Mitochondrial fatty acid oxidation disorders (FAODs) are caused by defects in β-oxidation enzymes, including very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TFP), carnitine palmitoyltransferase-2 (CPT2), carnitine-acylcarnitine translocase (CACT) and others. During prolonged fasting, infection, or exercise, patients with FAODs present with hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death. This article describes the diagnosis, newborn screening, and treatment of long-chain FAODs with a focus on VLCAD deficiency. VLCAD deficiency is generally classified into three phenotypes based on onset time, but the classification should be comprehensively determined based on genotype, residual enzyme activity, and clinical course, due to a lack of apparent genotype-phenotype correlation. With the expansion of newborn screening for FAODs, several issues have arisen, such as missed detection, overdiagnosis (including detection of benign/asymptomatic type), and poor prognosis of the neonatal-onset form. Meanwhile, dietary management and restriction of exercise have been unnecessary for patients with the benign/asymptomatic type of VLCAD deficiency with a high fatty acid oxidation flux score. Although L-carnitine therapy for VLCAD/TFP deficiency has been controversial, supplementation with L-carnitine may be accepted for CPT2/CACT and multiple acyl-CoA dehydrogenase deficiencies. Recently, a double-blind, randomized controlled trial of triheptanoin (seven-carbon fatty acid triglyceride) versus trioctanoin (regular medium-chain triglyceride) was conducted and demonstrated improvement of cardiac functions on triheptanoin. Additionally, although the clinical efficacy of bezafibrate remains controversial, a recent open-label clinical trial showed efficacy of this drug in improving quality of life. These drugs may be promising for the treatment of FAODs, though further studies are required.

Management and diagnosis of mitochondrial fatty acid oxidation disorders: focus on very-long-chain acyl-CoA dehydrogenase deficiency.

Expanded newborn screening for inborn errors of metabolism (IEMs) by tandem mass spectrometry (MS/MS) could simultaneously analyze more than 40 metabolites and identify about 50 kinds of IEMs. Next generation sequencing (NGS) targeting hundreds of IMEs-associated genes as a follow-up test in expanded newborn screening has been used for genetic analysis of patients. The spectrum, prevalence, and genetic characteristic of IEMs vary dramatically in different populations. To determine the spectrum, prevalence, and gene mutations of IEMs in newborns in Suzhou, China, 401,660 newborns were screened by MS/MS and 138 patients were referred to genetic analysis by NGS. The spectrum of 22 IEMs were observed in Suzhou population of newborns, and the overall incidence (excluding short chain acyl-CoA dehydrogenase deficiency (SCADD) and 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD)) was 1/3,163. The prevalence of each IEM ranged from 1/401,660 to 1/19,128, while phenylketonuria (PKU) (1/19,128) and Mild hyperphenylalaninemia (M-HPA) (1/19,128) were the most common IEMs, followed by primary carnitine uptake defect (PCUD) (1/26,777), SCADD (1/28,690), hypermethioninemia (H-MET) (1/30,893), 3-MCCD (1/33,412) and methylmalonic acidemia (MMA) (1/40,166). Moreover, 89 reported mutations and 51 novel mutations in 25 IMEs-associated genes were detected in 138 patients with one of 22 IEMs. Some hotspot mutations were observed for ten IEMs, including PAH gene c.728G > A, c.611A > G, and c.721C > T for Phenylketonuria, PAH gene c.158G > A, c.1238G > C, c.728G > A, and c.1315+6T > A for M-HPA, SLC22A5 gene c.1400C > G, c.51C > G, and c.760C > T for PCUD, ACADS gene c.1031A > G, c.164C > T, and c.1130C > T for SCAD deficiency, MAT1A gene c.791G > A for H-MET, MCCC1 gene c.639+2T > A and c.863A > G for 3-MCCD, MMUT gene c.1663G > A for MMA, SLC25A13 gene c.IVS16ins3Kb and c.852_855delTATG for cittrullinemia II, PTS gene c.259C > T and c.166G > A for Tetrahydrobiopterin deficiency, and ACAD8 gene c.1000C > T and c.286C > A for Isobutyryl coa dehydrogenase deficiency. All these hotspot mutations were reported to be pathogenic or likely pathogenic, except a novel mutation of ACAD8 gene c.286C > A. These mutational hotspots could be potential candidates for gene screening and these novel mutations expanded the mutational spectrum of IEMs. Therefore, our findings could be of value for genetic counseling and genetic diagnosis of IEMs.

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Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population.

Purpose of reviewWe review newborn screening (NBS) publications from the developing countries to identify global progress in improving child health.Recent findingsMany developing countries do not yet have national NBS. As infant mortality rates decline, NBS gains in public health priority. Local inc

Newborn screening in the developing countries.

Organic acidurias (OADs) are inherited neurometabolic diseases largely caused by deficiencies in enzymes involved in amino acid degradation, which result in accumulation of organic acids in the brain and other tissues. Disease presentation usually occurs in infancy, although late-onset variants can emerge during childhood or adulthood. Patients predominantly manifest with acute encephalopathy with life-threatening systemic manifestations (classical OADs) or progressive neurological symptoms (cerebral OADs), leading to permanent cerebral abnormalities. Some OADs are treatable, and early diagnosis and treatment implementation have substantially decreased the mortality and overall morbidity from OADs. However, long-term irreversible cerebral and systemic complications are frequent because the therapeutic options are currently limited. The pathophysiology of brain dysfunction is still unclear in most OADs, and further investigation is needed to enable the development of novel therapeutic strategies. This Review focuses on current knowledge of the OADs, including epidemiology, short-term and long-term neurological and systemic features, diagnosis and prognosis, and recent advances in therapy and pathophysiology. The goal of the article is to alert neurologists and related health professionals to the existence and importance of these neurometabolic diseases and to stimulate research into the damaging factors that contribute to their neurodegenerative sequelae. Organic acidurias (OADs) are inherited neurometabolic diseases usually caused by deficiencies in enzymes involved in amino acid catabolism. Wajner reviews the main features of the OADs, focusing particularly on the cerebral manifestations, and highlights recent advances regarding pathophysiology and treatment.

Neurological manifestations of organic acidurias.

This study explored the effectiveness of expanding newborn screening (NBS) by tandem mass spectrometry (TMS) and gene diagnosis by next-generation sequencing (NGS). First, we described the characteristics of gene variants in Jiangsu Province. We collected clinical data from three NBS centers. All infants followed a unified screening and diagnosis process. After obtaining informed consent, dried blood spots (DBSs) were collected and analyzed by TMS. If the results fell outside of the cut-off value, repeat analysis was performed. If the re-test results remained abnormal, the infant was recalled for further assessment. We performed targeted sequencing using the extended edition panel of inborn errors of metabolism (IEM) to detect 306 genes using the Illumina HiSeq 2500 platform. A total of 536,008 babies underwent NBS by TMS in three NBS centres. In total, 194 cases were eventually diagnosed with various types of inherited metabolic diseases, with an overall incidence of 1/2763. There were 23 types of diseases, including ten amino acid disorders (43.5%), eight organic acidaemias (34.8%) and five fatty acid oxidation defects (21.7%). In these infants, we clearly identified variants of disease-causing genes by next-generation sequencing (NGS). Most had two variants and others had one or three variants: 88% of gene variants were heterozygous and 12% were homozygous. There is a certain incidence of IEM in Jiangsu Province and it is necessary to carry out screening for 27 diseases. Meanwhile, NGS combined with TMS offers an enhanced plan for NBS for IEM.

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Application of Next-Generation Sequencing Following Tandem Mass Spectrometry to Expand Newborn Screening for Inborn Errors of Metabolism: A Multicenter Study

Background Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation disorders, (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in many Asian countries. This study aimed to determine the incidence rates of OAs, FAODs, and AAs in Asian countries and Germany using selective screening and ENBS records. Materials and methods Selective screening for IMDs using gas chromatography–mass spectrometry and MS/MS was performed among patients suspected to be afflicted in Asian countries (including Japan, Vietnam, China, and India) between 2000 and 2015, and the results from different countries were compared. Similarly, ENBS results from Japan, South Korea, Taiwan, and Germany were compared. Additionally, the results of selective screening and ENBS in Japan were compared. Results Among 39,270 patients who underwent selective screening, IMDs were detected in 1170. Methylmalonic acidemia was frequently identified in several countries, including Japan (81/377 diagnosed IMDs), China (94/216 IMDs), and India (72/293 IMDs). In Vietnam, however, β-ketothiolase deficiency was particularly frequent (33/250 IMDs). ENBS yielded differences in overall IMD rates by country: 1:8557 in Japan, 1:7030 in Taiwan, 1:13,205 in South Korea, and 1:2200 in Germany. Frequently discovered diseases included propionic acidemia (PPA) and phenylketonuria (PKU) in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I in South Korea, and PKU and medium-chain acyl-CoA dehydrogenase deficiency in Germany. Furthermore, in Japan, selective screening and ENBS yielded respective PPA frequencies of 14.7% and 49.4% among all organic acidemias. Conclusion The incidence rates of IMDs vary by country. Moreover, the disease spectra of IMDs detected via selective screening differ from those detected via ENBS.

Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening.

Dong Hwan Lee

Papers

Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening.