Palmitoyltransferase 1A Deficiency Research Articles

Clinical features and genetic variants of a case with carnitine palmitoyltransferase 1A deficiency

To identify the possible pathogenesis of a neonate with carnitine palmitoyltransferase 1A (CPT1A) deficiency by analyzing gene variants. Potential variants were detected with an Ion Torrent semiconductor sequencer using a gene panel for inherited diseases, and gene variants were verified by Sanger sequencing. Genetic testing indicated that the neonate has carried c.1895T>A(p.Leu632X) and c.1153G>A (p.Ala385Thr) compound heterozygous variants of the CPT1A gene, which were inherited from his father and mother, respectively. Both variants were verified as novel through the retrieval of HGMD database, ClinVar database and literature. According to the standards and guidelines of the American College of Medical Genetics and Genomics, the c.1895T>A variant was predicted to be pathogenic (PVS1+PM2+PP4) and c.1153G>A as likely pathogenic (PM1+PM2+PM3+PP3). The c.1895T>A and c.1153G>A compound heterozygous variants of the CPT1A gene might underlie the pathogenesis of this child. Above results have provided a basis for clinical diagnosis and genetic counseling, and enriched the variant spectrum of the CPT1 deficiency.

Three Novel and One Potential Hotspot CPT1A Variants in Chinese Patients With Carnitine Palmitoyltransferase 1A Deficiency.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is an inherited disorder of mitochondrial fatty acid β-oxidation that impairs fasting ketogenesis and gluconeogenesis in the liver. Few studies implementing newborn screening (NBS) for CPT1A deficiency in the Chinese population have been reported. This study aimed to determine the biochemical, clinical, and genetic characteristics of patients with CPT1A deficiency in China. A total of 204,777 newborns were screened using tandem mass spectrometry at Quanzhou Maternity and Children's Hospital between January 2017 and December 2018. Newborns with elevated C0 levels were recruited, and suspected patients were subjected to further genetic analysis. Additionally, all Chinese patients genetically diagnosed with CPT1A deficiency were reviewed and included in the study. Among the 204,777 screened newborns, two patients were diagnosed with CPT1A deficiency; thus, the estimated incidence in the selected population was 1:102,388. In addition to the two patients newly diagnosed with CPT1A deficiency, we included in our cohort 10 Chinese patients who were previously diagnosed. Five of these 12 patients were diagnosed via NBS. All patients exhibited elevated C0 and/or C0/(C16+C18) ratios. No clinical symptoms were observed in the five patients diagnosed via NBS, while all seven patients presented with clinical symptoms, including fever, cough, vomiting, diarrhea, and seizures. Eighteen distinct CPT1A variants were identified, 15 of which have been previously reported. The three novel variants were c.272T>C (p.L91P), c.734G>A (p.R245Q), and c.1336G>A (p.G446S). in silico analysis suggested that all three novel variants were potentially pathogenic. The most common variant was c.2201T>C (p.F734S), with an allelic frequency of 16.67% (4/24). Our findings demonstrated that NBS for CPT1A deficiency is beneficial. The three novel variants expand the mutational spectrum of CPT1A in the Chinese population, and c.2201T>C (p.F734S) may be a potential hotspot CPT1A mutation.

Clinical features and gene mutations of 6 patients with carnitine palmitoyltransferase 1A deficiency

The clinical and biochemical data and gene sequencing results of patients with carnitine palmitoyltransferase 1A deficiency were analyzed, in order to improve the understanding of the disease. Six patients (5 males and 1 female, aged from 1 to 8 years old) with carnitine palmitoyltransferase 1A deficiency from Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital between 2008 and 2019 were included. Two cases were detected by neonatal screening and had no clinical symptoms. The remaining 4 cases all showed seizures induced by fever, vomiting or diarrhea. All the 6 patients showed increased serum free carnitine (C0), decreased hexadecanoylcarnitine (C16) and octadecanoylcarnitine (C18), and increased C0/(C16+C18). Meanwhile, compound heterozygous mutations of CPT1A gene were detected in all 6 patients, of which 2 were reported mutations (c.281+1G>A and c.968-8C>T), and 10 were new mutations. The new mutations included 6 missense mutations, 1 nonsense mutation, 1 deletion mutation and 2 splicing mutations. Detection of free carnitine and acyl carnitine by tandem mass spectrometry is helpful for early screening and diagnosis of carnitine palmitoyltransferase 1A deficiency.

Three Patients with CPT1A Deficiency: Literature Review and Case Series

Background: Carnitine palmitoyltransferase 1A deficiency is a rare genetic disorder with autosomal recessive inheritance pattern of fatty acid metabolism secondary to CPT1A mutation. Several dozen infants and children have been described with a deficiency of the liver and kidney CPT1 isoenzyme (CPT1-A). Clinical manifestation includes fasting-induced hypoketotic hypoglycemia, occasionally with extremely abnormal liver function test (LFT) and rarely with renal tubular acidosis. Acyl carnitine analysis has been the main method for the diagnosis of CPT1A deficiency. Prompt treatment of hypoglycemia includes intravenous fluid containing 10% dextrose. To prevent hypoglycemia, infants should eat frequently during the day and have cornstarch continuously at night. Fasting should not last more than 12 hours during illness, surgery, or medical procedures.
 Case Presentation: We reported three patients with CPT1A deficiency presented with hypoglycemia and Reye like syndrome in early childhood that with early diagnosis and treatment they are well in follow-up.
 Conclusion: Prognosis of this genetic disorder will be good with appropriate treatment.

Carnitine Palmitoyltransferase 1A Deficiency: A Rare Cause of Chronic Liver Disease with Rare Presentation

Carnitine Palmitoyltransferase 1A (CPT1A) deficiency is a very rare autosomal recessive disorder of fatty acid oxidation (FAO) which presents in children during concurrent febrile or gastrointestinal illness with hepatic encephalopathy (HE), hepatomegaly and rarely acute liver failure. Chronic liver damage is not reported in CPT1A deficiency. A 27-year-old female with history of CPT1A deficiency diagnosed in early childhood and chronic liver disease (CLD) complicated by thrombocytopenia, splenomegaly with model for end stage liver disease (MELD) score of 12; presented to emergency department with massive hematemesis. Vitals signs were stable. Physical exam was unremarkable except splenomegaly. Labs were significant for hemoglobin 7 g/dL, platelets 45 uL, electrolytes and liver enzymes unremarkable, INR 1.42, prothrombin time 17.2 sec, and total bilirubin 1.6 mg/dL. Computed tomography abdomen revealed prominent para-esophageal and peri-splenic varices, marked splenomegaly and fatty infiltration of liver (Image 1). The patient was started on IV fluids, ceftriaxone and octreotide. EGD revealed four columns of Grade IV esophageal varices (EV) that required 10 variceal bands (Image 2). Hospital course was further complicated by HE, thought to be multifactorial i.e. worsening liver function, poor oral intake and underlying defect in FAO. The patient was treated with lactulose, rifaximin with minimum improvement. Liver function continued to worsen with bilirubin 5.2 mg/dL, INR of 1.8 and MELD score of 24. A diagnosis of ACLF was made as her liver function 3 months prior to this admission was with in normal limits. She was high risk for re-bleeding and not a candidate for TIPS, so emergently transferred to a liver transplant center. CPT1A deficiency is a rare disorder with 60 cases reported so far. Either CLD or presentation as ACLF has not been reported in CPT1A deficiency. Our patient did not have history alcohol use or risk factors for NAFLD and Hepatitis B and C, hemochromatosis, Wilson's disease, autoimmune hepatitis were ruled out.2293_A Figure 1 No Caption available.2293_B Figure 2 No Caption available.

Novel Mutations in theCPT1AGene Identified in the Patient Presenting Jaundice as the First Manifestation of Carnitine Palmitoyltransferase 1A Deficiency

Carnitine palmitoyltransferase 1A (CPT1A) is an enzyme functioning in mitochondrial fatty acid oxidation (FAO) of the liver. Patients with CPT1A deficiency have impaired mitochondrial FAO and display hypoketotic hypoglycemia and hepatic encephalopathy as typical manifestations. In this report, we present a case of CPT1A deficiency presenting jaundice as the first manifestation. A 1.9 years old boy showed jaundice and elevated levels of free and total carnitine were observed. From direct sequencing analysis of CPT1A, two novel mutations, c.1163+1G>A and c.1393G>A (p.Gly465Arg), were identified. At the age of 2.2 years, hypoglycemia, tachycardia, and altered mental status developed just after cranioplasty for craniosynostosis. High glucose infusion rate was required for recovery of his vital signs and mentality. Diet rich in high carbohydrate, low fat and inclusion of medium chain triglyceride oil resulted in improvement in cholestatic hepatitis and since then the boy has shown normal growth velocity and developmental milestones to date.

Atypical Manifestation of Carnitine Palmitoyltransferase 1A Deficiency

Atypical Manifestation of Carnitine Palmitoyltransferase 1A Deficiency

Carrier Frequency of a Common Mutation of Carnitine Palmitoyltransferase 1A Deficiency and Long-Term Follow-Up in Finland

To assess the long-term clinical course of carnitine palmitoyltransferase 1A (CPT1A) deficiency, caused by the c.1364A>C (p.K455T) mutation, and the carrier frequency of this mutation in Finland. This was a long-term follow-up of patients in whom the common mutation was detected. Between 1999 and 2010, 6 cases of CPT1A deficiency were diagnosed and treated with a high-carbohydrate, low-fat diet. The patients experienced their first symptoms during the first years of life, provoked by viral illness and/or fasting. The clinical features included hypoketotic hypoglycemia, hepatopathy, and loss of consciousness, ranging from transient unconsciousness to prolonged hyperlipidemic coma. Five cases carried a homozygous c.1364A>C (p.K455T) mutation, whereas 1 case had a compound c.1364A>C/c.1493A>C (p.Y498S) mutation. During dietary therapy, the patients had few transient decompensations. No carriers of mutation c.1364A>C were detected by minisequencing of 150 control samples. Even though CPT1A deficiency may be life-threatening and lead to prolonged coma, the long-term prognosis is good. A genotype-phenotype correlation implies that the mutations detected are disease-causing. Despite Finland's location close to the Arctic polar region, the carrier frequency of the c.1364A>C mutation in Finland is far lower than that of the variants found in Alaskan, Canadian, and Greenland native populations.

Functional and Structural Basis of Carnitine Palmitoyltransferase 1A Deficiency

Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. Human CPT1A deficiency is characterized by recurrent attacks of hypoketotic hypoglycemia. We presently analyzed at both the functional and structural levels five missense mutations identified in three CPT1A-deficient patients, namely A275T, A414V, Y498C, G709E, and G710E. Heterologous expression in Saccharomyces cerevisiae permitted to validate them as disease-causing mutations. To gain further insights into their deleterious effects, we localized these mutated residues into a three-dimensional structure model of the human CPT1A created from the crystal structure of the mouse carnitine acetyltransferase. This study demonstrated for the first time that disease-causing CPT1A mutations can be divided into two categories depending on whether they affect directly (functional determinant) or indirectly the active site of the enzyme (structural determinant). Mutations A275T, A414V, and Y498C, which exhibit decreased catalytic efficiency, clearly belong to the second class. They are located more than 20 A away from the active site and mostly affect the stability of the protein itself and/or of the enzyme-substrate complex. By contrast, mutations G709E and G710E, which abolish CPT1A activity, belong to the first category. They affect Gly residues that are essential not only for the structure of the hydrophobic core in the catalytic site, but also for the chain-length specificity of CPT isoforms. This study provides novel insights into the functionality of CPT1A that may contribute to the design of drugs for the treatment of lipid disorders.