Carnitine-acylcarnitine translocase deficiency with c.199-10 T>G and novel c.1A>G mutation

Abstract

Rationale:Carnitine-acylcarnitine translocate deficiency (CACTD) is a rare and life-threatening, autosomal recessive disorder of fatty acid β-oxidation characterized by hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, liver dysfunction, and muscle weakness; culminating in early death. To date, CACTD cases screened from the Chinese mainland population, especially patient with compound heterozygote with c.199-10T>G and a novel c.1A>G mutation in the SLC25A20 gene has never been described.Patient concerns:Herein, we report 2 neonatal cases of CACTD identified from the mainland China. These 2 patients were presented with severe metabolic crisis and their clinical conditions deteriorate rapidly and both died of cardiorespiratory collapse in the first week of life. We present the clinical and biochemical features of 2 probands and a brief literature review of previously reported CACTD cases with the c.199-10T>G mutation.Diagnoses:The acylcarnitine profiles by tandem-mass-spectrometry and the mutation analysis of SLC25A20 gene confirmed the diagnosis of CACTD in both patients. Mutation analysis demonstrated that patient No. 1 was homozygous for c.199-10T>G mutation, while patient No. 2 was a compound heterozygote for 2 mutations, a maternally-inherited c.199-10T>G and a paternally-inherited, novel c.1A>G mutation.Interventions:Both patients were treated with an aggressive treatment regimen include high glucose and arginine infusion, respiratory, and circulatory support.Outcomes:The first proband died 3 days after delivery due to sudden cardiac arrest. The second patient's clinical condition, at one time, was improved by high glucose infusion, intravenous arginine, and circulatory support. However, the patient failed to wean from mechanical ventilation. Unfortunately, her parents refused further treatment due to fear of financial burdens. The patient died of congestive heart failure in the 6th day of life.Lessons:We report the first 2 cases of CACTD identified from the mainland China. Apart from a founder mutation c.199-10T>G, we identified a novel c.1A>G mutation. Patients with CACTD with a genotype of c.199-10T>G mutation usually presents with a severe clinical phenotype. Early recognition and appropriate treatment is crucial in this highly lethal disorder. This case series highlights the importance of screening for metabolic diseases including CACTD in cases of sudden infant death and unexplained abrupt clinical deterioration in the early neonatal period.

Clinical presentation and proteomic signature of patients with TANGO2 mutations

“…We performed proteomic profiling in fibroblasts, which indicated altered fatty acid oxidation, folic acid and pyrimidine metabolism in mitochondria . Impaired fatty acid oxidation was suggested by decrease of fatty aldehyde dehydrogenases (ALDH3A2, ALDH4A1, ALDH6A1;) and SLC25A20, encoding a mitochondrial carnitine/acylcarnitine carrier protein . Mutations in these genes lead to severe neurological abnormalities, developmental delay, cardiomyopathy, arrhythmias, skeletal muscle damage, liver dysfunction, and episodes of life‐threatening coma, many of these clinical findings are also present in TANGO2‐deficient patients.…”

Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1)

“…Substantially elevated acylcarnitines have been previously associated with disorders of mitochondrial fatty acid oxidation and organic academia's [28,29]. Furthermore, elevated plasma C16 and C18:1 acylcarnitines are the formal diagnostic criteria for carnitine-acylcarnitine translocase deficiency [30], and support diagnosis of carnitine palmitoyltransferase II deficiency [31]. The acylcarnitine levels were further increased with dietary modification.…”

Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

“…The disease can occur in a mild or severe form, with remaining protein activity of about 5% or below 1%, respectively. CAC pathophysiology, common clinical features, and interventions of the disease have been reviewed recently (Indiveri et al, 2011;Yan et al, 2017). The severe phenotype is usually present in the neonatal period with a high mortality rate within the first year of life due to cardiac arrest and respiratory failure (Yan et al, 2017).…”

“…CAC pathophysiology, common clinical features, and interventions of the disease have been reviewed recently (Indiveri et al, 2011;Yan et al, 2017). The severe phenotype is usually present in the neonatal period with a high mortality rate within the first year of life due to cardiac arrest and respiratory failure (Yan et al, 2017). Therefore, early appropriate diagnosis and treatment are necessary to manage the highly lethal disorder and to ameliorate disease progression.…”

“…Therapeutic approaches include intravenous glucose injection to suppress fatty acid mobilization and oxidation, as well as ammonia detoxification through arginine administration. Longterm management requires strict diet with frequent meals to avoid fasting periods, high-carbohydrate intake, medium-chain triglyceride supplementation, and limitation of long-chain fatty acids (Indiveri et al, 2011;Yan et al, 2017).…”