Newborn Screening for Mitochondrial Carnitine-Acylcarnitine Cycle Disorders in Zhejiang Province, China

Abstract

Background: Disorders of mitochondrial carnitine–acylcarnitine cycle is a heterogeneous group of hereditary diseases of mitochondrial β-oxidation of fatty acids tested in NBS program in Zhejiang province, China. Large-scale studies reporting disorders of mitochondrial carnitine–acylcarnitine cycle among Chinese population in NBS are limited. The aim of this study was to explain the incidence and biochemical, clinical, and genetic characteristics of disorders of mitochondrial carnitine–acylcarnitine cycle in NBS.Methods: From January 2009 to June 2021, 4,070,375 newborns were screened by tandem mass spectrometry. Newborns with elevated C0 levels and/or C0/(C16 + C18) ratios were identified as having CPT1D, whereas those with decreased C0 levels and/or C0/(C16 + C18) ratios and/or elevated C12-C18:1 level were identified as having CPT2D or CACTD. Suspected positive patients were further subjected to genetic analysis. All confirmed patients received biochemical and nutritional treatment, as well as follow-up sessions.Results: Overall, 20 patients (12 with CPT1D, 4 with CPT2D, and 4 with CACTD) with disorders of mitochondrial carnitine–acylcarnitine cycle were diagnosed by NBS. The overall incidence of these disorders was one in 203,518 newborns. In toal, 11 patients with CPT1D exhibited increased C0 levels and C0/(C16 + C18) ratios. In all patients of CPT2D, all long chain acyl-carnitines levels were elevated except for case 14 having normal C12 levels. In all patients with CACTD, all long chain acyl-carnitines levels were elevated except for case 17 having normal C12, C18, and C18:1 levels. Most patients with CPT1D were asymptomatic. Overall, two of 4 patients with CPT2D did not present any clinical symptom, but other two patients died. In 4 cases with CACTD, the disease was onset after birth, and 75% patients died. In total, 14 distinct mutations were identified in CPT1A gene, of which 11 were novel and c.1910C > A (p.S637T), c.740C > T (p.P247L), and c.1328T > C (p.L443P) were the most common mutations. Overall, 3 novel mutations were identified in CPT2 gene, and the most frequent mutation was c.1711C > A (p.P571T). The most common variant in SLC25A20 gene was c.199-10T > G.Conclusion: Disorders of mitochondrial carnitine–acylcarnitine cycle can be detected by NBS, and the combined incidence of these disorders in newborns was rare in Zhejiang province, China. Most patients presented typical acylcarnitine profiles. Most patients with CPT1D presented normal growth and development, whereas those with CPT2D/CACTD exhibited a high mortality rate. Several novel CPT1A and CPT2 variants were identified, which expanded the variant spectrum.

Newborn Screening with (C16 + C18:1)/C2 and C14/C3 for Carnitine Palmitoyltransferase II Deficiency throughout Japan Has Revealed C12/C0 as an Index of Higher Sensitivity and Specificity

“…Even after the ratios of long-chain acylcarnitines to C3, especially C14/C3, were proposed as promising indices for NBS in 2017 [4,5], we found only two articles in which data for C14/C3 are presented: one single-case report from Canada [10] and one about a study on NBS for carnitine cycle disorders conducted in a province of China [11]. In the latter article, decreases in free carnitine (C0) or C0/(C16 + C18) levels or elevated levels of C12 to C18:1 were used as indices for detecting CPT II deficiency, and four cases were identified.…”

One potential hotspot SLC25A20 gene variants in Chinese patients with carnitine-acylcarnitine translocase deficiency

“…NBS (Newborn screening) plays an important role in early detection of deficiency in enzymes of mitochondrial carnitine-acylcarnitinecycle. Most patients with CACT and CPT2 deficiency had a higher C12–C18:1 level than those without these ( 3 ). SLC25A20 gene mutational analysis is required to identify CACT deficiency, but this can be done without CACT activity assessment.…”

“…Carnitine-acylcarnitine translocase deficiency (CACT deficiency, OMIM # 212138) was first described by Stanley CA et al in 1992 ( 1 ). It is a rare and life-threatening autosomal recessive disorder with an incidence of 1:60,000 in Hongkong and 1:1,017,593 in Zhejiang province China ( 2 , 3 ). CACT deficiency, encoded by the SLC25A20 gene on chromosome 3p21.31, is the cause of this condition ( 4 ).…”

Carnitine-acylcarnitine translocase deficiency caused by SLC25A20 gene heterozygous variants in twins: a case report

“…Data from 1.8 million newborns that were screened in Zhejiang Province confirmed the diagnosis of CACTD in none of the patients. 12 Among approximately 150 000 newborns that were screened in Zhejiang Province, two cases were diagnosed with CACTD, which gives an incidence rate of approximately 1/76 895. 12 The incidence rate in Hong Kong is approximately 1/60 000.…”

“…12 Among approximately 150 000 newborns that were screened in Zhejiang Province, two cases were diagnosed with CACTD, which gives an incidence rate of approximately 1/76 895. 12 The incidence rate in Hong Kong is approximately 1/60 000. 13,14 Most of the reported cases have a poor prognosis and approximately 82% patients develop the disease in the neonatal period.…”