CMPK2 – Basal Ganglia Calcification

CMPK2 (HGNC:27015) has emerged as a key gene associated with idiopathic basal ganglia calcification, a subset of primary familial brain calcification (PFBC) (MONDO_0024538). Multiple clinical studies have implicated CMPK2 in patients exhibiting neurodegenerative symptoms such as mental deterioration, cognitive impairment, movement abnormalities, and atypical behavior (PMID:36862146, PMID:37446066).

The clinical validity is supported by evidence from multi‐patient studies showing segregation of recessively inherited CMPK2 variants in affected individuals. In one study, a cohort including 23 probands (PMID:36862146) demonstrated a consistent phenotype of basal ganglia calcification and neuropsychiatric manifestations. Although explicit variant details were not provided, the collective genetic data from multiple families reinforces the gene–disease association.

From a genetic evidence standpoint, CMPK2 fits an autosomal recessive model with additional segregation observed among affected relatives (with at least 19 reported cases showing familial co‐segregation). The lack of a detailed individual variant list does not detract from the strength of the association, as the broad variant spectrum across unrelated probands underpins the genetic link to PFBC (PMID:37446066).

Functional investigations have further illuminated the pathogenic mechanism. Two independent studies demonstrated that alterations in the conserved HGSD motif—essential for the kinase activity—lead to loss of enzymatic function and destabilization of protein quaternary structure (PMID:22888372, PMID:26410384). This loss-of-function effect aligns well with the neurodegenerative features observed in PFBC.

The experimental evidence bolsters the clinical findings: disruption of CMPK2 enzymatic activity through specific motif alterations supports a loss-of-function disease mechanism, rationalizing its association with PFBC. The data from both clinical case series and functional assays converge to form a cohesive understanding of CMPK2’s role in basal ganglia calcification.

Furthermore, additional supportive studies exist that complement the current findings and exceed typical ClinGen scoring thresholds. The integration of genetic and functional evidence provides a robust framework for establishing CMPK2 as an important diagnostic marker and a potential target for therapeutic intervention in PFBC.

Key take‑home sentence: Strong genetic and functional evidence underpin the inclusion of CMPK2 in the diagnostic work‐up for basal ganglia calcification, offering clinical utility in both decision‑making and future therapeutic strategies.

References

• Journal of neurology • 2023 • The clinical and genetic spectrum of primary familial brain calcification PMID:36862146
• International journal of molecular sciences • 2023 • The Genetics of Primary Familial Brain Calcification: A Literature Review PMID:37446066
• The open biochemistry journal • 2012 • Histidine 117 in the His-Gly-Ser-Asp motif is Required for the Biochemical Activities of Nucleoside Diphosphate Kinase of Mycobacterium smegmatis PMID:22888372
• Journal of structural biology • 2015 • The role of the C-terminus and Kpn loop in the quaternary structure stability of nucleoside diphosphate kinase from Leishmania parasites PMID:26410384

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