Are carriers of the SLC22A5 (solute carrier family 22 member 5) gene symptomatic?

Carriers of SLC22A5 Gene Are Typically Asymptomatic

Carriers of the SLC22A5 gene (heterozygotes with one mutated copy) are generally asymptomatic and do not develop clinical manifestations of primary carnitine deficiency.

Understanding SLC22A5 and Primary Carnitine Deficiency

The SLC22A5 gene encodes the organic cation transporter type 2 (OCTN2), which is responsible for transporting carnitine across cell membranes 1. Mutations in both copies of this gene cause systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder characterized by:

• In infants: hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia
• In children: skeletal myopathy, elevated creatine kinase, and cardiomyopathy
• In adults: cardiomyopathy, arrhythmias, or fatigability 1

Carrier Status vs. Affected Status

Carriers (Heterozygotes):

• Have one normal copy and one mutated copy of SLC22A5
• Maintain sufficient carnitine transport activity
• Do not develop clinical symptoms of the disease
• May have slightly lower plasma carnitine levels than non-carriers, but still within normal range

Affected Individuals (Homozygotes or Compound Heterozygotes):

• Have mutations in both copies of SLC22A5
• Show significantly reduced carnitine transport (<10% of controls) 1
• Present with clinical manifestations of varying severity
• Require L-carnitine supplementation (50-400 mg/kg/day) 1

Evidence Supporting Asymptomatic Carrier Status

Research has demonstrated that cells from asymptomatic carriers have significantly higher levels of residual carnitine transport activity compared to symptomatic patients 2. This is typically due to:

1. Having one fully functional copy of the SLC22A5 gene
2. The presence of at least one missense mutation that retains partial function rather than nonsense mutations 2

Clinical Implications for Carriers

While carriers do not require treatment, they should be aware of their carrier status for:

• Family planning purposes (25% risk of having an affected child if both parents are carriers) 1
• Understanding that carrier screening requires targeted mutation analysis of the SLC22A5 gene, as plasma carnitine analysis alone is insufficient 1

Important Considerations

• Carrier testing is recommended for family members of affected individuals
• Prenatal diagnosis is possible if both mutations in the affected family are known 1
• Some previously asymptomatic mothers have been identified through newborn screening of their infants with low carnitine levels 2

Conclusion

The evidence clearly indicates that carriers of SLC22A5 mutations maintain sufficient carnitine transport function to prevent clinical manifestations of primary carnitine deficiency. This is consistent with the autosomal recessive inheritance pattern of this disorder, where two defective copies of the gene are required for disease expression.