CPT2 – Carnitine Palmitoyltransferase II Deficiency

Carnitine palmitoyltransferase II (CPT2; HGNC:2330) is a mitochondrial enzyme that catalyzes the final step of long-chain fatty acid import into the mitochondrial matrix for β-oxidation. Pathogenic biallelic CPT2 variants cause carnitine palmitoyltransferase II deficiency (MONDO:0015515), an autosomal recessive disorder with three clinical subtypes: lethal neonatal, severe infantile hepatocardiomuscular, and adult myopathic phenotypes ([PMID:1999498]).

The infantile form presents with hypoketotic hypoglycemia and hepatomuscular involvement, often leading to sudden death in early infancy, whereas the adult myopathic form manifests as recurrent rhabdomyolysis triggered by exercise or fever. Over 50 unrelated probands across multiple populations have been reported with biallelic CPT2 variants, confirming recessive inheritance and phenotype concordance ([PMID:9309694]).

Genetic evidence includes both missense (e.g., c.338C>T (p.Ser113Leu)) and truncating variants, with S113L accounting for ~50% of alleles in European cohorts and founder E174K/F383Y alleles in Japanese families. Case reports and series document compound heterozygosity and homozygosity for these variants, with >20 distinct pathogenic alleles described ([PMID:9600456]).

Segregation data demonstrate variant co-segregation in families: e.g., an Italian pedigree with homozygous S113L in the proband, symptomatic twin brothers, and a sibling who died in childhood, totaling 3 additional affected relatives.

Functional studies reveal that the S113L variant markedly reduces steady-state CPT II protein stability and enzymatic activity, exhibits thermolability, and increases sensitivity to malonyl-CoA inhibition. Patient fibroblasts and recombinant mutant enzymes show <20% residual activity and impaired long-chain fatty acid oxidation, consistent with disease mechanism ([PMID:8358442]).

In sum, genetic and experimental data support a Strong association between CPT2 and CPT II deficiency, guiding molecular diagnostics and family screening. Early genetic testing and newborn screening with acylcarnitine profiling enable timely initiation of dietary management and avoidance of fasting or strenuous exercise. Key take-home: CPT2 sequencing and functional confirmation are clinically actionable for diagnosis and management.

References

• The Journal of clinical investigation | 1991 | Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death PMID:1999498
• Molecular and cellular biochemistry | 1997 | Carnitine palmitoyltransferase II deficiency: diagnosis by molecular analysis of blood PMID:9309694
• Human mutation | 1998 | Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes PMID:9600456
• Nature genetics | 1993 | Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients PMID:8358442

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