CHKB – Megaconial Congenital Muscular Dystrophy

Choline kinase beta (CHKB) is an enzyme catalyzing the first step in phosphatidylcholine biosynthesis, critical for mitochondrial membrane integrity. Autosomal recessive loss-of-function variants in CHKB cause megaconial congenital muscular dystrophy (MCMD), characterized by enlarged peripheral mitochondria and central mitochondrial depletion in muscle fibers. MCMD presents in infancy with hypotonia, muscle wasting, and multisystem involvement including neurodevelopmental and cardiac features.

Genetic studies have identified CHKB mutations in over 49 unrelated patients worldwide ([PMID:36896673]). Variants include homozygous and compound heterozygous nonsense, frameshift, missense, splice-site, and large deletion alleles. Segregation of pathogenic alleles has been documented in at least four consanguineous or multiplex families ([PMID:27123443], [PMID:26782016]). A recurrent nonsense variant, c.810T>A (p.Tyr270Ter), was first reported in a Spanish patient with combined respiratory chain defects and mtDNA depletion ([PMID:24997086]).

Affected individuals uniformly present early-onset proximal muscle weakness and mildly elevated creatine kinase levels. Intellectual disability ranges from mild to severe, and dilated cardiomyopathy occurs in approximately half of cases. Additional features include motor delay, hypotonia, and skin changes such as ichthyosis‐like dryness and eczema, which can guide differential diagnosis.

Histological analysis of muscle biopsies consistently shows peripheral “megaconial” mitochondria with central sarcoplasmic clearance. Spectrophotometric assays reveal combined complex I, III, and IV deficiencies, whereas mtDNA content may be variably depleted. Intronic and missense mutations disrupt normal splicing and reduce CHKB protein levels, as demonstrated in patient muscle RNA studies ([PMID:36175989]).

Functional characterization supports a haploinsufficiency mechanism: loss of CHKB activity impairs phospholipid synthesis, alters mitochondrial membrane homeostasis, and diminishes respiratory chain assembly. Cellular models show defective complex V subassemblies, and rescue experiments normalize mitochondrial morphology and function in vitro.

Collectively, genetic and experimental data spanning >10 years establish a definitive association between CHKB and MCMD. Early recognition of the phenotype enables prompt genetic testing, informs prognosis, and supports carrier screening. Key take-home: CHKB mutation analysis is essential for diagnosing megaconial congenital muscular dystrophy and guiding multidisciplinary management.

References

• European journal of paediatric neurology • 2014 • Exome sequencing identifies a CHKB mutation in Spanish patient with megaconial congenital muscular dystrophy and mtDNA depletion. PMID:24997086
• Neuromuscular disorders • 2016 • Proximal myopathy with focal depletion of mitochondria and megaconial congenital muscular dystrophy are allelic conditions caused by mutations in CHKB. PMID:26782016
• BioMed research international • 2016 • Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies. PMID:27123443
• Skeletal muscle • 2022 • Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review. PMID:36175989
• Molecular genetics & genomic medicine • 2023 • Large heterozygous deletion and uniparental disomy masquerading as homozygosity in CHKB gene. PMID:36896673

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