Diagnosis Of Fatty Acid Oxidation Disorders Research Articles

Screening for newborn fatty acid oxidation disorders in Chongqing and the follow-up of confirmed children.

To investigate the incidence, clinical characteristics, gene mutations and prognosis of fatty acid oxidation disorders (FAOD) in newborns in Chongqing. Blood samples were collected from 35 374 newborns for screening of FAOD in the Neonatal Screening Center of Women and Children's Hospital of Chongqing Medical University from July 2020 to February 2022. The acylcarnitine spectrum was detected by tandem mass spectrometry, the positive children in primary screening were recalled within 2 weeks, and the diagnosis of FAOD was confirmed by urine organic acid measurement, blood biochemistry testing and genetic analysis. The confirmed children were given early intervention, treatment and followed-up. Among 35 374 newborns, there were 267 positive children in primary screening, with a positive rate of 0.75%. Five children with FAOD were diagnosed by gene detection, with an incidence rate of 1/7075. Among them, there were 3 cases of primary carnitine deficiency (PCD, 1/11 791), 1 case of short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/35 374) and 1 case of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 1/35 374). The c.1400C>G and c.338G>A were the common mutations of SLC22A5 gene in 3 children with PCD, while c.621G>T was a novel mutation. There were no clinical manifestations during the follow-up period in 2 children with supplementation of L-carnitine. Another child with PCD did not follow the doctor's advice of L-carnitine treatment, and had acute attack at the age of 6 months. The child recovered after treatment, and developed normally during the follow-up. The detected ACADS gene mutations were c.417G>C and c.1054G>A in child with SCADD, who showed normal intelligence and physical development without any clinical symptoms. The mutations of ACADVL gene were c.1349G>A and c.1843C>T in child with VLCADD, who showed acute attack in the neonatal period and recovered after treatment; the child was fed with milk powder rich in medium-chain fatty acids and had normal development during the follow-up. The incidence of FAOD in Chongqing area is relatively high. PCD is the most common type, and the clinical phenotype of VLCADD is serious. After early diagnosis through neonatal screening, standardized treatment and management is followed, most of FAOD children can have good prognosis.

Screening for fatty acid oxidation disorders of newborns in Zhejiang province:prevalence, outcome and follow-up

To screen fatty acid oxidation disorders (FAOD) in newborns in Zhejiang province. A total of 1 861 262 newborns were screened for FAOD in Neonatal Screening Center of Zhejiang Province during January 2009 and December 2016. The blood samples from newborns were screened by tandem mass spectrometry, and diagnosis of FAOD was confirmed by urine organic acid measurement combined with genetic analysis. The prognosis and follow-up of patients with FAOD were also evaluated. Of 1 861 262 newborns screened, 121 cases of FAOD were diagnosed. Among 121 cases of FAOD, primary carnitine deficiency (PCD) was the most common type (n=78, 64.5%), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD, n=27, 22.3%), medium-chain acyl-CoA dehydrogenase deficiency (n=5, 4.1%), multiple acyl-CoA dehydrogenase deficiency (MADD, n=4, 3.3%), very long-chain acyl-CoA dehydrogenase deficiency (n=3, 2.5%), carnitine palmitoyltransferase Ⅰ deficiency(n=2, 1.7%)and carnitine palmitoyltransferase Ⅱ deficiency (CPTⅡD, n=2, 1.7%). During 2-82 month follow-up, 15 patients were lost, 4 were dead (1 PCD, 1 MADD, and 2 CPTⅡD), and the remaining 102 subjects had normal intelligence and physical development without any clinical symptoms. PCD and SCADD are the most common FAODs in newborns in Zhejiang province. Most of FAOD patients are asymptomatic, and have normal growth and development after early intervention and management.

Feature Construction Can Improve Diagnostic Criteria for High-Dimensional Metabolic Data in Newborn Screening for Medium-Chain Acyl-CoA Dehydrogenase Deficiency

In newborn screening with tandem mass spectrometry, multiple intermediary metabolites are quantified in a single analytical run for the diagnosis of fatty-acid oxidation disorders, organic acidurias, and aminoacidurias. Published diagnostic criteria for these disorders normally incorporate a primary metabolic marker combined with secondary markers, often analyte ratios, for which the markers have been chosen to reflect metabolic pathway deviations. We applied a procedure to extract new markers and diagnostic criteria for newborn screening to the data of newborns with confirmed medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and a control group from the newborn screening program, Heidelberg, Germany. We validated the results with external data of the screening center in Hamburg, Germany. We extracted new markers by performing a systematic search for analyte combinations (features) with high discriminatory performance for MCADD. To select feature thresholds, we applied automated procedures to separate controls and cases on the basis of the feature values. Finally, we built classifiers from these new markers to serve as diagnostic criteria in screening for MCADD. On the basis of chi(2) scores, we identified approximately 800 of >628,000 new analyte combinations with superior discriminatory performance compared with the best published combinations. Classifiers built with the new features achieved diagnostic sensitivities and specificities approaching 100%. Feature construction methods provide ways to disclose information hidden in the set of measured analytes. Other diagnostic tasks based on high-dimensional metabolic data might also profit from this approach.

Recognition and management of fatty acid oxidation defects: a series of 107 patients.

In a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty-eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long-chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long-term dietary therapy aims to prevent periods of fasting and restrict long-chain fatty acid intake with supplementation of medium-chain triglycerides. Despite these therapeutic measures, the long-term prognosis remains uncertain.