CHKB mutations
Choline Kinase β (CHKB) gene is located on chromosome 22q13.33 and contains 11 exons. Homozygous or compound heterozygous mutations including frameshift deletions, non-sense, splice site, and missense mutations or small deletion are identified in CHKB in all patients. The recessive CHKB loss-of-function mutations are distributed across all coding regions of the 11 exons with no specific hot spots.
Megaconial CMD and CHKB mutations-- genotypic-phenotypic correlation
Same homozygous CHKB mutations in different patients of the same ethic group often have different presentations. Hence the genotypic-phenotypic correlation for CHKB-related CMD is not clear.
Molecular-Pathomechanistic link
• The molecular pathomechanistic link was first evidenced in the spontaneous mutated mice with neonatal onset rostrocaudal muscular dystrophy (rmd) having autosomal recessive mutation in choline kinase β(Chkb).
• The most striking feature of the muscle pathology in the rmd mice is the peculiar mitochondrial abnormality – mitochondria are greatly enlarged at the periphery of the fiber and absent from the center, the same appearance as in human patients.
• In the skeletal muscles of rmd mice, the choline kinase (CHK) activity was absent, and the phosphatidylcholine (PC) levels were decreased. Similarly, in the skeletal muscles of the three affected Japanese patients, CHK activities were barely detectable, and the PC levels were markedly reduced, suggesting that CMDs due to CHKB mutations in affected patients and rmd mice are not only clinically, molecularly and pathologically similar but also pathomechanistically alike.
Diagnostic testing
The diagnosis of megaconial CMD is confirmed in a proband with compatible clinical characteristics and the identification of homozygous or compound heterozygous pathogenic variants in the CHKB gene identified by one of the following molecular genetic tests.
Single gene testing -- Sequencing of CHKB is performed to detect small intragenic deletions, insertions and missense, nonsense and splice site pathogenic variants. This method is often considered when there are both typical clinical presentation and muscle biopsy findings.
A muscular dystrophy multigene panel -- The multigene panel includes CHKB and other genes of interest.
Comprehensive genomic testing -- Genomic testing does not require the clinicians to determine which gene is likely involved. Whole exome sequencing is most commonly used. Whole genome sequencing is also possibly used if deep intronic mutation is suspected.
CHKB