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Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (ANCL; Kufs disease) is a rare neurodegenerative disorder characterized by progressive seizures, myoclonus, cognitive decline, and premature death. Pathologically, neuronal lipofuscin accumulation and granular osmiophilic deposits (GRODs) are hallmarks on neuropathological examination. ANCL typically presents in the third to fifth decade and shows autosomal dominant inheritance in ∼20–30% of kindreds.
Genetic studies have identified heterozygous mutations in DNAJC5 encoding cysteine string protein α (CSPα) as causative in ANCL. Initial whole-exome sequencing in the multigenerational Parry family pinpointed an in-frame deletion c.343CTC (p.Leu116del) segregating with disease across seven generations (2 additional affected relatives) (PMID:22235333). An independent cohort of eight families confirmed c.344T>G (p.Leu115Arg) in one pedigree and recurrent c.346_348del (p.Leu116del) in three siblings (PMID:22073189). Subsequent linkage and sequencing in three further families (n=20 affected) reaffirmed hotspots at p.Leu115 and p.Leu116 (PMID:22978711).
Segregation analysis across nine unrelated families demonstrates complete co-segregation of CSPα mutations with ANCL in >20 mutation-positive individuals. Neuropathological confirmation of NCL in autopsy specimens underscores the high penetrance and diagnostic specificity of these variants.
The variant spectrum in ANCL is narrow, dominated by in-frame events within the CSPα cysteine-string domain: c.346_348del (p.Leu116del) and c.344T>G (p.Leu115Arg). More recently, an in-frame duplication c.370_399dup (p.Cys124_Cys133dup) was reported in a single kindred, highlighting this region’s susceptibility to replication errors (PMID:31919451). No hypomorphic or deep-intronic alleles have been described.
Functional assays reveal that CSPα mutations impair its J-domain–mediated Hsc70 co-chaperone activity and mislocalize CSPα, disrupting synaptic vesicle exocytosis and endolysosomal homeostasis. In vitro studies show defective Hsc70‐CSPα binding and reduced ATPase stimulation (PMID:9395474; PMID:9437017). A Drosophila ANCL model and Thy1‐driven transgenic mice expressing p.Leu115Arg or p.Leu116del develop lipofuscin accumulation, GRODs, motor deficits, and neurodegeneration, consistent with a toxic gain‐of‐function mechanism (PMID:40397740). Recent work implicates dual chaperoning roles of CSPα in microautophagy and misfolding‐associated protein secretion (MAPS), with ANCL mutants uncoupling these processes to cause lipofuscin deposition and neuronal loss (PMID:35506243).
No studies have refuted the CSPα–ANCL link, and no alternative phenotypes have been reliably mapped to these variants. The gene–disease relationship has been replicated across diverse populations and multiple independent laboratories.
Overall, the genetic and functional evidence for DNAJC5 in autosomal dominant ANCL is Strong. Diagnostic testing targeting the CSPα cysteine-string domain reliably identifies pathogenic variants, informs familial risk, and supports early therapeutic intervention.
Key Take-home: Pathogenic variants in DNAJC5 are a well-validated cause of autosomal dominant adult-onset neuronal ceroid lipofuscinosis and should be included in gene panels for late-onset progressive myoclonus epilepsy and neurodegeneration.
Gene–Disease AssociationStrong9 families (including 20 mutation-positive individuals), multi-family segregation, histopathological confirmation Genetic EvidenceStrong20 co-segregating cases across 3 pedigrees; recurrent hotspots at p.Leu115 and p.Leu116 Functional EvidenceModerateCellular and animal models demonstrate disrupted chaperone activity, vesicle exocytosis defects, and lipofuscin accumulation in vivo |