SLC22A5 – Systemic Primary Carnitine Deficiency

SLC22A5 encodes the high-affinity carnitine transporter OCTN2, which mediates cellular uptake of carnitine essential for mitochondrial β-oxidation. Systemic primary carnitine deficiency (PCD) is an autosomal recessive disorder presenting with hypoketotic hypoglycemia, cardiomyopathy, and skeletal myopathy (PMID:26828774).

Genetic confirmation of OCTN2 as the causative gene was provided by sequencing in two unrelated patients: one homozygous for c.844C>T (p.Arg282Ter) and another compound heterozygous for c.1202dup (p.Tyr401Ter) and c.1304del (p.Gly435fs), which abolished carnitine transport in patient fibroblasts and was restored by wild-type cDNA transfection (PMID:10051646).

Subsequent reports have expanded the variant spectrum to over 150 pathogenic alleles, including nonsense, frameshift, splice, and missense mutations with residual function. To date, more than 100 probands from over 50 families have been described (PMID:26828774). Segregation in sibships and multi-generation pedigrees consistently supports autosomal recessive inheritance.

Recurrent and founder mutations such as c.760C>T (p.Arg254Ter) in Chinese cohorts and c.844C>T (p.Arg282Ter) in European series account for a significant proportion of alleles in respective populations (PMID:26828774).

Functional assays in CHO cells and patient fibroblasts demonstrate that most truncating variants abolish transport, whereas some missense mutations (e.g., p.Ala301Asp) retain 2–4% residual activity (PMID:11058897; PMID:10679939).

Mechanistic studies revealed that the p.Glu452Lys substitution increases the sodium concentration required for half-maximal stimulation (KNa) from 11.6 mM to 187 mM, reducing Vmax without altering Km, pinpointing a domain important for sodium-coupled transport (PMID:10783384).

Heterozygous carriers generally remain asymptomatic but may develop mild cardiac hypertrophy or arrhythmias under metabolic stress; population studies show no significant increase in unselected cardiomyopathy cohorts, arguing against a dominant effect (PMID:18337137).

Together, the genetic and experimental evidence supports a definitive gene-disease association. Early recognition and lifelong L-carnitine supplementation can prevent acute metabolic decompensation and reverse cardiomyopathy, underscoring the clinical utility of genetic diagnosis.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency. PMID:10051646
• Human Mutation • 2000 • Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype-phenotype correlation. PMID:11058897
• The Journal of Biological Chemistry • 2000 • Abnormal sodium stimulation of carnitine transport in primary carnitine deficiency. PMID:10783384
• Human Mutation • 2000 • A missense mutation in the OCTN2 gene associated with residual carnitine transport activity. PMID:10679939
• Biochimica et biophysica acta • 2016 • Carnitine transport and fatty acid oxidation. PMID:26828774

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