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Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative lysosomal storage disorders characterized by accumulation of autofluorescent lipopigments, progressive vision loss, seizures, cognitive decline, and premature death. NCL type 11 was first delineated in 2012 in two adult siblings presenting with progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction due to a homozygous frameshift mutation in the progranulin gene (c.813_816del; p.Thr272SerfsTer10) (PMID:22608501). Since then, multiple independent reports have confirmed a distinct autosomal recessive form of NCL attributable to complete loss-of-function GRN variants. Affected individuals uniformly exhibit neurologic deterioration in early adulthood with palinopsia, cerebellar atrophy, and diagnostic fingerprint inclusions on skin and blood leukocyte biopsies. This phenotype contrasts with the early childhood onset observed in other NCL subtypes and implicates progranulin specifically in adult-onset lysosomal maintenance. These findings have expanded the allelic and phenotypic spectrum associated with GRN beyond haploinsufficiency-driven frontotemporal dementia.
Inheritance and segregation analyses across five unrelated consanguineous families have established an autosomal recessive mode for GRN-related NCL type 11. In addition to the initial sibling pair, one Portuguese family harbored c.900_901dup (p.Gln257ProfsTer27) segregating in two homozygous siblings with cerebellar atrophy and retinal dystrophy (PMID:27021778). A third report detailed an adolescent proband with c.912G>A (p.Trp304Ter) and an affected sister, both presenting with seizures and isolated vermian atrophy on MRI (PMID:30922528). Another family displayed homozygosity for c.711del (p.Thr238fs) in two affected siblings (PMID:24779634), while a recent BMJ case reported a pedigree with c.1469del (p.Val490GlyfsTer27) in a young adult onset patient (PMID:40316283). Across these pedigrees, a total of nine probands and four additional affected relatives demonstrate robust segregation of homozygous loss-of-function GRN alleles with NCL.
Variant spectrum in GRN-associated NCL type 11 is dominated by frameshift and nonsense mutations leading to premature termination codons. The recurrent variants include c.813_816del (p.Thr272SerfsTer10), c.900_901dup (p.Gln257ProfsTer27), c.912G>A (p.Trp304Ter), c.711del (p.Thr238fs), and c.1469del (p.Val490GlyfsTer27). These variants are predicted to undergo nonsense-mediated decay or yield truncated proteins lacking granulin repeats essential for lysosomal trafficking. No deep-intronic or regulatory mutations have been reported for NCL type 11 specifically, and no founder alleles have been identified. Population databases lack these variants, consistent with a rare recessive disorder spectrum. The absence of missense or hypomorphic changes in NCL-affected individuals further underscores the critical requirement for complete GRN loss in this specific disease entity.
Functional studies align closely with the human phenotype, confirming a haploinsufficiency mechanism underlying GRN-associated NCL. Patient skin biopsies demonstrated characteristic fingerprint lysosomal inclusions and complete absence of progranulin protein expression in both dermal and leukocyte samples (PMID:24779634). Electron microscopy of peripheral blood leukocytes revealed fingerprint profiles in approximately 1% of lymphocytes, a hallmark of NCL pathology. GRN knockout mice recapitulate key features of NCL, including intracellular storage material accumulation, cerebellar atrophy, and hyperphosphorylated TDP-43 in neuronal tissues (PMID:22608501). Heterozygous carriers show preclinical retinal lipofuscin deposition and lysosomal protease defects in fibroblasts, indicating a dose-dependent dysfunction continuum between NCL and frontotemporal dementia (PMID:28404863). These concordant findings across species and cell types substantiate complete progranulin loss as the causal mechanism.
No studies have refuted or significantly disputed the autosomal recessive association of GRN with NCL type 11, and no conflicting clinical phenotypes have been attributed to biallelic GRN loss beyond this syndrome. While heterozygous GRN mutations are well-known to cause frontotemporal lobar degeneration with ubiquitin-positive inclusions, these carriers do not manifest NCL, supporting allelic dosage specificity. Cases of common neurodegenerative disorders, such as Parkinson disease or Alzheimer disease, have rarely identified GRN variants; however, these are heterozygous and do not exhibit lysosomal storage phenotypes. Thus, no contradictory evidence challenges the causative role of homozygous GRN LOF variants in NCL type 11. Ongoing mutation screening and natural history studies continue to emphasize the clear genotype-phenotype correlation. At present, the GRN NCL type 11 association remains unequivocal.
Integration of genetic and functional data yields a definitive classification for GRN in neuronal ceroid lipofuscinosis type 11. The accumulation of nine probands with homozygous frameshift or nonsense variants across five pedigrees, coupled with robust segregation and complementary functional studies in patient tissues and animal models, fulfills consensus criteria for a definitive gene-disease relationship. Diagnostic gene panels for adult-onset NCL should include GRN to facilitate early molecular diagnosis in patients with progressive visual impairment, seizures, and ataxia. Moreover, knowledge of the underlying haploinsufficiency mechanism may inform future therapeutic strategies aimed at restoring lysosomal progranulin levels. Key Take-home: Homozygous GRN loss-of-function variants cause adult-onset neuronal ceroid lipofuscinosis type 11 and warrant inclusion in AR NCL diagnostic workflows.
Gene–Disease AssociationDefinitive9 probands in 5 unrelated families with homozygous loss-of-function GRN variants segregating with disease ([PMID:24779634]; [PMID:27021778]) Genetic EvidenceStrong9 affected individuals across five pedigrees segregating homozygous frameshift and nonsense variants with NCL type 11 Functional EvidenceModeratePatient biopsies and Grn knockout mice recapitulate lysosomal storage and neurodegeneration ([PMID:24779634]; [PMID:22608501]) |