Abstract
Inherited metabolic disorders (IMDs) in neonates are a diagnostic and therapeutic challenge for the neonatologist, with the priority being to rapidly flag the treatable diseases. The objective of this study was to evaluate the contribution of targeted metabolic testing for diagnosing suspected IMDs on the basis of suggestive clinical setting or family history in neonates. We conducted an observational study over five years, from January 1st, 2010 to December 31, 2014 in the neonatal intensive care unit (NICU) at Robert Debré University Hospital, Paris, France. We assessed the number of neonates for whom a metabolic testing was performed, the indication for each metabolic test and the diagnostic yield of this selected metabolic workup for diagnosing an IMD. Metabolic testing comprised at least one of the following testings: plasma, urine or cerebrospinal fluid amino acids, urine organic acids, plasma acylcarnitine profile, and urine mucopolysaccharides and oligosaccharides. 11,301 neonates were admitted at the neonatal ICU during the study period. One hundred and ninety six neonates underwent metabolic testing. Eleven cases of IMDs were diagnosed. This diagnostic approach allowed the diagnosis, treatment and survival of 4 neonates (maple syrup urine disease, propionic acidemia, carnitine-acylcarnitine translocase deficiency and type 1 tyrosinemia). In total, metabolic testing was performed for 1.7% of the total number of neonates admitted in the NICU over the study period. These included 23% finally unaffected neonates with transient abnormalities, 5.6% neonates suffering from an identified IMD, 45.4% neonates suffering from a non-metabolic identified disease and 26% neonates with chronic abnormalities but for whom no final causal diagnosis could be made. In conclusion, as expected, such a metabolic targeted workup allowed the diagnosis of classical neonatal onset IMDs in symptomatic newborns. However, this workup remained normal or unspecific for 94.4% of the tested patients. It allowed excluding an IMD in 68.4% of the tested neonates. In spite of the high rate of normal results, such a strategy seems acceptable due to the severity of the symptoms and the need for immediate treatment when available in neonatal IMDs. However, its cost-effectiveness remains low especially in a clinically targeted population in a country where newborn screening is still unavailable for IMDs except for phenylketonuria in 2019.
Highlights
Inherited metabolic diseases (IMD) represent roughly over 700 different genetic disorders
Among metabolic testings in our population, abnormalities were specific of an IMD for 4.3% of plasma aminoacids, 3.9% of urine aminoacids, 4.2% of cerebrospinal fluid (CSF) aminoacids, 3.4% of urine organic acids, 5.8% of plasma acylcarnitine profile (Fig. 2)
There were 23% neonates with a final diagnosis of transient disorder, 5.6% neonates diagnosed with an IMD confirmed by molecular testing [a) 4 aminoacidopathies: 1 case of maple syrup urine disease (MSUD), 1 hereditary tryosinemia type 1 (HT1), 2 nonketotic hyperglycinemia (NKH); b) 2 fatty acid oxidation disorders (FAO): 1 carnitine acylcarnitine translocase deficiency (CACT), 1 Long chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD); c) 1 organic aciduria: 1 case of propionic academia (PA); d) 2 mitochondriopathies; e) 2 urea cycle disorders: 1 N-acetylglutamate synthase deficiency (NAGS), 1 citrullinemia type 1], 45.4% neonates suffering from a non-metabolic identified disease and 26% neonates with chronic clinical abnormalities but for whom no final diagnosis could be made (Fig. 3)
Summary
Inherited metabolic diseases (IMD) represent roughly over 700 different genetic disorders They occur especially during infancy and are severe in the neonatal period. The diagnostic approach relies on nonspecific clinical and laboratory testing data, leading to the prescription of metabolic tests[6,7,8,9,10,11]. The absence of specificity of clinical signs in neonates and the numerous nonspecific abnormalities of metabolic testing make the diagnosis of IMD difficult in the neonatal period[11,13,14,15,16]. Our objective was to retrospectively evaluate the diagnostic contribution of selected metabolic tests (covering most of the treatable IMDs and performed in a single metabolic laboratory) when an IMD is suspected in the neonatal period
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