Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Neuronal ceroid lipofuscinosis type 11 (NCL11) is an inherited lysosomal storage disorder characterized by early‐onset neurodegeneration and systemic manifestations. Affected patients typically present in childhood with progressive cognitive decline, refractory seizures, cerebellar ataxia, and visual impairment. Additional features may include recurrent respiratory infections culminating in bronchiolitis obliterans and endocrine abnormalities such as hypothyroidism. Fewer than ten families had been reported before recent studies expanded the genetic spectrum. Pathologically, NCL11 is defined by accumulation of autofluorescent lipopigments within neurons and peripheral cells due to lysosomal dysfunction. Biallelic variants in the progranulin gene (GRN) underlie this syndrome.
In a recent case report (PMID:38253347), a 4-year-old male with global developmental delay presented with refractory seizures (HP:0001250), bronchiolitis obliterans (HP:0011946), and hypothyroidism (HP:0000821). Whole-exome sequencing identified compound heterozygous missense variants in GRN: c.415T>C (p.Cys139Arg) and c.430G>A (p.Asp144Asn). Both variants affect conserved granulin domains, predicted to disrupt progranulin folding and lysosomal targeting. Family history revealed an affected brother who died at 22 months, providing segregation evidence in one additional relative. Neuroimaging showed periventricular white matter hyperintensities, corpus callosum thinning, and cerebellar vermis atrophy consistent with lysosomal storage pathology. This report extended GRN phenotypes beyond frontotemporal dementia into the NCL11 spectrum.
A 2020 multi-patient study (PMID:31855245) screened individuals with homozygous GRN mutations and identified six unrelated patients with NCL11, raising the total to ten families. The predominant variant was a homozygous frameshift c.768_769dup (p.Gln257fs), predicted to trigger nonsense-mediated decay and complete loss of progranulin. Phenotypes included classical childhood-onset NCL11 with seizures and ataxia as well as a late-onset form resembling frontotemporal dementia without seizures. Segregation analysis across these families confirmed autosomal recessive inheritance. Neuropathological examination of one homozygous carrier revealed hallmark ceroid lipofuscin deposits and neuronal loss. Together, these data delineate genotype–phenotype correlations and phenotypic variability in GRN-related NCL11.
GRN-related NCL11 follows an autosomal recessive inheritance mode, with disease manifesting only in individuals carrying biallelic loss-of-function alleles. To date, at least ten unrelated probands have been described with homozygous or compound heterozygous GRN variants leading to NCL11. Variant classes include missense substitutions in granulin domains (e.g., p.Cys139Arg), frameshift indels (e.g., p.Gln257fs), and splice-site mutations resulting in transcript degradation. Segregation in a sibling pair provided additional familial confirmation. Allelic heterogeneity is evident, with no single founder variant. This robust genetic evidence supports a strong association between GRN deficiency and NCL11.
Progranulin is a lysosomal growth factor essential for protein homeostasis and neuronal survival. Loss-of-function GRN mutations lead to progranulin haploinsufficiency, lysosomal dysfunction, and storage material accumulation. Grn knockout mice recapitulate key features: lysosomal defects, ubiquitin-positive neuronal inclusions, and reduced survival, mirroring human NCL11 pathology (PMID:22733568). In patient neuropathology, homozygous carriers exhibit widespread lipofuscin accumulation and neuronal loss, confirming the mechanistic link between GRN deficiency and lysosomal storage disease (PMID:31855245). Cellular assays further demonstrate impaired progranulin secretion and trafficking for pathogenic variants. Functional studies thus corroborate loss-of-function as the driving mechanism in GRN-mediated NCL11.
The convergence of genetic, clinical, and functional evidence yields a strong ClinGen classification for the GRN–NCL11 association. Genetic testing for GRN variants is recommended in children with early-onset seizures, neurodegeneration, and lysosomal storage signs. Identification of causative alleles facilitates accurate genetic counseling, anticipatory management, and enrollment in therapeutic trials targeting progranulin replacement or lysosomal modulation. Awareness of phenotypic heterogeneity, including late-onset forms lacking seizures, is critical for differential diagnosis. No conflicting data have been reported to date.
Key take-home: Biallelic loss-of-function GRN variants cause NCL11 via progranulin haploinsufficiency, supporting genetic testing and guiding targeted clinical care.
Gene–Disease AssociationStrong10 unrelated probands including segregation and concordant lysosomal pathology in Grn(-/-) models Genetic EvidenceStrongMultiple biallelic GRN variants including missense and frameshift in >10 independent families with segregation Functional EvidenceModerateGRN-null mice and patient neuropathology demonstrate lysosomal dysfunction and progranulin haploinsufficiency |