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

Weifeng Zhang,Qingliu Fu,Yanru Chen,Weilin Peng,Chunmei Lin,Yiming Lin

doi:10.3389/fped.2021.771922

Abstract

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.

Highlights

Carnitine palmitoyltransferase 1A (CPT1A) (OMIM 255120; EC 2.3.1.21) deficiency is an inherited autosomal recessive disorder of mitochondrial fatty acid β-oxidation that impairs fasting ketogenesis and gluconeogenesis in the liver
In addition to the two patients newly diagnosed with CPT1A deficiency, we included in our cohort 10 Chinese patients who were previously diagnosed
All variants were classified as variants of unknown significance (PM2+PP3) according to the ACMG/AMP guidelines for interpretation of sequence variation. The pathogenicity of these novel variants could not be confirmed, we provided the following evidence supporting an association between these variants and CPT1A deficiency: (i) the variants were inherited from the parents, who were carriers; (ii) the variants were not present or had extremely low allelic frequencies in population databases, altered the strictly conserved amino acid residues of CPT1A, and were predicted to be deleterious by different computational tools; and (iii) protein modeling analysis indicated that the variants could lead to structural damage or CPT1A dysfunction

Summary

Introduction

Carnitine palmitoyltransferase 1A (CPT1A) (OMIM 255120; EC 2.3.1.21) deficiency is an inherited autosomal recessive disorder of mitochondrial fatty acid β-oxidation that impairs fasting ketogenesis and gluconeogenesis in the liver. Patients may present with a variety of symptoms, including seizures, lethargy, hypoglycemia, vomiting, diarrhea, fever, and hepatomegaly triggered by fasting. Sudden infant death and hypoketotic hypoglycemia have been reported in patients with severe deficiency [1]. Tandem mass spectrometry (MS/MS) has been widely used in newborn screening (NBS) for inherited metabolic diseases. CPT1A deficiency can be detected by MS/MS, with free carnitine (C0) and C0 to free long-chain acylcarnitine [C0/(C16+C18)] as the primary screening markers [2, 3]. As early identification and timely treatment can prevent clinical symptoms, NBS is an important tool for diagnosing CPT1A deficiency

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