Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

Abstract

BackgroundMitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are long-chain fatty acid oxidation disorders with particularly high morbidity and mortality. Outcome can be favorable if diagnosed in time, prompting the implementation in newborn screening programs. Sporadic cases missed by the initial screening sample have been reported. However, little is known on pitfalls during confirmatory testing resulting in fatal misconception of the diagnosis.ResultsWe report a series of three patients with MTP and LCHAD deficiency, in whom diagnosis was missed by newborn screening, resulting in life-threatening metabolic decompensations within the first half year of life. Two of the patients showed elevated concentrations of primary markers C16-OH and C18:1-OH but were missed by confirmatory testing performed by the maternity clinic. A metabolic center was not consulted. Confirmatory testing consisted of analyses of acylcarnitines in blood and organic acids in urine, the finding of normal excretion of organic acids led to rejection and underestimation of the diagnosis, respectively. The third patient, a preterm infant, was not identified in the initial screening sample due to only moderate elevations of C16-OH and C18:1-OH and normal secondary markers and analyte ratios.ConclusionOur observations highlight limitations of newborn screening for MTP/LCHAD deficiency. They confirm that analyses of acylcarnitines in blood and organic acids in urine alone are not suitable for confirmatory testing and molecular or functional analysis is crucial in diagnosing MTP/LCHAD deficiency. Mild elevations of primary biomarkers in premature infants need to trigger confirmatory testing. Our report underscores the essential role of specialized centers in confirming or ruling out diagnoses in suspicious screening results.

Long-term experience with triheptanoin in 12 Austrian patients with long-chain fatty acid oxidation disorders

“…No restart was attempted. Patient 10 was previously reported as Patient 3 in Lotz-Havla et al [ 16 ] and in Karall et al as Patient 8 [ 15 ].…”

“…al. ( https://doi.org/10.1186/s13023-018-0875-6 ) [ 16 ], Patient 10 is Patient 3 C7: triheptanoin; LC-FAOD: long-chain fatty acid oxidation disorder; LCHADD: long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency; VLCADD: very long-chain acyl-CoA dehydrogenase deficiency; CPT2: carnitine palmitoyl transferase 2 deficiency; NG: nasogastric; PEG: percutaneous endoscopic gastrostomy a born before April 2002, when newborn screening for LC-FAOD was implemented in Austria a1 Newborn screening was false-negative due to prematurity and parenteral nutrition with carnitine supplementation b At study date, all patients have normal liver function tests c In Patients 1, 6, 10, 11, 12, cardiomyopathy was dilatative; in Patients 3, 4, 9 hypertrophic. At study date Patients 1, 3, 4, 6, 9, 10 have normal cardiac function.…”

Long-term Experience with Triheptanoin in 12 Austrian Patients with Long-chain Fatty Acid Oxidation Disorders

“…No restart was attempted. Patient 10 was previously reported as Patient 3 in Lotz-Havla et al(16) and inKarall et al as Patient 8 (15).…”

Recent Advances in the Pathophysiology of Fatty Acid Oxidation Defects: Secondary Alterations of Bioenergetics and Mitochondrial Calcium Homeostasis Caused by the Accumulating Fatty Acids

“…Untreated MTP and LCHAD deficiencies have high mortality and morbidity. The clinical features are usually manifested during fasting or metabolic stress triggered by common illness and mainly affect the heart and skeletal muscles that are highly dependent on fatty acids for their energy needs (Sykut-Cegielska et al, 2011;De Biase et al, 2017;Lotz-Havla et al, 2018). Individuals with MTP deficiency usually present a severe neonatal early onset form with elevated mortality caused by cardiomyopathy, as well as peripheral neuropathy, whereas patients with LCHAD deficiency commonly have a moderate late-onset phenotype with cardiomyopathy, retinal disease, and peripheral neuropathy during adulthood.…”

“…Patients affected by these diseases may also present with hepatopathy and episodes of rhabdomyolysis during situations of intense lipolysis (Rocchiccioli et al, 1990;Tyni et al, 1997;Den Boer et al, 2002Moczulski et al, 2009;De Biase et al, 2017). Longterm complications include rhabdomyolysis, cardiomyopathy, peripheral neuropathy, and retinopathy (Karall et al, 2015;Lotz-Havla et al, 2018). High levels of the long-chain 3-hydroxy fatty acids (LCHFA), 3-hydroxytetradecanoic acid (3HTA), 3-hydroxypalmitic acid (3HPA), and 3-hydroxytetradecanedioic acid (3HTDA) and their respective carnitine by-products accumulate in the patients, with 3-hydroxypalmitoylcarnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH) being the primary biomarkers characteristically found at high concentrations in their blood (Hagenfeldt et al, 1990;Costa et al, 1998;Jones et al, 2001;Hintz et al, 2002;Olpin, 2005;Sander et al, 2005).…”