Free carnitine concentrations and biochemical parameters in medium‐chain acyl‐CoA dehydrogenase deficiency: Genotype–phenotype correlation

Abstract

Biallelic variants in the ACADM gene cause medium-chain acyl-CoA dehydrogenase deficiency (MCADD). This study reports on differences in the occurrence of secondary free carnitine (C0) deficiency and different biochemical phenotypes related to genotype and age in 109 MCADD patients followed-up at a single tertiary care center during 22 years. C0 deficiency occurred earlier and more frequently in c.985A>G homozygotes (genotype A) compared to c.985A>G compound heterozygotes (genotype B) and individuals carrying variants other than c.985A>G and c.199C>T (genotype D) (median age 4.2 vs. 6.6 years; p < 0.001). No patient carrying c.199C>T (genotype C) developed C0 deficiency. A daily dosage of 20-40 mg/kg carnitine was sufficient to maintain normal C0 concentrations. Compared to genotype A as reference group, octanoylcarnitine (C8) was significantly lower in genotypes B and C, whereas C0 was significantly higher by 8.28 μmol/L in genotype C (p < 0.05). In conclusion, C0 deficiency is mainly found in patients with pathogenic genotypes associated with high concentrations of presumably toxic acylcarnitines, while individuals carrying the variant c.199C>T are spared and show consistently mild biochemical phenotypes into adulthood. Low-dose carnitine supplementation maintains normal C0 concentrations. However, future studies need to evaluate clinical benefits on acute and chronic manifestations of MCADD.

The significance of machine learning in neonatal screening for inherited metabolic diseases

“…Among the cohort of 80 patients classified as heterozygous carriers, the ML system displayed a remarkable capacity by accurately identifying 71 cases, thus underscoring its consistent performance across a spectrum of diverse metabolic indices. It is imperative to note that heterozygous carriers, particularly those bearing partially functional alleles, exhibited discernible variations in metabolic profiles when compared to cases characterized by classical mutations ( 23 – 25 ). The presence of a single mutated allele induced noteworthy alterations in associated proteins and enzymes, thereby engendering variations in pertinent metabolic markers.…”