Nithiwat Vatanavicharn1, Kenji Yamada2, Yuka Aoyama3, Toshiyuki Fukao4, Narumon Densupsoontorn5, Pipop Jirapinyo5, Achara Sathienkijkanchai6, Seiji Yamaguchi2, Pornswan Wasant6. 1. Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Electronic address: nithiwat_v@hotmail.com. 2. Department of Pediatrics, Shimane University School of Medicine, Izumo, Shimane, Japan. 3. Medical Information Sciences Division, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan. 4. Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan. 5. Division of Nutrition, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 6. Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Abstract
BACKGROUND: Mitochondrial fatty acid oxidation (FAO) disorders are among the causes of acute encephalopathy- or myopathy-like illness. Carnitine-acylcarnitine translocase (CACT) deficiency is a rare FAO disorder, which represent an energy production insufficiency during prolonged fasting, febrile illness, or increased muscular activity. CACT deficiency is caused by mutations of the SLC25A20 gene. Most patients developed severe metabolic decompensation in the neonatal period and died in infancy despite aggressive treatment. PATIENTS AND METHODS: We herein report the clinical findings of two unrelated cases of CACT deficiency with mutation confirmation, and in vitro bezafibrate responses using in vitro probe acylcarnitine (IVP) assay. Patients 1 and 2 are products of nonconsanguineous parents. Both patients developed cardiac arrest at day 3 of life but survived the initial events. Their blood chemistry revealed hypoglycemia and metabolic acidosis. The acylcarnitine profiles in both patients demonstrated increased long-chain acylcarnitines, suggesting CACT or carnitine palmitoyltransferase-2 (CPT2) deficiency. RESULTS: The mutation analysis identified homozygous IVS2-10T>G in the SLC25A20 gene in both patients, confirming the diagnosis of CACT deficiency. The IVP assay revealed increased C16, C16:1, but decreased C2 with improvement by bezafibrate in the cultured fibroblasts. The short-term clinical trial of bezafibrate in Patient 1 did not show clinical improvement, and died after starting the trial for 6 months. CONCLUSION: This splicing mutation has been identified in other Asian populations indicating a possible founder effect. IVP assay of cultured fibroblasts could determine a response to bezafibrate treatment. A long-term clinical trial of more enrolled patients is required for evaluation of this therapy.
BACKGROUND: Mitochondrial fatty acid oxidation (FAO) disorders are among the causes of acute encephalopathy- or myopathy-like illness. Carnitine-acylcarnitine translocase (CACT) deficiency is a rare FAO disorder, which represent an energy production insufficiency during prolonged fasting, febrile illness, or increased muscular activity. CACT deficiency is caused by mutations of the SLC25A20 gene. Most patients developed severe metabolic decompensation in the neonatal period and died in infancy despite aggressive treatment. PATIENTS AND METHODS: We herein report the clinical findings of two unrelated cases of CACT deficiency with mutation confirmation, and in vitro bezafibrate responses using in vitro probe acylcarnitine (IVP) assay. Patients 1 and 2 are products of nonconsanguineous parents. Both patients developed cardiac arrest at day 3 of life but survived the initial events. Their blood chemistry revealed hypoglycemia and metabolic acidosis. The acylcarnitine profiles in both patients demonstrated increased long-chain acylcarnitines, suggesting CACT or carnitine palmitoyltransferase-2 (CPT2) deficiency. RESULTS: The mutation analysis identified homozygous IVS2-10T>G in the SLC25A20 gene in both patients, confirming the diagnosis of CACT deficiency. The IVP assay revealed increased C16, C16:1, but decreased C2 with improvement by bezafibrate in the cultured fibroblasts. The short-term clinical trial of bezafibrate in Patient 1 did not show clinical improvement, and died after starting the trial for 6 months. CONCLUSION: This splicing mutation has been identified in other Asian populations indicating a possible founder effect. IVP assay of cultured fibroblasts could determine a response to bezafibrate treatment. A long-term clinical trial of more enrolled patients is required for evaluation of this therapy.
Authors: Stephen F Kingsmore; Audrey Henderson; Mallory J Owen; Michelle M Clark; Christian Hansen; David Dimmock; Christina D Chambers; Laura L Jeliffe-Pawlowski; Charlotte Hobbs Journal: NPJ Genom Med Date: 2020-11-02 Impact factor: 8.617
Authors: Stephen F Kingsmore; Audrey Henderson; Mallory J Owen; Michelle M Clark; Christian Hansen; David Dimmock; Christina D Chambers; Laura L Jeliffe-Pawlowski; Charlotte Hobbs Journal: NPJ Genom Med Date: 2020-11-02 Impact factor: 8.617