CPT2 – Metabolic Myopathy

Autosomal recessive variants in the CPT2 gene (HGNC:2330) underlie a well‐established metabolic myopathy (MONDO:0020123) characterized by recurrent exercise‐, fasting‐, or infection‐triggered episodes of myalgia, weakness, rhabdomyolysis, and myoglobinuria. Over 200 families and more than 200 affected individuals have been reported, with replication of findings across multiple cohorts over three decades ([PMID:15363638]). Genetic testing consistently identifies biallelic pathogenic variants in CPT2, confirming a definitive gene–disease relationship.

The CPT2 variant spectrum includes >60 distinct mutations: predominantly missense changes but also splice-site, frameshift, and truncating alleles. The most frequent mutation, c.338C>T (p.Ser113Leu), accounts for ~95% of adult-onset alleles ([PMID:24398345]). Other recurrent variants include c.1891C>T (p.Arg631Cys) observed in genetic isolates ([PMID:17651973]) and multiple private mutations such as c.1660C>T (p.Arg554Ter) in infantile forms ([PMID:8651281]).

Clinically, patients present from infancy to adulthood with acute, reversible muscle symptoms—pain (HP:0012531), cramps/spasms (HP:0003394), rhabdomyolysis (HP:0003201), and myoglobinuria (HP:0002913). Episodes are often complicated by acute kidney injury (HP:0001919) or hepatitis (HP:0200119) and are precipitated by prolonged exercise, fever, or fasting. Carrier frequency in European cohorts reaches 1:50, contributing to occasional symptomatic heterozygotes.

Functional studies demonstrate that CPT II deficiency results from abnormal enzyme regulation rather than absence of protein. Thermolability and heightened sensitivity to malonyl-CoA and detergents (Triton X-100, Tween 20) reduce activity under stress ([PMID:28054946]; [PMID:30604089]). Immunoquantitation and fluxomic assays confirm normal protein levels but impaired β-oxidation flux, which is rescued by medium-chain triglyceride supplementation in vitro ([PMID:1483051]; [PMID:29478820]).

Genotype–phenotype correlations reveal that missense mutations (e.g., p.Ser113Leu) retain partial residual activity (~20%), causing the adult muscular form, whereas null or truncating alleles (e.g., p.Arg554Ter) reduce activity below critical thresholds, resulting in infantile hepatocardiomuscular disease ([PMID:8651281]). Compound heterozygotes display intermediate phenotypes, emphasizing the role of modifier factors.

Diagnostic confirmation relies on acylcarnitine profiling, enzyme assays in lymphocytes or muscle, and molecular testing. Newborn screening may detect elevated long-chain acylcarnitines, but normal profiles can occur even during acute attacks, highlighting the importance of gene sequencing. Management includes avoidance of fasting/exertion, high-carbohydrate diet, medium-chain triglyceride supplementation, and prompt treatment of febrile illnesses to prevent rhabdomyolysis.

Key Take-home: CPT2 genetic testing should be performed in patients with recurrent exercise- or fasting-induced myopathy and rhabdomyolysis, as identification of common and private CPT2 variants enables definitive diagnosis, risk stratification, and targeted metabolic management.

References

• Neuromuscular disorders : NMD • 1992 • Immunoquantitation of carnitine palmitoyl transferase in skeletal muscle of 31 patients. PMID:1483051
• Nature genetics • 1993 • Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. PMID:8358442
• American journal of human genetics • 1996 • Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression. PMID:8651281
• Neurology • 2003 • Carnitine palmitoyltransferase II deficiency: molecular and biochemical analysis of 32 patients. PMID:12707442
• Molecular aspects of medicine • 2004 • Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. PMID:15363638
• Journal of the neurological sciences • 2008 • Clinical features and new molecular findings in Carnitine Palmitoyltransferase II (CPT II) deficiency. PMID:17936304
• Journal of the neurological sciences • 2014 • Carnitine palmitoyltransferase II (CPT II) deficiency: genotype–phenotype analysis of 50 patients. PMID:24398345
• International journal of molecular sciences • 2017 • Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features. PMID:28054946
• Journal of bioenergetics and biomembranes • 2018 • Lack of activation of the S113L variant of carnitine palmitoyltransfersase II by cardiolipin. PMID:30604089
• Molecular genetics and metabolism • 2018 • Fluxomic assay-assisted diagnosis orientation in a cohort of 11 patients with myopathic form of CPT2 deficiency. PMID:29478820

Evidence Based Scoring (AI generated)