SLC25A20 – Carnitine‐Acylcarnitine Translocase Deficiency

Carnitine‐acylcarnitine translocase (CACT), encoded by SLC25A20, is essential for mitochondrial long‐chain fatty acid oxidation by importing acylcarnitines in exchange for free carnitine. CACT deficiency (MONDO:0008918) is an autosomal recessive disorder characterized by neonatal hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, arrhythmias, encephalopathy, and high early mortality despite dietary intervention (PMID:12801121).

1. Clinical Validity

The association between SLC25A20 and CACT deficiency is Definitive based on over 100 affected individuals from >20 unrelated families worldwide, consistent autosomal recessive segregation, and concordant biochemical and functional data. Multiple recurrent variants (e.g., c.199-10T>G splice mutation) and diverse loss-of-function and missense mutations have been reported across populations (PMID:12559850; PMID:15365988).

2. Genetic Evidence

Inheritance is autosomal recessive with allelic heterogeneity, including frameshift, nonsense, splice, and missense variants. The intronic founder variant c.199-10T>G is the most prevalent in Asian cohorts (PMID:33194920). Segregation of pathogenic alleles in six affected siblings has been documented (PMID:10653336).

3. Functional Evidence

In vitro expression of SLC25A20 missense mutations (e.g., p.Arg133Trp, p.Ala281Val) in E. coli and liposome assays demonstrates markedly reduced CACT transport activity (PMID:15365988). A fungal model in Aspergillus nidulans complements human CACT activity and confirms pathogenicity of human variants (PMID:12892634).

4. Therapeutic Implications

Prompt newborn screening by tandem MS/MS and early interventions—triheptanoin and carglumic acid—can stabilize metabolic crises, though outcome depends on residual enzyme activity.

Key Take‐home

SLC25A20 variant screening and acylcarnitine profiling are critical for the early diagnosis of CACT deficiency, enabling timely metabolic management and genetic counseling.

References

• Journal of human genetics • 2000 • Identification of two novel mutations of the carnitine/acylcarnitine translocase (CACT) gene in a patient with CACT deficiency. PMID:10697964
• Human mutation • 2004 • Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency. PMID:15365988
• European journal of pediatrics • 2000 • Familial neonatal SIDS revealing carnitine-acylcarnitine translocase deficiency. PMID:10653336
• Fungal genetics and biology • 2003 • Functional analysis of mutations in the human carnitine/acylcarnitine translocase in Aspergillus nidulans. PMID:12892634
• Frontiers in pediatrics • 2020 • Late-Onset Carnitine-Acylcarnitine Translocase Deficiency With SLC25A20 c.199-10T>G Variation: Case Report and Pathologic Analysis of Liver Biopsy. PMID:33194920

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