Disorder of carnitine cycle and carnitine transport
-Rare genetic disease
Fatty acid oxidation and ketogenesis disorder with hypertrophic cardiomyopathy
-Rare cardiac disease
-Rare genetic disease
Comment:
Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disease in the mitochondrial transport of long-chain fatty acids (PMID:25614308).
Carnitine-acylcarnitine translocase deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder. Metabolic consequences include hypoketotic hypoglycemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and abnormal acylcarnitine profile with ... Carnitine-acylcarnitine translocase deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder. Metabolic consequences include hypoketotic hypoglycemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have been reported (summary by Rubio-Gozalbo et al., 2004).
In a newborn male infant who developed seizures, apneic periods, and bradycardia at 36 hours of age, Stanley et al. (1992) discovered a deficiency of the carnitine-acylcarnitine translocase (CACT) that transfers fatty acylcarnitines into mitochondria in exchange for ... In a newborn male infant who developed seizures, apneic periods, and bradycardia at 36 hours of age, Stanley et al. (1992) discovered a deficiency of the carnitine-acylcarnitine translocase (CACT) that transfers fatty acylcarnitines into mitochondria in exchange for free carnitine. The attack was apparently provoked by fasting. He had recurrent premature ventricular contractions, ventricular tachycardia, and hypotension. Subsequently, fasting during intercurrent illnesses provoked several episodes of coma, which responded to intravenous administration of glucose. At 30 months of age, the child had generalized weakness of skeletal muscles. Electrocardiogram showed mild ventricular hypertrophy and echocardiogram showed reduced ejection fraction. He died at 37 months of age of increasing weakness, hepatomegaly, and reduced liver function. The parents were nonconsanguineous and healthy. An older brother had died at 4 days of age, 2 days after a sudden, unexplained cardiorespiratory arrest. Pande et al. (1993) described CACT deficiency with severe hypoketotic hypoglycemia, hyperammonemia, and auriculoventricular block in a male, with healthy first-cousin parents, who died at age 8 days. A total deficiency of CACT was found in fibroblasts by use of the carnitine acetylation assay. Brivet et al. (1994) identified CACT deficiency in a patient with impaired long-chain fatty acid (LCFA) oxidation by complementation analysis in cultured fibroblasts. Restoration of release of tritiated water from labeled palmitate was used as a criterion for complementation. The 'case' consisted of premature dizygotic twins, both affected. On the second day of life, they both displayed neurologic deterioration associated with hyperammonemia without hypoglycemia. At 2 months, both displayed acute decompensation within the days following the introduction of a normal diet with nocturnal fast. The deterioration was associated with hypoglycemia, hyperammonemia, huge dicarboxylic aciduria, and hypocarnitinemia. From a clinical point of view, both children had intracardiac conduction defects, hepatomegaly, and liver insufficiency. Despite supportive care, they died within a few days. Niezen-Koning et al. (1995) described an affected child who was the second born in a family in which the first child was probably affected, having died of cardiorespiratory insufficiency 24 hours postpartum. The patient presented at 36 hours postpartum with sudden cardiorespiratory insufficiency, extreme hypoglycemia (glucose not detectable), high potassium, and hyperammonemia. Treatment with carnitine and a low-fat diet supplemented with medium-chain triglycerides were instituted. The patient gradually developed microcephaly with progressive enlargement of the liver and heart. The patient died at 24 months of age. Autopsy demonstrated hypertrophic cardiomegaly and storage fat in liver and striated muscle fibers. The CACT activity in fibroblasts was very low. Brivet et al. (1996) reported the sudden death of a 2-month-old boy, the fifth child of healthy, unrelated parents. The family history was highly suggestive of an LCFA oxidation defect: 2 sibs had died at 24 and 48 hours of life, respectively. Brivet et al. (1996) assessed the acylcarnitine profile in the blood spots of the fifth child's Guthrie card by tandem mass spectrometry 3 years after the baby's death and found accumulation of long-chain acylcarnitine species. The finding suggested a CACT or carnitine palmitoyltransferase (CPT) II deficiency (see 255110). CACT activity was determined in both lymphocytes and fibroblasts from the parents and the 2 healthy sibs. The results suggested a carrier status for a CACT deficiency. CPT II activity was normal in the parents and the 2 healthy sibs, confirming the diagnosis of a CACT deficiency. Olpin et al. (1997) found 6 previous reports of CACT deficiency, all of them showing a severe phenotype with very low or undetectable enzyme activity and very low beta-oxidation flux. All of these patients had a fatal outcome, most of them in the neonatal period, although 1 child survived for 3 years with early medical intervention. On the other hand, Olpin et al. (1997) described the case of a 15-month-old Pakistani child, the offspring of first-cousin parents, who was admitted to hospital following a prolonged clonic convulsion. Plasma glucose was very low and his urine contained no ketones. His condition improved rapidly with intravenous glucose. He was placed on a high-carbohydrate, low-fat diet with frequent feeds and supplementary L-carnitine, with the recommendation that he should not fast for more than 6 hours. At the age of 2 years his growth and development were normal. His cardiac function, as measured by ultrasonography, had remained normal throughout. CACT activity was measured at 6% of controls and mean residual beta-oxidation activity in lymphocytes and fibroblasts was 16%. The residual enzyme activity presumably accounted for the mild phenotype. Morris et al. (1998) reported carnitine-acylcarnitine translocase deficiency in a consanguineous Pakistani family. The fifth child died at 3 months of age. The sixth child died at 2 days of age. Autopsy of this child revealed steatosis of the myocardium, liver, and renal tubules. Urine organic acid analysis showed elevated lactate, dicarboxylic, and hydroxydicarboxylic acids with no ketones. The seventh child was electively admitted to the neonatal unit, breast fed every 3 hours, and given supplemental formula by nasogastric tube. At 3 years of age, the child was physically and developmentally normal with normal echocardiogram, but with mild abnormalities on electromyography of the deltoid. Enzyme assay showed approximately 5% CACT activity. The authors attributed the mild course to residual enzyme activity, but noted that the degree of neonatal lipolysis was another important determinant of the clinical outcome. - Reviews Pande and Murthy (1994) and Rubio-Gozalbo et al. (2004) provided reviews of CACT deficiency.
By direct sequencing of CACT cDNA from a CACT-deficient infant, Huizing et al. (1997) identified a homozygous cytosine nucleotide insertion (613698.0001). The insertion caused a frameshift and an extension of the open reading frame with 23 novel codons. ... By direct sequencing of CACT cDNA from a CACT-deficient infant, Huizing et al. (1997) identified a homozygous cytosine nucleotide insertion (613698.0001). The insertion caused a frameshift and an extension of the open reading frame with 23 novel codons. In a child with CACT deficiency who was the product of a consanguineous marriage, Iacobazzi et al. (2004) identified homozygosity for a gln238-to-arg mutation in the SLC25A20 gene (Q238R; 613698.0007). Both parents were heterozygous for the mutation. The patient presented shortly after birth with cardiac myopathy and arrhythmia coupled with severe nonketotic hypoglycemia. Therapy with a formula which provided most of the fat in the form of medium chain triglycerides as well as carnitine supplementation reduced the concentration of long chain acylcarnitines and reversed cardiac symptoms and hypoglycemia. Iacobazzi et al. (2004) found significant clinical heterogeneity among 6 CACT-deficient patients from Italy, Spain, and North America. In 5 patients, the disease manifested in the neonatal period, whereas the remaining patient, the younger sib of an infant who had died with clinical suspicion of fatty acid oxidation defect, had been treated since birth and was clinically asymptomatic at 4.5 years of age. Sequence analysis of the SLC25A20 gene identified 5 novel mutations and 3 previously reported mutations. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between phenotype and genotype.