Weiss Katharina J, Berger Ursula, Haider Maliha, Wagner Matias, Märtner E M Charlotte, Regenauer-Vandewiele Stephanie, Lotz-Havla Amelie, Schuhmann Elfriede, Röschinger Wulf, Maier Esther M
Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany.
Clin Genet. 2023 Jun;103(6):644-654. doi: 10.1111/cge.14316. Epub 2023 Mar 13.
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.
ACADM基因的双等位基因变异会导致中链酰基辅酶A脱氢酶缺乏症（MCADD）。本研究报告了在一家三级医疗中心对109例MCADD患者进行22年随访期间，继发性游离肉碱（C0）缺乏的发生率以及与基因型和年龄相关的不同生化表型的差异。与c.985A>G复合杂合子（基因型B）和携带c.985A>G和c.199C>T以外变异的个体（基因型D）相比，c.985A>G纯合子（基因型A）中C0缺乏出现得更早且更频繁（中位年龄4.2岁对6.6岁；p<0.001）。携带c.199C>T（基因型C）的患者均未出现C0缺乏。每日20 - 40mg/kg的肉碱剂量足以维持正常的C0浓度。以基因型A作为参照组，基因型B和C中的辛酰肉碱（C8）显著降低，而基因型C中的C0显著升高8.28μmol/L（p<0.05）。总之，C0缺乏主要见于与可能有毒的酰基肉碱高浓度相关的致病基因型患者，而携带c.199C>T变异的个体未受影响，成年后生化表型始终较轻。低剂量补充肉碱可维持正常的C0浓度。然而，未来的研究需要评估其对MCADD急性和慢性表现的临床益处。
