NRROS – Seizures, Early-Onset Neurodegeneration and Brain Calcifications (SENEBAC)

Biallelic variants in NRROS have been implicated in a rare early-onset neurodegenerative syndrome characterised by refractory seizures, brain calcifications, and progressive cerebral atrophy ([PMID:35099671], [PMID:39422130]). This condition, referred to as Seizures, Early-Onset Neurodegeneration and Brain Calcifications (SENEBAC), manifests with developmental regression, microcephaly, hypotonia, areflexia, and dysmorphic features. Initial studies described nine individuals with biallelic NRROS variants ([PMID:35099671]), and a recent report expands this to eleven unrelated affected individuals ([PMID:39422130]). Here, we integrate genetic and functional data to support the association between NRROS and SENEBAC syndrome.

Clinically, SENEBAC presents in infancy with normal early development followed by regression of milestones, refractory seizures, and characteristic neuroimaging features including cerebral atrophy, thin corpus callosum, and basal ganglia calcifications. Additional features such as areflexia and dysmorphic facies, reported in a recent Indian patient, expand the phenotypic spectrum of NRROS-related disease ([PMID:39422130]). Hypotonia and microcephaly were nearly universal across reported cases, and deep tendon reflexes were absent in several individuals. Carrier frequency data are not available given the rarity of this condition.

NRROS-related SENEBAC follows an autosomal recessive inheritance pattern, consistent with homozygous or compound heterozygous variants disrupting protein function. To date, eleven probands harbour biallelic NRROS mutations: two individuals with premature stop codons c.310C>T (p.Gln104Ter) and c.720G>A (p.Trp240Ter) and one with a missense change c.185C>T (p.Leu62Pro) in combination with p.Gln104Ter ([PMID:35099671], [PMID:39422130]). These variants include loss-of-function alleles affecting leucine-rich repeat domains that are critical for microglial function. No reports have described segregation beyond proband cohorts or detailed multi-generational pedigrees.

The variant spectrum comprises predominantly truncating alleles (nonsense or frameshift) and a smaller number of missense substitutions clustering in LRR motifs. Recurrent or founder variants have not been observed, and all mutations to date are private to individual families. No deep-intronic or structural variants have been reported thus far.

NRROS encodes a leucine-rich repeat protein expressed predominantly in microglia and perivascular macrophages, acting as a negative regulator of reactive oxygen species. Pathological examination of affected brain tissue revealed extensive grey and white matter degeneration, dystrophic calcifications, and foamy macrophage infiltration with mitochondrial ultrastructural abnormalities ([PMID:35099671]). These findings demonstrate concordance between human phenotypes and mechanistic data, implicating NRROS loss-of-function in SENEBAC pathogenesis.

Collectively, eleven unrelated probands and consistent functional observations provide moderate evidence for a gene-disease association according to ClinGen criteria. Although segregation data are limited, multiple independent case reports and compelling pathological data support pathogenicity through a loss-of-function mechanism. No conflicting studies have refuted this association. Key take-home: NRROS testing should be considered in patients with early-onset seizures, neurodegeneration, and brain calcifications, as identification of biallelic LoF variants has diagnostic and potential therapeutic implications.

References

• American Journal of Medical Genetics Part A • 2025 • Expanding the Phenotype of NRROS-Related SENEBAC Syndrome. PMID:39422130
• Neurogenetics • 2022 • Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration. PMID:35099671

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