DNAJC5 and Neuronal Ceroid Lipofuscinosis

Multiple independent studies have demonstrated a strong association between DNAJC5 (HGNC:16235) mutations and neuronal ceroid lipofuscinosis (MONDO:0016295). The evidence is underpinned by autosomal dominant inheritance patterns where affected individuals across several families consistently present with neurodegenerative features including seizures, cognitive decline, and visual impairment (PMID:22235333, PMID:22978711).

Genetic investigations in these studies report recurrent variants, with one representative alteration being c.344T>G (p.Leu115Arg). This variant has been identified in more than 23 probands across multiple unrelated families, supported by robust segregation analyses and detailed neuropathological confirmation (PMID:22235333, PMID:22978711).

In addition to the strong genetic evidence, functional studies have contributed to elucidating the pathogenic mechanism. In vitro assays demonstrate that mutations in DNAJC5 disrupt its chaperone activity and impair vesicle trafficking, which is essential for neuronal maintenance. These functional deficits are consistent with the neurodegenerative phenotype observed in patients (PMID:9395474, PMID:35506243).

While some studies noted occasional co‐segregation of additional features such as visual impairment, the overall clinical and experimental data largely converge on a phenotype consistent with neuronal ceroid lipofuscinosis. This highlights the clinical importance of DNAJC5 variant screening in patients presenting with these symptoms.

Furthermore, multi‐patient analyses have reinforced the association by documenting a broad spectrum of neurological manifestations including seizures, myoclonus, ataxia, and dementia. Such convergence of data from both isolated case reports and larger cohort studies underscores the utility of incorporating DNAJC5 into diagnostic algorithms for neurodegenerative disorders (PMID:35462699).

In summary, the integration of genetic segregation data and functional assay results provides compelling support for the role of DNAJC5 mutations in neuronal ceroid lipofuscinosis. Key‐take‐home message: comprehensive genetic analysis of DNAJC5 is crucial for accurate diagnosis and improved management of patients with this neurodegenerative disorder.

References

• PloS One • 2012 • Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in a proportion of cases: study of the Parry family and 8 other families PMID:22235333
• Clinical Genetics • 2013 • Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease PMID:22978711
• Frontiers in Aging Neuroscience • 2022 • Adult-Onset Neuronal Ceroid Lipofuscinosis With a Novel DNAJC5 Mutation Exhibits Aberrant Protein Palmitoylation PMID:35462699
• The Journal of Biological Chemistry • 1997 • The molecular chaperone function of the secretory vesicle cysteine string proteins PMID:9395474
• Autophagy • 2023 • Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated DNAJC5/CSPα mutants causes lipofuscin accumulation PMID:35506243

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