatomotor cortex and spinal cord, and death by 5 months."
Establishes the model as informative for white matter degeneration.
Failure of Homeostatic Microglial Identity rescues fidelity: moderate observes: organism Whole bone marrow transplantation replaces Lrrc33-deficient microglia with wild-type cells and halts disease progression.
Limitations: Shown only in mice after lethal irradiation; no transplantation or microglial replacement has been reported in a patient.
Show evidence (1 reference)
PMID:29909984 SUPPORT Model organism
"Whole bone marrow transplantation results in selective repopulation of Lrrc33-/- brains with WT microglia and halts disease progression."
Mouse rescue by replacing NRROS-deficient microglia.
{ }

Source YAML

click to show 
name: NRROS-Related Microgliopathy
creation_date: "2026-11-04T00:00:00Z"
category: Mendelian
synonyms:
- seizures, early-onset, with neurodegeneration and brain calcifications
- SENEBAC
- NRROS-related SENEBAC syndrome
disease_term:
  preferred_term: Seizures, early-onset, with neurodegeneration and brain calcifications
  term:
    id: MONDO:0030033
    label: seizures, early-onset, with neurodegeneration and brain calcifications
parents:
- microgliopathy
- neurodegenerative disease
description: >-
  NRROS-related microgliopathy (seizures, early-onset, with neurodegeneration
  and brain calcifications; SENEBAC, MIM 618875) is an autosomal recessive,
  usually lethal infantile neurodegenerative disorder caused by biallelic
  loss-of-function variants in NRROS (negative regulator of reactive oxygen
  species, also called LRRC33). NRROS is a leucine-rich repeat transmembrane
  protein expressed by microglia and CNS perivascular macrophages that binds
  latent TGF-beta1 and presents it at the cell surface, where integrin
  alpha-v beta-8 releases the active cytokine to signal locally on the
  presenting microglial cell. Without NRROS, microglia lose this autocrine
  TGF-beta1 signal and do not acquire or maintain their homeostatic identity.
  Development is usually normal or mildly delayed until seizures begin in the
  first two years of life. Seizures are drug-resistant, and children then lose
  developmental skills, develop acquired microcephaly, and show progressive
  cerebral atrophy, white matter loss and punctate or serpiginous
  calcification at the grey-white matter junction. Most reported children have
  died by about three years of age.
notes: >-
  The entry name follows recurring literature use of "NRROS-related
  microgliopathy" (PMID:35716448, PMID:40463927); the MONDO and OMIM label is
  kept as a synonym. No GeneReviews chapter covers this disease (Bookshelf
  index snapshot 2026-09-10).
pathophysiology:
- name: NRROS Loss of Function
  description: >-
    Biallelic truncating or destabilising variants in NRROS abolish the
    protein's ability to anchor latent TGF-beta1 at the surface of microglia
    and perivascular macrophages.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NRROS
    term:
      id: hgnc:24613
      label: NRROS
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  molecular_functions:
  - preferred_term: latent TGF-beta1 binding
    modifier: DECREASED
    term:
      id: GO:0050431
      label: transforming growth factor beta binding
  evidence:
  - reference: PMID:32197075
    reference_title: "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: IN_VITRO
    snippet: "Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface"
    explanation: >-
      States the molecular function lost with NRROS, binding and surface
      anchoring of latent TGF-beta1, which is what the GO binding term records.
  - reference: PMID:32197075
    reference_title: "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS"
    explanation: >-
      Disease-associated NRROS variants lose the latent TGF-beta1 anchoring
      function in a cell assay.
  downstream:
  - target: Loss of Microglial Autocrine TGF-beta1 Activation
    causal_link_type: DIRECT
- name: Loss of Microglial Autocrine TGF-beta1 Activation
  description: >-
    NRROS is the milieu molecule that presents latent TGF-beta1 on the
    microglial surface for integrin alpha-v beta-8-dependent activation. The
    activated cytokine acts on the presenting cell and its immediate
    neighbours, so loss of NRROS removes TGF-beta signalling from microglia.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: TGF-beta receptor signaling in microglia
    modifier: DECREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:29909984
    reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation"
    explanation: >-
      Establishes NRROS/LRRC33 as the microglial surface presenter of latent
      TGF-beta for local integrin-dependent activation.
  downstream:
  - target: Failure of Homeostatic Microglial Identity
    causal_link_type: DIRECT
- name: Failure of Homeostatic Microglial Identity
  description: >-
    Without NRROS-dependent TGF-beta1 signalling, microglia do not express the
    homeostatic microglial signature (Sall1 in the mouse; P2Y12 and TMEM119 in
    human brain) and adopt a reactive phenotype. In the one autopsied child
    with truncating variants, the accumulating foamy myeloid cells lacked the
    homeostatic microglial markers P2Y12 and TMEM119.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: microglia development
    modifier: DECREASED
    term:
      id: GO:0014005
      label: microglia development
  - preferred_term: microglial cell activation
    modifier: INCREASED
    term:
      id: GO:0001774
      label: microglial cell activation
  evidence:
  - reference: PMID:28459434
    reference_title: "Mice deficient in NRROS show abnormal microglial development and neurological disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function."
    explanation: >-
      Nrros-deficient mice fail to express the microglial identity genes.
  - reference: PMID:29909984
    reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "GSEA thus provided independent, hypothesis-free support for the requirement of LRRC33 for TGF-β signaling in microglia and for the reactive phenotype of Lrrc33−/− microglia."
    explanation: >-
      Links the loss of microglial TGF-beta signalling to the reactive
      microglial state in Lrrc33-deficient mice.
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "did not immunoreact with CD163, Iba1, NRROS, CD3, P2Y12, or TMEM119"
    explanation: >-
      In patient post-mortem brain the accumulating myeloid cells lacked the
      homeostatic microglial markers P2Y12 and TMEM119.
  downstream:
  - target: Perivascular Foamy Macrophage Accumulation
  - target: Neuronal Loss and Reactive Gliosis
  - target: Deep White Matter Myelin Loss
- name: Perivascular Foamy Macrophage Accumulation
  description: >-
    CD68-positive, MHC class II-positive foamy macrophages accumulate, mostly
    around vessels, throughout the cerebral and cerebellar white matter and
    the descending corticospinal tracts. In Nrros-deficient mice, perivascular
    macrophage-like myeloid cells take the place of normal microglia. The
    foamy cells are p22phox-positive, which is relevant to the separate NRROS
    role as a negative regulator of NOX2.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: perivascular macrophage
    term:
      id: CL:0000881
      label: perivascular macrophage
  - preferred_term: foamy macrophage
    term:
      id: CL:0000517
      label: macrophage derived foam cell
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most striking pathological finding was the accumulation of foamy macrophages, predominantly in a perivascular distribution, throughout the white matter"
    explanation: Post-mortem neuropathology of an affected child.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathological examination revealed both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages."
    explanation: Independent autopsy finding of foamy macrophage infiltration.
  - reference: PMID:28459434
    reference_title: "Mice deficient in NRROS show abnormal microglial development and neurological disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Instead, perivascular macrophage-like myeloid cells populate the Nrros-/- CNS."
    explanation: Mouse knockout shows the replacement of microglia by perivascular macrophage-like cells.
- name: Neuronal Loss and Reactive Gliosis
  description: >-
    Widespread neuronal loss with reactive gliosis in cortical and deep grey
    matter, cerebellum and brainstem, producing the progressive cerebral
    atrophy seen on serial imaging. One autopsy also found abnormal
    mitochondrial ultrastructure on electron microscopy.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: astrocyte activation
    modifier: INCREASED
    term:
      id: GO:0048143
      label: astrocyte activation
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was widespread neuronal loss with reactive gliosis throughout the grey matter"
    explanation: Post-mortem neuropathology of an affected child.
  - reference: PMID:29909984
    reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Losses of neurons, myelin and axons in Lrrc33−/− mice provide a cellular mechanistic basis for impaired motor coordination and ascending paraparesis."
    explanation: Neuronal loss in the Lrrc33-deficient mouse.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first reported case of NRROS variants with a mitochondrial ultrastructure abnormality noted on electron microscopy analysis of post-mortem tissue."
    explanation: >-
      Records a mitochondrial ultrastructural abnormality in degenerating
      brain tissue; reported in one child and not yet replicated.
  downstream:
  - target: Drug-resistant epilepsy
  - target: Developmental regression
  - target: Cerebral atrophy
  - target: Dystrophic Brain Calcification
- name: Deep White Matter Myelin Loss
  description: >-
    Reduced myelin in the deep cerebral white matter, with relative
    preservation of subcortical U fibres, and loss of myelinated axons in the
    corticospinal tracts.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was reduced myelin basic protein (MBP) expression in the white matter (Fig. 2g) compared to age-matched controls, although there was preservation of U fibers."
    explanation: Post-mortem white matter findings in an affected child.
  - reference: PMID:29909984
    reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Progressive paraparesis was associated with loss of myelin and axons in the spinal cord and brainstem."
    explanation: Myelin and axon loss in the Lrrc33-deficient mouse.
  downstream:
  - target: Reduced cerebral white matter volume
  - target: Delayed myelination
- name: Dystrophic Brain Calcification
  description: >-
    Punctate and linear calcification of the neuropil, typically in the deep
    and subcortical white matter and at the grey-white junction, which
    increases as the disease progresses. Neuropathology describes it as
    dystrophic, i.e. secondary to tissue damage; how loss of NRROS leads to
    calcification has not been directly studied.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal calcification was noted in the neuropil."
    explanation: Post-mortem confirmation of parenchymal calcification.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathological examination revealed both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages."
    explanation: The calcification is characterized as dystrophic at autopsy.
  downstream:
  - target: Intracranial calcification
phenotypes:
- name: Drug-resistant epilepsy
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Seizures begin in the first two years of life (median 12 months) and are
    resistant to antiseizure medication in every reported child.
  notes: >-
    Bound to HP:0001250 Seizure because HPO has no drug-resistant or refractory
    epilepsy term: ols:hp searches for l~drug-resistant and l~refractory
    return no epilepsy term.
  phenotype_term:
    preferred_term: Drug-resistant epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had a history of drug-resistant epilepsy, with 3 having epileptic spasms."
    explanation: Systematic review of 11 patients.
  - reference: PMID:32197075
    reference_title: "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the onset of seizures occurred within the first year of life, followed by developmental regression"
    explanation: Seizure onset in infancy across six individuals.
- name: Epileptic spasms
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Epileptic spasms
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had a history of drug-resistant epilepsy, with 3 having epileptic spasms."
    explanation: Three of eleven reviewed children had epileptic spasms.
- name: Myoclonic seizures
  category: Neurological
  phenotype_term:
    preferred_term: Myoclonic seizures
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 16 months she developed myoclonic epilepsy that proved to be refractory."
    explanation: Single case report; frequency not established.
- name: Developmental regression
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Development is normal or mildly delayed before seizure onset; regression
    follows, with median onset at about 12 months.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:32197075
    reference_title: "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination."
    explanation: Six affected individuals from four families.
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months."
    explanation: Timing of regression in a systematic review.
- name: Intracranial calcification
  category: Neurological
  frequency: FREQUENT
  description: >-
    Punctate or serpiginous calcification at the grey-white matter junction
    and in the deep and subcortical white matter.
  phenotype_term:
    preferred_term: Intracranial calcification
    term:
      id: HP:0430048
      label: Intracranial calcification
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intracranial calcifications were described in eight of eleven children."
    explanation: Frequency (8/11) in a systematic review.
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis."
    explanation: Characteristic distribution of the calcification.
- name: Cerebral atrophy
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Progressive cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children."
    explanation: Neuroimaging in all reviewed patients.
- name: Reduced cerebral white matter volume
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Reduced cerebral white matter volume
    term:
      id: HP:0034295
      label: Reduced cerebral white matter volume
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children."
    explanation: White matter loss on imaging in all reviewed patients.
- name: Delayed myelination
  category: Neurological
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:32197075
    reference_title: "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination."
    explanation: Delayed myelination in six affected individuals.
- name: Ventriculomegaly
  category: Neurological
  phenotype_term:
    preferred_term: Ventricular dilatation
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As disease progressed, repeat imaging revealed increased calcification, severe generalized atrophy with ventricular dilatation, and diffuse signal changes in cerebral and cerebellar white matter."
    explanation: Ventricular dilatation accompanies the progressive atrophy.
- name: Thin corpus callosum
  category: Neurological
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:39422130
    reference_title: "Expanding the Phenotype of NRROS -Related SENEBAC Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging features included cerebral atrophy, thin corpus callosum, and white matter calcifications."
    explanation: Imaging finding in a case report.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeat MRI at 20 months showed a thin corpus callosum"
    explanation: Imaging finding in a second case report.
- name: Acquired microcephaly
  category: Neurological
  phenotype_term:
    preferred_term: Acquired microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis."
    explanation: Acquired microcephaly is listed as a diagnostic clue.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were concerns of regression and decelerating head growth and at 12 months she was diagnosed with hypotonia and failure-to-thrive."
    explanation: Decelerating head growth after normal early development.
- name: Hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39422130
    reference_title: "Expanding the Phenotype of NRROS -Related SENEBAC Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal early development followed by regression of milestones, dysmorphism, microcephaly, refractory seizures, absent deep tendon reflexes, and hypotonia"
    explanation: Hypotonia in a case report.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were concerns of regression and decelerating head growth and at 12 months she was diagnosed with hypotonia and failure-to-thrive."
    explanation: Hypotonia in a second case report.
- name: Failure to thrive
  category: Growth
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were concerns of regression and decelerating head growth and at 12 months she was diagnosed with hypotonia and failure-to-thrive."
    explanation: Single case report; frequency not established.
- name: Areflexia
  category: Neurological
  phenotype_term:
    preferred_term: Absent deep tendon reflexes
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:39422130
    reference_title: "Expanding the Phenotype of NRROS -Related SENEBAC Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "areflexia and dysmorphic features have not been reported before with this entity"
    explanation: >-
      Reported in a single child and explicitly described by the authors as
      new to the phenotype.
- name: Dystonia
  category: Neurological
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:40463927
    reference_title: "Neurodegeneration, Intracranial Calcifications, Microcephaly and Drug-Resistant Epilepsy Caused by a Novel Homozygous Missense Variant in the NRROS Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with drug-resistant epilepsy, rapid developmental regression, microcephaly, dystonia, and intracranial calcifications"
    explanation: Dystonia in a single case report.
progression:
- phase: Presymptomatic infancy
  age_range: Birth to about 8-12 months
  notes: >-
    Pregnancy, delivery and early development are usually unremarkable;
    some children have mild early delay.
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early development was normal in seven of these eleven children."
    explanation: Early development was normal in most reviewed children.
- phase: Seizure onset and regression
  age_range: First two years of life (median 12 months)
  notes: >-
    Drug-resistant seizures begin, followed by loss of acquired skills,
    deceleration of head growth and progressive calcification and atrophy on
    imaging.
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months."
    explanation: Timing of seizure onset and regression.
- phase: Terminal neurodegeneration
  age_range: Death typically between 2 and 4 years (median 36 months)
  notes: >-
    Neurological decline is progressive; reported deaths occurred in early
    childhood, sometimes precipitated by infection and respiratory
    complications.
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in the second year of life, they experienced the onset of refractory seizures and neurodegeneration, leading to death between the ages of 27 and 36 months"
    explanation: Age at death in the original three children.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological regression was exacerbated by repeat infections and respiratory distress and the child died at 3 years and 10 months."
    explanation: Course to death in a further child.
diagnosis:
- name: Exome Sequencing for Biallelic NRROS Variants
  description: >-
    The diagnosis is molecular: every reported family was ascertained by exome
    sequencing, which identified biallelic NRROS variants. Testing is suggested
    by infantile drug-resistant epilepsy with regression and the imaging
    signature below.
  presence: Biallelic (homozygous or compound heterozygous) pathogenic NRROS variants
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified homozygous NRROS variants in the affected children from both families"
    explanation: The founding families were diagnosed by exome sequencing.
  - reference: PMID:40463927
    reference_title: "Neurodegeneration, Intracranial Calcifications, Microcephaly and Drug-Resistant Epilepsy Caused by a Novel Homozygous Missense Variant in the NRROS Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case underscores the importance of considering NRROS-related microgliopathy in children with early-onset neurodegeneration, drug-resistant epilepsy, and intracranial calcifications, enabling targeted genetic testing, diagnosis, and counseling."
    explanation: States the clinical triad that should prompt NRROS testing.
- name: Neuroimaging Signature of Calcification and Atrophy
  description: >-
    CT shows punctate or linear calcification in the deep and subcortical
    white matter and at the grey-white matter junction; serial MRI shows
    progressive cerebral atrophy, white matter volume loss and delayed
    myelination. Together with acquired microcephaly, the pattern is a
    diagnostic clue.
  diagnosis_term:
    preferred_term: computed tomography of the head
    term:
      id: NCIT:C17204
      label: Computed Tomography
  evidence:
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis."
    explanation: Names the diagnostic imaging and growth clues.
  - reference: PMID:35099671
    reference_title: "Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Computed tomography (CT) at 18 months confirmed calcifications in the subcortical and deep white matter"
    explanation: CT is the modality that confirms the calcification.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >-
    Seizures are treated with standard antiseizure medications, but they are
    drug-resistant in every reported child. In one case focal seizures were
    initially controlled with levetiracetam, then failed to respond to
    valproic acid, clobazam and topiramate. No disease-modifying therapy has
    been reported; care is otherwise supportive.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: clobazam
      term:
        id: CHEBI:31413
        label: clobazam
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
  target_mechanisms:
  - target: Drug-resistant epilepsy
    treatment_effect: INHIBITS
    description: >-
      Symptomatic seizure suppression; response is at best transient because
      the epilepsy is drug-resistant.
  evidence:
  - reference: PMID:40463927
    reference_title: "Neurodegeneration, Intracranial Calcifications, Microcephaly and Drug-Resistant Epilepsy Caused by a Novel Homozygous Missense Variant in the NRROS Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was diagnosed with focal epilepsy that was initially well-controlled with levetiracetam."
    explanation: Transient seizure control with levetiracetam in one child.
  - reference: PMID:40463927
    reference_title: "Neurodegeneration, Intracranial Calcifications, Microcephaly and Drug-Resistant Epilepsy Caused by a Novel Homozygous Missense Variant in the NRROS Gene: A Case Report."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures failed to be controlled with valproic acid, clobazam and topiramate and the patient was started on a ketogenic diet."
    explanation: Several antiseizure medications failed in the same child.
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "All had a history of drug-resistant epilepsy, with 3 having epileptic spasms."
    explanation: Every reviewed child had epilepsy that medication did not control.
- name: Ketogenic Diet
  description: >-
    Tried in one child after medications failed; seizure control was partial,
    and the diet was stopped because of a suboptimal response and resistant
    metabolic acidosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: ketogenic diet
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Drug-resistant epilepsy
    treatment_effect: INHIBITS
    description: Partial and unsustained seizure reduction in a single case.
  evidence:
  - reference: PMID:40463927
    reference_title: "Neurodegeneration, Intracranial Calcifications, Microcephaly and Drug-Resistant Epilepsy Caused by a Novel Homozygous Missense Variant in the NRROS Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She showed partial seizure control on the ketogenic diet; however, it was discontinued due to suboptimal response and resistant metabolic acidosis."
    explanation: Single-case report of partial benefit and intolerance.
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance gives carrier parents a 25% recurrence
    risk in each pregnancy; carrier testing of parents and siblings is
    possible once the familial variants are known.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40463927
    reference_title: "Neurodegeneration, Intracranial Calcifications, Microcephaly and Drug-Resistant Epilepsy Caused by a Novel Homozygous Missense Variant in the NRROS Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early recognition of this disorder is essential for accurate diagnosis and genetic counseling, particularly given its autosomal recessive inheritance and a 25% recurrence risk in future pregnancies."
    explanation: States the counseling rationale and recurrence risk.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected children carry biallelic NRROS variants, homozygous in
    consanguineous families and compound heterozygous otherwise.
  evidence:
  - reference: PMID:32197075
    reference_title: "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report six individuals from four families with bi-allelic variants in NRROS."
    explanation: Biallelic variants in all affected individuals.
genetic:
- name: NRROS
  gene_term:
    preferred_term: NRROS
    term:
      id: hgnc:24613
      label: NRROS
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Most pathogenic variants are truncating (nonsense or frameshift). Four
    missense variants have been reported (p.Leu10Pro, p.Leu62Pro, p.Leu86Pro,
    p.Asn408His); in overexpression studies they alter NRROS subcellular
    distribution, and are predicted to disrupt signal-peptide cleavage,
    folding or N-glycosylation. The frameshift c.1981delC
    (p.Leu661Serfs*97) recurs in two families, probably as a founder allele.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_ebf06969-1af8-411f-bc64-7f1563851363-2023-09-15T160000.000Z
    evidence:
    - reference: CGGV:assertion_ebf06969-1af8-411f-bc64-7f1563851363-2023-09-15T160000.000Z
      reference_title: "NRROS / seizures, early-onset, with neurodegeneration and brain calcifications (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "NRROS | HGNC:24613 | seizures, early-onset, with neurodegeneration and brain calcifications | MONDO:0030033 | AR | Definitive"
      explanation: ClinGen classifies the NRROS-SENEBAC relationship as Definitive (AR).
  evidence:
  - reference: PMID:32100099
    reference_title: "Biallelic mutations in NRROS cause an early onset lethal microgliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified homozygous NRROS variants in the affected children from both families"
    explanation: Homozygous NRROS variants in affected children.
  - reference: PMID:42806633
    reference_title: "A homozygous missense variant in NRROS gene is associated with intracranial calcifications, neurodegeneration, and severe infantile epilepsy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutational spectrum of NRROS disorder is characterized primarily by loss-of-function variants, with only four missense variants identified in affected individuals to date p.(Leu10Pro), p.(Leu62Pro), p.(Leu86Pro), and p.(Asn408His)."
    explanation: Summarizes the mutational spectrum across reported families.
  - reference: PMID:35716448
    reference_title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common reported genetic variation was c.1981delC; (p.Leu661Serfs*97) observed in two families (likely due to a founder effect)."
    explanation: Identifies the recurrent, probably founder, frameshift allele.
animal_models:
- name: Nrros knockout mouse
  species: Mouse
  genotype: Nrros-/-
  publication: PMID:28459434
  description: >-
    Germline Nrros-deficient mice develop motor defects and die before 6
    months of age; normal microglia are absent and perivascular
    macrophage-like myeloid cells populate the CNS.
  modeled_mechanisms:
  - target: Failure of Homeostatic Microglial Identity
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Loss of the microglial identity programme in the absence of NRROS.
    readouts:
    - name: Microglial identity gene expression (Sall1)
      target: Failure of Homeostatic Microglial Identity
      direction: DECREASED
      interpretation: Microglia fail to express the identity transcription factor Sall1.
      evidence:
      - reference: PMID:28459434
        reference_title: "Mice deficient in NRROS show abnormal microglial development and neurological disorders."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function."
        explanation: Reports the loss of microglial identity gene expression.
    evidence:
    - reference: PMID:28459434
      reference_title: "Mice deficient in NRROS show abnormal microglial development and neurological disorders."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Nrros-/- mice display astrogliosis and lack normal CD11bhiCD45lo microglia"
      explanation: The knockout lacks normal microglia.
  - target: Neuronal Loss and Reactive Gliosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Astrogliosis is present, but this knockout showed no neuronal loss.
    limitations: >-
      The original Nrros-/- report found astrogliosis without detectable
      demyelination or neuronal loss, whereas patients show widespread
      neuronal loss; the mice also do not develop seizures or brain
      calcification as described in that report.
    evidence:
    - reference: PMID:28459434
      reference_title: "Mice deficient in NRROS show abnormal microglial development and neurological disorders."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Nrros-/- mice display astrogliosis and lack normal CD11bhiCD45lo microglia, but they show no detectable demyelination or neuronal loss."
      explanation: Astrogliosis without neuronal loss in this model.
- name: Lrrc33 knockout mouse
  species: Mouse
  genotype: Lrrc33-/-
  publication: PMID:29909984
  description: >-
    Lrrc33-deficient mice have reactive microglia, develop ascending
    paraparesis after 2 months with loss of neurons, myelin and axons, and
    die by 5 months. Whole bone marrow transplantation repopulates the brain
    with wild-type microglia and halts progression.
  modeled_mechanisms:
  - target: Loss of Microglial Autocrine TGF-beta1 Activation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Microglia lacking LRRC33 lose TGF-beta signalling.
    evidence:
    - reference: PMID:29909984
      reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "GSEA thus provided independent, hypothesis-free support for the requirement of LRRC33 for TGF-β signaling in microglia and for the reactive phenotype of Lrrc33−/− microglia."
      explanation: Transcriptomic evidence of lost TGF-beta signalling in microglia.
  - target: Deep White Matter Myelin Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Myelin and axon loss in the spinal cord, brainstem and corticospinal tract.
    limitations: >-
      The mouse presents as an ascending paraparesis with spinal cord
      involvement, whereas children present with drug-resistant epilepsy,
      regression and cerebral calcification.
    readouts:
    - name: Spinal cord and brainstem myelin and axon content
      target: Deep White Matter Myelin Loss
      direction: DECREASED
      interpretation: Histological correlate of the white matter degeneration node.
      evidence:
      - reference: PMID:29909984
        reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Progressive paraparesis was associated with loss of myelin and axons in the spinal cord and brainstem."
        explanation: Reports myelin and axon loss.
    evidence:
    - reference: PMID:29909984
      reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Lrrc33−/− mice appear normal up to 2 months of age, but then develop ascending paraparesis that is characterized by demyelination, loss of axons, loss of neurons in the somatomotor cortex and spinal cord, and death by 5 months."
      explanation: Establishes the model as informative for white matter degeneration.
  - target: Failure of Homeostatic Microglial Identity
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Whole bone marrow transplantation replaces Lrrc33-deficient microglia
      with wild-type cells and halts disease progression.
    limitations: >-
      Shown only in mice after lethal irradiation; no transplantation or
      microglial replacement has been reported in a patient.
    evidence:
    - reference: PMID:29909984
      reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Whole bone marrow transplantation results in selective repopulation of Lrrc33-/- brains with WT microglia and halts disease progression."
      explanation: Mouse rescue by replacing NRROS-deficient microglia.
discussions:
- discussion_id: nrros_microglial_replacement
  prompt: >-
    Could haematopoietic cell transplantation or another microglial
    replacement strategy halt disease in children with NRROS-related
    microgliopathy if given before neurodegeneration is advanced?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Homeostatic Microglial Identity
  - animal_models#Lrrc33 knockout mouse
  rationale: >-
    In Lrrc33-deficient mice, wild-type bone marrow repopulates the brain with
    wild-type microglia and halts progression. Because the defect is cell
    autonomous to NRROS-deficient myeloid cells, replacement is a mechanistic
    rationale for transplantation, but no human outcome has been reported and
    the children in published series were diagnosed after regression had
    begun.
  evidence:
  - reference: PMID:29909984
    reference_title: "A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Whole bone marrow transplantation results in selective repopulation of Lrrc33-/- brains with WT microglia and halts disease progression."
    explanation: Preclinical rescue that motivates the question.
- discussion_id: nrros_tgfb_versus_nox2
  prompt: >-
    Does the human disease follow from loss of microglial TGF-beta1 activation
    alone, or does loss of NRROS-mediated restraint of NOX2 and reactive
    oxygen species production also contribute?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#NRROS Loss of Function
  - pathophysiology#Perivascular Foamy Macrophage Accumulation
  rationale: >-
    NRROS was first described as a negative regulator of NOX2 in phagocytes,
    and the foamy macrophages in patient brain are p22phox-positive. The
    phenotype of the knockouts, rescue by wild-type marrow, and the overlap
    with human TGF-beta1 deficiency point to the TGF-beta axis, but no study
    has separated the two functions in the CNS disease.
  evidence:
  - reference: PMID:24739962
    reference_title: "NRROS negatively regulates reactive oxygen species during host defence and autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known as gp91(phox) and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway"
    explanation: Establishes the second, NOX2-regulating function of NRROS.
  - reference: PMID:32197075
    reference_title: "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency."
    explanation: Clinical overlap with TGF-beta1 deficiency favours the TGF-beta axis.
  - reference: PMID:29483653
    reference_title: "Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy"
    explanation: >-
      Human TGF-beta1 deficiency produces epilepsy, brain atrophy and
      leukoencephalopathy, the CNS features shared with NRROS deficiency.
references:
- reference: PMID:35716448
  title: "Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review."
- reference: PMID:39422130
  title: "Expanding the Phenotype of NRROS -Related SENEBAC Syndrome."
- reference: PMID:29483653
  title: "Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy."
📚

References & Deep Research

References

3
PMID:35716448
Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review.
No top-level findings curated for this source.
PMID:39422130
Expanding the Phenotype of NRROS -Related SENEBAC Syndrome.
No top-level findings curated for this source.
PMID:29483653
Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: NRROS-Related_Microgliopathy · 2026-11-04T19:00:07Z · View source

Created the entry for SENEBAC (MONDO:0030033, NRROS) from claim #16506, named NRROS-Related Microgliopathy after recurring literature use, with the MONDO label kept as a synonym. Curated from the primary case series (PMIDs 32100099, 32197075, 35099671, 39422130, 40463927, 42806633), the systematic review PMID:35716448 and the Nrros/Lrrc33 knockout mouse papers (PMIDs 28459434, 29909984, 24739962), plus the ClinGen Definitive AR assertion. Built the causal chain NRROS loss, loss of microglial autocrine TGF-beta1 activation, failure of homeostatic microglial identity, then foamy macrophage accumulation, neuronal loss and white matter loss, with calcification recorded as dystrophic. No GeneReviews chapter exists (just check-genereviews: NO_CHAPTER). Falcon was requested but no Edison key was configured, so the run fell back to openscientist (research/NRROS-Related_Microgliopathy-deep-research-openscientist.md; 13/13 references resolved). That report was used as a lead only: it gives the wrong HGNC identifier for NRROS (HGNC:25124; the entry uses hgnc:24613), which just preflight-dr flagged. From it the entry took the recurrent c.1981delC founder allele, the mitochondrial ultrastructure finding, and human TGFB1 deficiency (PMID:29483653) as convergent evidence for the TGF-beta1 axis. Validated with just validate (56/56 snippets verified, terms pass) and the per-file structural gates.

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NRROS-Related Microgliopathy (SENEBAC): Comprehensive Disease Characterization
openscientist-autonomous 11 citations 2026-11-04T19:10:27.491994

NRROS-Related Microgliopathy (SENEBAC): Comprehensive Disease Characterization

Disease: NRROS-Related Microgliopathy — Seizures, Early-onset, with Neurodegeneration And Brain Calcification (SENEBAC) Causal gene: NRROS (Negative Regulator of Reactive Oxygen Species; also known as LRRC33; HGNC:25124; NCBI Gene 375387; UniProt Q86YC3; cytoband 3q29) Identifiers: MONDO:0030033 · OMIM:618875 Category: Mendelian, autosomal recessive, ultra-rare

Causal gene stated up front: This disorder is caused by biallelic loss-of-function variants in the NRROS gene (also called LRRC33). The OMIM phenotype title ("Seizures, early-onset, with neurodegeneration and brain calcification"; SENEBAC) is descriptive and does not name a gene, but all identifiers above (MONDO:0030033, OMIM:618875) point to the same NRROS-related entity.

Summary

NRROS-Related Microgliopathy is an ultra-rare, autosomal-recessive, infantile-onset, progressive and usually lethal neurodegenerative disorder caused by biallelic loss-of-function (LoF) variants in the NRROS gene (also called LRRC33). NRROS is a microglial/macrophage transmembrane "milieu" protein whose principal function is to anchor latent transforming growth factor-β1 (TGF-β1) at the cell surface, where it enables highly localized, integrin-αVβ8-dependent activation of the cytokine. A second, distinct function of NRROS is to serve as an endoplasmic-reticulum-based negative regulator of the NADPH oxidase subunit NOX2, restraining reactive oxygen species (ROS) production.

The disease mechanism follows a coherent causal chain: biallelic NRROS LoF variants produce absent or non-functional protein that fails to anchor latent TGF-β1 at the microglial surface; this abolishes local integrin-αVβ8-dependent TGF-β1 activation, depriving microglia of the autocrine/paracrine TGF-β1 signal required for their homeostatic maturation program. The resulting microglial dysfunction — compounded by a loss of NOX2 restraint that permits excess oxidative damage — produces a calcifying leukoencephalopathy with combined grey- and white-matter degeneration, foamy macrophage infiltration, and dystrophic intracranial calcification. Clinically, affected children typically develop normally for several months, then present with drug-resistant epilepsy, developmental regression, acquired microcephaly, and relentless neurodegeneration, with a median age at death of approximately 3 years.

Fewer than ~15 individuals have been reported worldwide. Diagnosis is molecular (exome or genome sequencing) supported by a characteristic neuroimaging signature of progressive cerebral atrophy, white-matter volume loss/delayed myelination, and punctate or serpiginous calcifications at the grey-white matter junction. There is no disease-modifying therapy; management is entirely supportive and palliative, with genetic counseling as the only means of prevention. The Nrros-knockout mouse and the Lrrc33-deficient mouse faithfully recapitulate key features, and human biallelic TGFB1 deficiency causes a convergent encephalopathy, together validating the mechanistic model.

Section 1 — Disease Information

Overview. NRROS-Related Microgliopathy (SENEBAC) is a Mendelian, infantile-onset neurodegenerative disease characterized by the triad of early-onset drug-resistant seizures, progressive neurodegeneration with developmental regression, and intracranial (brain) calcification. It is a disorder of microglial dysfunction (a "microgliopathy") driven by failure of localized TGF-β1 activation in the central nervous system.

Key identifiers.

Resource Identifier
MONDO MONDO:0030033
OMIM (phenotype) 618875 (SENEBAC)
Gene NRROS / LRRC33 — HGNC:25124; NCBI Gene 375387; Ensembl ENSG00000174004; UniProt Q86YC3
Cytoband 3q29
ICD-10 / ICD-11 / MeSH / Orphanet No NRROS-specific code (ultra-rare; not separately coded)

Synonyms / alternative names. Seizures, early-onset, with neurodegeneration and brain calcification; SENEBAC; NRROS-related microgliopathy; NRROS-related lethal microgliopathy.

Information source. The knowledge base for this disease is derived from aggregated, disease-level primary literature — small case series and systematic case-based reviews of individual patients identified via research exome/genome sequencing — rather than from large EHR-based or registry cohorts. This reflects the extreme rarity of the condition.

Section 2 — Etiology

Primary cause (genetic). The disease is caused exclusively by biallelic (autosomal-recessive) loss-of-function variants in NRROS. Dong et al. (2020) reported six individuals from four families with bi-allelic NRROS variants (PMID: 32197075): "We report six individuals from four families with bi-allelic variants in NRROS." Subsequent reports (Macintosh 2022; Madaan 2022) expanded the cohort to ~15 individuals.

Genetic risk factors. The only established risk factor is inheritance of two LoF NRROS alleles. Variant classes include nonsense, frameshift, splice-site, and damaging missense variants affecting two functional NRROS domains. A recurrent c.1981delC (p.Leu661Serfs*97) frameshift was observed in two families, attributed to a likely founder effect (PMID: 35716448): "The most common reported genetic variation was c.1981delC; (p.Leu661Serfs97) observed in two families (likely due to a founder effect)." Other reported variants include c.185T>C (p.Leu62Pro), c.310C>T (p.Gln104Ter), and c.1359del (p.Ser454Alafs11). Consanguinity contributes to recessive inheritance in some families.

Environmental risk factors. None identified. This is a monogenic disorder; no toxic, infectious, lifestyle, or occupational contributor has been described.

Protective factors. None identified (genetic or environmental). No protective modifier alleles have been reported.

Gene–environment interactions. None established. Given the fully penetrant monogenic etiology, the disease is not known to depend on environmental modifiers.

Section 3 — Phenotypes

Phenotypes derive principally from the Madaan 2022 systematic review (n=11 children, 6 girls), Dong 2020, and Macintosh 2022.

Phenotype Type Frequency Onset / course HPO term
Drug-resistant epilepsy Clinical sign 11/11 (100%) Median onset ~12 mo; refractory, progressive HP:0032794 (and HP:0001250 Seizure)
Epileptic/infantile spasms Clinical sign 3/11 Infantile HP:0012469
Developmental regression Symptom Majority (normal early development in 7/11, then regression) Median ~12 mo HP:0002376
Progressive cerebral atrophy Imaging/structural All Progressive HP:0002059
Cerebral white-matter abnormality / loss Imaging/structural All Progressive; delayed myelination HP:0002500; HP:0012448 (Delayed CNS myelination)
Intracranial calcification Imaging/structural 8/11 Punctate/serpiginous at grey-white junction HP:0002514 (Cerebral calcification)
Acquired (secondary) microcephaly Physical sign Reported Acquired, progressive HP:0005484

Phenotype characteristics. Onset is typically infantile (early development normal in 7/11 before seizure onset and regression at a median of 12 months). Severity is severe; course is progressive and usually fatal. Madaan 2022 quantified the natural history (PMID: 35716448): "The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months. Intracranial calcifications were described in eight of eleven children."

Macintosh 2022 documented the neuropathology (PMID: 35099671): "Pathological examination revealed both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages."

Quality-of-life impact. Profound. Affected children experience refractory seizures, loss of acquired motor and cognitive milestones, acquired microcephaly, and progressive neurological disability leading to early death; impact on daily functioning is total, requiring full caregiving support. No formal EQ-5D/SF-36 QoL instrument data exist for this ultra-rare disease.

Section 4 — Genetic / Molecular Information

Causal gene. NRROS / LRRC33 (HGNC:25124; NCBI Gene 375387; Ensembl ENSG00000174004; UniProt Q86YC3), on chromosome 3q29. Associated OMIM phenotype 618875.

Pathogenic variants. - Classification: Reported variants are pathogenic/likely pathogenic LoF (ACMG/AMP); some damaging missense variants affect conserved functional domains. - Variant types: Nonsense (e.g., c.310C>T, p.Gln104Ter), frameshift (c.1981delC p.Leu661Serfs97; c.1359del p.Ser454Alafs11), splice-site, and missense (c.185T>C, p.Leu62Pro). - Allele frequency: All reported pathogenic variants are extremely rare/absent in population databases (gnomAD), consistent with a severe recessive phenotype. - Origin: Germline, biallelic (autosomal recessive). - Functional consequence: Loss of function. Functional studies showed mutant NRROS proteins co-localize intracellularly with latent TGF-β1 but fail to anchor it at the cell surface (PMID: 32197075): "these variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-β1 on the cell surface."

Modifier genes. None established. The recurrent founder variant suggests population-specific recurrence rather than modifier effects.

Epigenetic information (gene regulation). NRROS/LRRC33 expression is epigenetically modulated: TLR ligands down-regulate LRRC33 via H3K4me3 and H3K27me3 chromatin modifications (PMID: 24550525). This pertains to normal gene regulation rather than a disease-specific epimutation.

Chromosomal abnormalities. None reported; the disease results from point/small indel variants, not large structural rearrangements.

Section 5 — Environmental Information

No environmental, lifestyle, or infectious contributors are implicated in NRROS-Related Microgliopathy. The disease is monogenic and recessive. Of mechanistic note, NRROS's normal physiology intersects with host defense — NRROS-deficient phagocytes show enhanced bactericidal activity against E. coli and Listeria due to increased ROS (PMID: 24739962) — but no infectious trigger is required for or associated with the human neurodegenerative disease.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic NRROS LoF variants → absent or non-functional NRROS/LRRC33 protein (loss of function; demonstrated).
  2. → Failure to anchor latent proTGF-β1 at the microglial/macrophage cell surface (demonstrated by flow cytometry; Dong 2020). Mutant protein co-localizes with latent TGF-β1 intracellularly but is not displayed at the surface.
  3. → Loss of integrin-αVβ8-dependent local activation of TGF-β1 (demonstrated in Lrrc33/NRROS biology; Qin 2018).
  4. → Deficient autocrine/paracrine TGF-β1 signaling that normally maintains the microglial homeostatic/maturation program → microglial dysmaturation and dysfunction (inferred from mouse convergence with TGF-β1 deficiency).
  5. → (Branch) Loss of NOX2 restraint permits excess phagocyte ROS and oxidative CNS tissue damage (inferred contribution from Noubade 2014 NRROS-NOX2 biology).
  6. → Neuroinflammation, foamy macrophage infiltration, dysmyelination / white-matter loss, grey-matter degeneration, and dystrophic calcification (demonstrated neuropathology; Macintosh 2022).
  7. → Clinical disease: infantile drug-resistant epilepsy, developmental regression, acquired microcephaly, progressive neurodegeneration, and early death (median ~36 months).
NRROS biallelic LoF
│
▼
No surface anchoring of latent TGF-β1 ───────────┐
│                                         │ (branch)
▼                                         ▼
Loss of integrin-αVβ8 activation of TGF-β1   Loss of NOX2 restraint
│                                         │
▼                                         ▼
Deficient microglial TGF-β1 signaling      Excess phagocyte ROS
│                                         │
└──────────────┬──────────────────────────┘
       ▼
     Microglial dysfunction + oxidative CNS damage
       ▼
 Leukoencephalopathy: dysmyelination, grey+white matter
 degeneration, foamy macrophages, dystrophic calcification
       ▼
 Drug-resistant epilepsy, regression, microcephaly,
 progressive neurodegeneration, early death (~3 yr)

Mechanistic detail

Molecular pathway — TGF-β1 activation. NRROS/LRRC33 is a transmembrane leucine-rich-repeat "milieu molecule" that covalently links proTGF-β1 and presents it on the microglial surface for localized, integrin-αVβ8-dependent activation (PMID: 29909984): "LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation." The structural basis for LRRC33's specificity for TGF-β1 and its integrin recognition was resolved by Duan et al. 2022 (PMID: 36008481). GO term: GO:0007179 (TGF-β receptor signaling pathway).

Second function — NOX2 / ROS regulation. NRROS was originally defined (Noubade et al. 2014, Nature) as an ER-resident negative regulator of NOX2 (PMID: 24739962): "NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known as gp91(phox) and encoded by Cybb) monomer ... and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway." NRROS-deficient phagocytes produce increased ROS and NRROS-deficient mice develop severe EAE from CNS oxidative damage, supporting an oxidative-injury branch (GO:2000377, regulation of ROS metabolic process; CHEBI:26523, reactive oxygen species).

Cellular processes. Microglial cell activation/maturation (GO:0001774), myelination (GO:0042552), neuroinflammation, and dystrophic calcification. Cell types: microglia (CL:0000129) and CNS/perivascular macrophages (CL:0000881).

Protein dysfunction. Loss of function via truncation or destabilizing missense; retained intracellular latent-TGF-β1 binding but lost surface display and activation.

Immune system involvement. NRROS/LRRC33 is also a negative regulator of multiple Toll-like receptors and NF-κB signaling (PMID: 23545260; PMID: 24550525). Dysregulated innate-immune/microglial homeostasis is central to the CNS pathology.

Subcellular components. Plasma membrane (GO:0005886, TGF-β1 presentation), ER (GO:0005783, NOX2 regulation), and mitochondrion (GO:0005739; mitochondrial ultrastructural abnormalities seen on EM, Macintosh 2022).

Section 7 — Anatomical Structures Affected

  • Organ / system: Central nervous system (brain) — the nervous system is the primary and essentially exclusive system affected. UBERON:0000955 (brain).
  • Tissue level: Both grey matter (UBERON:0000956, cerebral cortex) and white matter (UBERON:0003544, cerebral white matter) are affected — "extensive grey and white matter involvement" (Macintosh 2022).
  • Cell populations: Microglia (CL:0000129) and infiltrating foamy macrophages (CL:0000881) are the key cellular players.
  • Subcellular: Plasma membrane (GO:0005886), endoplasmic reticulum (GO:0005783), mitochondria (GO:0005739).
  • Localization / lateralization: Diffuse and bilateral; calcifications are typically located at the grey-white matter junction (punctate/serpiginous).

Section 8 — Temporal Development

  • Onset: Infantile. Early development is often normal (7/11 children), followed by seizure onset and developmental regression at a median of ~12 months. Onset pattern is subacute-to-chronic with regression.
  • Progression: Relentlessly progressive — progressive cerebral atrophy, white-matter loss, and acquired microcephaly. No remission.
  • Disease course: Progressive neurodegenerative; median age at death ~36 months (Madaan 2022).
  • Critical period: The first 1–3 years of life represent the window of clinical manifestation; by extension, any disease-modifying intervention (hypothetical) would need to act very early, likely before irreversible neurodegeneration.

Section 9 — Inheritance and Population

  • Inheritance: Autosomal recessive (biallelic NRROS LoF). Consanguinity reported; recurrent founder variant c.1981delC in two families.
  • Penetrance / expressivity: Apparently complete penetrance in reported biallelic LoF individuals; the phenotype is consistently severe, though age at death varies.
  • Epidemiology: Ultra-rare. Fewer than ~15 individuals reported worldwide; no formal prevalence/incidence estimate exists (Orphanet-level ultra-rare, <1/1,000,000).
  • Founder effect: Yes — the recurrent c.1981delC (p.Leu661Serfs*97) frameshift.
  • Carrier frequency: Not established; pathogenic alleles are extremely rare in gnomAD.
  • Sex ratio: No strong skew reported (6 girls among 11 in Madaan 2022); consistent with autosomal-recessive inheritance.
  • Geographic distribution: Scattered case reports; no defined endemic region.

Section 10 — Diagnostics

Primary diagnostic route — molecular. Diagnosis is established by identifying biallelic NRROS variants via whole-exome sequencing (WES) or whole-genome sequencing (WGS); all reported families were ascertained by exome sequencing (PMID: 32197075). Single-gene NRROS testing and epilepsy/leukodystrophy/neurodegeneration gene panels are appropriate when the phenotype is recognized. Chromosomal microarray and karyotyping are not informative (no structural abnormality).

Neuroimaging. Characteristic and diagnostically useful: - Progressive cerebral atrophy and cerebral white-matter volume loss / delayed myelination. - Punctate or serpiginous calcifications at the grey-white matter junction (CT is most sensitive for calcification). Madaan 2022: "Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further c[haracteristic features]" (PMID: 35716448).

Neuropathology (where available). Extensive grey + white matter degeneration, dystrophic calcification, foamy macrophage infiltration, and mitochondrial ultrastructural abnormalities on EM (Macintosh 2022).

Electrophysiology. EEG demonstrates epileptiform/epileptic-encephalopathy patterns consistent with drug-resistant epilepsy and infantile/epileptic spasms.

Biomarkers. No disease-specific blood or CSF biomarker is established; diagnosis is molecular.

Differential diagnosis. Other infantile leukoencephalopathies with intracranial calcification — notably Aicardi-Goutières syndrome, cerebroretinal microangiopathy with calcifications and cysts (CRMCC/CTC1-related; PMID: 28072696), congenital (TORCH) infections, Coats plus, and other microgliopathies/leukodystrophies. NRROS testing distinguishes this entity.

Screening. Carrier screening and cascade testing of at-risk relatives once a familial variant is known; prenatal/preimplantation testing is feasible for known biallelic variants.

Section 11 — Outcome / Prognosis

  • Survival / life expectancy: Poor. Median age at death ~36 months (Madaan 2022). The disease is usually lethal in early childhood.
  • Mortality: Disease-specific; death results from progressive neurodegeneration and its complications (refractory seizures, respiratory/nutritional failure).
  • Morbidity / disability: Profound and universal — loss of developmental milestones, refractory epilepsy, acquired microcephaly, and severe neurological disability.
  • Disease course / complications: Relentlessly progressive; complications include status epilepticus, aspiration, feeding difficulty, and respiratory compromise.
  • Recovery potential: None; no recovery or remission reported.
  • Prognostic factors: Biallelic LoF genotype predicts the severe phenotype; no validated molecular prognostic biomarker beyond genotype.

Section 12 — Treatment

No disease-modifying or curative therapy exists. Management is entirely symptomatic, supportive, and palliative:

Intervention Role NCIT suggestion
Antiseizure/anticonvulsant medications Seizure control (often refractory) C264 (Anticonvulsant Agent)
Rehabilitation (PT/OT/speech) Function/comfort C15917 (Rehabilitation Therapy)
Nutritional & respiratory support Supportive care C15277 (Supportive Care)
Palliative / end-of-life care Comfort C15284 (Palliative Care)
Genetic counseling Family guidance/prevention C15516 (Genetic Counseling)

Advanced therapeutics. No gene therapy, cell therapy, RNA-based therapy, or TGF-β1-replacement trials have been reported for this indication. Conceptually, because the downstream effector is localized TGF-β1 activation, strategies restoring microglial TGF-β1 signaling or NRROS function are of theoretical interest but remain unexplored clinically.

Pharmacogenomics / personalized medicine. None established.

Section 13 — Prevention

  • Primary prevention: Not applicable in the conventional sense (monogenic). Prevention is through genetic counseling and reproductive options for carrier couples (prenatal diagnosis, preimplantation genetic testing) once a familial biallelic NRROS genotype is known.
  • Secondary prevention / screening: Cascade carrier testing of relatives; no population newborn screen exists given rarity.
  • Tertiary prevention: Supportive management to limit complications (aspiration, status epilepticus).
  • Counseling: Autosomal-recessive recurrence risk is 25% for carrier couples; genetic counseling is central.
  • Immunization / public health / environmental interventions: Not applicable.

Section 14 — Other Species / Natural Disease

  • Taxonomy / orthologs: Mouse ortholog Nrros (NCBI Gene 70571; NCBITaxon:10090). The gene and its TGF-β1/NOX2 functions are evolutionarily conserved in mammals.
  • Natural disease in other species: No naturally occurring companion-animal or wildlife disease specifically attributed to NRROS has been reported (no OMIA entry noted).
  • Comparative biology: The mouse recapitulates the human phenotype (see Section 15), supporting conservation of the disease mechanism. The TGF-β1/LRRC33 axis is also studied extensively in mouse tumor immunology.
  • Zoonotic potential: Not applicable (non-infectious genetic disease).

Section 15 — Model Organisms

  • Mouse (primary mammalian model). The Nrros-knockout mouse and the Lrrc33-deficient mouse are the principal models.
  • Phenotype recapitulation: Strong. Dong 2020 states (PMID: 32197075): "The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency." Qin 2018 showed Lrrc33⁻/⁻ mice have microglial dysfunction from loss of localized TGF-β1 activation. Noubade 2014 showed Nrros-deficient mice develop severe EAE from CNS oxidative damage (ROS branch).
  • Model types available: Constitutive knockout; the NOX2-interaction and TGF-β1-presentation functions have both been dissected in mouse.
  • Limitations: Mouse models may not fully capture the human calcification phenotype or exact clinical course; the two NRROS functions (TGF-β1 vs NOX2) are partly separable in different mouse studies.
  • Convergent human genetic model — TGFB1 deficiency. Biallelic human TGFB1 LoF causes severe infantile inflammatory bowel disease and encephalopathy (PMID: 29483653). This confirms CNS dependence on TGF-β1 — the downstream effector of NRROS — and supports the mechanistic model.
  • In vitro / cellular. Flow-cytometry assays of surface vs intracellular latent TGF-β1 anchoring in cells expressing wild-type vs mutant NRROS (Dong 2020) provided the functional proof of the anchoring defect. Structural studies (Duan 2022) defined LRRC33–TGF-β1–integrin specificity.

Mechanistic Model / Interpretation

NRROS-Related Microgliopathy is best understood as a microglial TGF-β1-activation deficiency with a superimposed oxidative-damage component. The unifying insight is that NRROS/LRRC33 has two conserved jobs in myeloid/microglial cells: (1) at the plasma membrane, it anchors and presents latent TGF-β1 for integrin-αVβ8-dependent local activation; and (2) in the ER, it degrades nascent NOX2 to restrain ROS. Biallelic LoF simultaneously removes a pro-homeostatic signal (TGF-β1) and a brake on oxidative stress (NOX2). In the CNS, microglia critically depend on autocrine/paracrine TGF-β1 to adopt and maintain their homeostatic identity; losing this signal yields dysfunctional microglia, while unrestrained ROS adds oxidative tissue injury. The combined insult produces a calcifying leukoencephalopathy with grey- and white-matter degeneration and foamy macrophage infiltration, which clinically manifests as early-onset refractory epilepsy, regression, microcephaly, and progressive, usually fatal neurodegeneration.

The model is strongly triangulated: (i) patient variants functionally fail to anchor TGF-β1 (in vitro), (ii) the Nrros/Lrrc33 mouse phenocopies the disease, and (iii) human TGFB1 deficiency — the downstream effector — independently causes encephalopathy. The relative contributions of the TGF-β1 (upstream, best-supported) versus NOX2/ROS (branch, inferred) arms to the human calcification phenotype remain to be fully quantified.

Evidence Base

PMID Title (abbrev.) Contribution
32197075 Bi-allelic LoF NRROS variants impairing active TGF-β1 delivery cause severe infantile neurodegeneration Establishes causality (6 individuals/4 families), anchoring defect, mouse/TGF-β1 convergence
35716448 Delineating the epilepsy phenotype of NRROS-related microgliopathy Natural history (n=11): onset ~12 mo, death ~36 mo, calcification 8/11, founder variant
35099671 Novel biallelic NRROS variants; lethal microgliopathy Neuropathology: grey+white matter, dystrophic calcification, foamy macrophages, mitochondrial EM
29909984 A milieu molecule for TGF-β required for microglia function Defines NRROS/LRRC33 microglial TGF-β1 activation (integrin-αVβ8)
24739962 NRROS negatively regulates ROS during host defence and autoimmunity ER/NOX2 function; ROS branch; EAE
29483653 Human TGF-β1 deficiency causes IBD and encephalopathy Confirms CNS dependence on downstream TGF-β1
36008481 Specificity of TGF-β1 signal by LRRC33 and integrin Structural basis of LRRC33–TGF-β1–integrin
23545260 / 24550525 LRRC33 inhibits TLR/NF-κB; epigenetically modulated Immune-regulatory role; H3K4me3/H3K27me3 regulation
28072696 CRMCC case report Differential diagnosis (calcifying leukoencephalopathy, CTC1)

Supporting tumor-immunology literature (PMID: 35181792, 40992270, 31600200) corroborates the LRRC33/TGF-β1 axis in myeloid cells, reinforcing the mechanistic foundation.

Limitations and Knowledge Gaps

  • Very small N (<~15 patients). All epidemiology, natural-history, and genotype-phenotype statements rest on small case series; prevalence/incidence are unquantified.
  • TGF-β1 vs NOX2 contribution. The relative weight of lost TGF-β1 signaling (best-supported) versus the NOX2/ROS oxidative branch (inferred) in producing human calcification and neurodegeneration is not quantitatively resolved.
  • No validated biomarker. No blood/CSF biomarker exists for diagnosis or disease monitoring.
  • No therapeutic data. No trials of any disease-modifying approach; all treatment is supportive.
  • Mechanism-to-calcification link. The precise mechanism linking microglial dysfunction/ROS to dystrophic grey-white junction calcification is not fully elucidated.
  • Citation caveat. One cited abstract snippet (PMID:29483653) was logged as a title-derived paraphrase in the knowledge state; the underlying claim (human TGF-β1 deficiency → encephalopathy) is correct and consistent with the paper's subject.

Proposed Follow-up Experiments / Actions

  1. International patient registry & natural-history study to refine prevalence, genotype-phenotype correlations, and survival with larger N.
  2. Dissect the TGF-β1 vs NOX2 contributions using conditional/separation-of-function Nrros mouse alleles (TGF-β1-presentation-dead vs NOX2-binding-dead) to attribute calcification and neurodegeneration to each arm.
  3. Microglial single-cell/spatial transcriptomics from patient-derived iPSC microglia or mouse models to map the dysmaturation signature and identify druggable nodes.
  4. Biomarker discovery (CSF/plasma neurofilament, TGF-β pathway readouts, ROS markers) for diagnosis and potential trial endpoints.
  5. Preclinical therapeutic exploration: test whether restoring TGF-β1 signaling (e.g., engineered/targeted TGF-β1 delivery to microglia) or antioxidant/NOX2 modulation mitigates phenotype in Nrros mouse models; evaluate gene-replacement feasibility given the early critical window.
  6. Standardized imaging protocol (CT for calcification + MRI for white matter) to enable earlier recognition and differential diagnosis from Aicardi-Goutières/CRMCC.

Report compiled from an autonomous multi-iteration investigation (8 confirmed findings; 18 papers reviewed). Evidence sources span human clinical case series, mouse models, in vitro functional assays, and structural/computational studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 13
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 26
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 9
Terms named correctly 2
Terms named as a different term 3
Terms whose name is worth a second look 4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0030033 (3 mentions) - the report calls it "MONDO"; MONDO calls it seizures, early-onset, with neurodegeneration and brain calcifications
  • HP:0002376 (1 mention) - the report calls it "Median ~12 mo"; HP calls it Developmental regression
  • HP:0002059 (1 mention) - the report calls it "Progressive"; HP calls it Cerebral atrophy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0012469 (1 mention) - the report calls it "Infantile"; HP calls it Infantile spasms
  • HP:0005484 (1 mention) - the report calls it "Acquired, progressive"; HP calls it Secondary microcephaly, and lists "Acquired microcephaly" among its other names
  • CL:0000129 (2 mentions) - the report calls it "Cell populations: Microglia"; CL calls it microglial cell**, and lists "microglia" among its other names
  • GO:0005886 (2 mentions) - the report calls it "Subcellular: Plasma membrane"; GO calls it plasma membrane**, and lists "cellular membrane" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM.