Disorders of Mitochondrial Fatty Acid Oxidation &amp; Riboflavin Metabolism

Morris, Andrew A. M.; Spiekerkoetter, Ute

doi:10.1007/978-3-662-49771-5_12

Cited by 11 publications

(14 citation statements)

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“…Several laboratory studies can be used to characterize MADD‐patients, including urine organic acid analysis, plasma acylcarnitine profiling, and ultimately molecular studies to pinpoint the genetic defect . Unfortunately, prognostic biomarkers that may predict disease severity are not available.…”

Section: Introductionmentioning

confidence: 99%

“…2,7,8 Several laboratory studies can be used to characterize MADD-patients, including urine organic acid analysis, plasma acylcarnitine profiling, and ultimately molecular studies to pinpoint the genetic defect. 2,9,10 Unfortunately, prognostic biomarkers that may predict disease severity are not available. In fibroblasts, FAO flux activities provide an estimate of the rate of mitochondrial FAO, whereas acylcarnitine profiling improves insight on both the site and the severity of the enzymatic block.…”

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confidence: 99%

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Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Rijt

Ferdinandusse

Giannopoulos

et al. 2019

J of Inher Metab Disea

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Summary Multiple acyl‐CoA dehydrogenase deficiency (MADD) is an ultra‐rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes. We performed a retrospective nationwide cohort study; then developed an MADD‐disease severity scoring system (MADD‐DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD‐DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts. Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD‐DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD‐DS3 scores of patients in our cohort ranged from 0 to 29. FAO flux and [U‐13C]C2‐, C5‐, and [U‐13C]C16‐acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all P < .05) and strongly correlated to MADD‐DS3 scores (oleate: r = −.86; myristate: r = −.91; [U‐13C]C2‐acylcarnitine: r = −.96; C5‐acylcarnitine: r = .97; [U‐13C]C16‐acylcarnitine: r = .98, all P < .01). Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD‐patients and were correlated to MADD‐DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow‐up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Rijt

Ferdinandusse

Giannopoulos

et al. 2019

J of Inher Metab Disea

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“…Multiple acyl‐CoA dehydrogenase deficiency (MADD; MIM #231680) is a rare mitochondrial fatty acid oxidation (FAO) disorder caused by pathogenic mutations in the electron transfer flavoprotein genes (ETFs; ETFA or ETFB) or ETF dehydrogenase (ETFDH) 1 . These flavoproteins are essential for electron transfer from multiple FAD‐linked acyl‐CoA dehydrogenases of β‐oxidation to the respiratory chain 2 . The disrupted transfer of electrons generated by dehydrogenation reactions, to the mitochondrial respiratory chain leads to impaired mitochondrial FAO and accumulation of short‐, medium‐, and long‐chain acyl‐carnitines in various tissues and lipid accumulation in skeletal muscles, while impaired amino acid and choline metabolism represent additional pathways affected in the disease 3 .…”

Section: Introductionmentioning

confidence: 99%

Pancreatitis in multiple acyl CoA dehydrogenase deficiency: An underdiagnosed complication

et al. 2020

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BackgroundMultiple acyl‐CoA dehydrogenase (MADD) deficiency represents a rare fatty acid oxidation disorder where sporadic reports of pancreatitis already exist. Here, we report three cases of MADD with pancreatic involvement raising questions whether this represents an incidental finding or it is related to the pathophysiology of MADD.MethodsWe have retrospectively studied the clinical, biochemical and radiologic data of patients with MADD diagnosed in our department over the last 20 years to identify patients with pancreatic involvement.RESULTSThree out of 17 patients had pancreatic involvement. All three patients were diagnosed with MADD in the neonatal period (two‐third symptomatic—riboflavin nonresponsive, one‐third asymptomatic via newborn screening—riboflavin responsive). Age at presentation of pancreatitis ranged from 20 months to 11 years. Presentations included a single episode of acute pancreatitis in the first patient, chronic necrotizing pancreatitis in the second patient, while the third patient was diagnosed with chronic pancreatitis (CP) incidentally through ultrasonography. All patients had inflammation features on either abdominal computed tomography or ultrasound. Pancreatic enzymes were elevated in two patients. Management of pancreatitis was done conservatively while the patient with necrotic CP required subtotal pancreatectomy.DISCUSSIONOur data suggest that pancreatitis might be more common in patients with MADD than previously reported, requiring a high index of suspicion in patients with acute metabolic decompensation or nonspecific abdominal symptoms. We hypothesize that the underlying mechanism of pancreatitis in MADD is similar to that in mitochondrial disorders, both resulting from disordered energy metabolism and oxidative phosphorylation.

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“…Since the start of screening in the Netherlands in 2007, 8 patients with MTP deficiency have been identified, which corresponds to an annual incidence of 1 patient per 200,000 newborns (personal communication). MTP deficiency has a heterogeneous clinical presentation, with disease severity depending on both residual enzyme activity and the exposure to stress (Morris and Spiekerkoetter 2016). Patients with severe deficiency present with severe neonatal disease, characterized by cardiomyopathy, arrhythmias, (hepatic) encephalopathy, and early death.…”

Section: Introductionmentioning

confidence: 99%

“…Another phenotype, resembling that of patients with isolated LCHAD deficiency, is characterized by recurrent episodes of hypoketotic hypoglycaemia that are generally induced by illness and prolonged fasting. A milder phenotype, with late-onset (juvenile/adolescent) type of disease, presents with myopathy, episodic rhabdomyolysis, peripheral neuropathy, and retinopathy (Morris and Spiekerkoetter 2016;Boutron et al 2011;Spiekerkoetter et al 2003b). Although there is no strict genotype-phenotype correlation, mutations in HADHB gene are primarily associated with the severe neonatal disease form, whereas mutations in the HADHA gene associate with all disease phenotypes (Boutron et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Neuropathy, Episodic Rhabdomyolysis, and Hypoparathyroidism in a Patient with Mitochondrial Trifunctional Protein Deficiency

et al. 2017

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A combination of unexplained peripheral neuropathy, hypoparathyroidism, and the inability to cope with metabolic stress could point to a rare inborn error of metabolism, such as mitochondrial trifunctional protein (MTP) deficiency.Here, we describe a 20-year-old woman who was known since childhood with axonal motor sensory polyneuropathy of unknown origin. She presented with progressive dyspnoea, and increased muscle weakness, preceded by 6 days of fever, vomiting, and diarrhoea. Laboratory testing showed rhabdomyolysis, and hypocalcaemia with low parathyroid levels. The patient was intubated because of respiratory insufficiency and a viral and bacterial pneumonia was diagnosed. She was discharged after 16 days of admission. Metabolic screening, performed at the time of rhabdomyolysis, showed increased concentrations of longchain 3-hydroxyacyl carnitine species, together with elevated urinary excretion of 3-hydroxy dicarboxylic acids. Decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase in peripheral lymphocytes and fibroblasts confirmed a MTP deficiency. Sequence analysis of the HADHB gene showed two heterozygous variants: c.209+1G>C (splicing defect) and c.980T>C (p.Leu327Leu). When the acylcarnitine profile was repeated after the episode of rhabdomyolysis had resolved it showed no abnormalities.Our case illustrates a cluster of peripheral neuropathy, episodic rhabdomyolysis, and hypoparathyroidism in a patient with MTP deficiency caused by mutations in the HADHB gene. It stresses the importance of performing metabolic screening when patients are most symptomatic, as normal results can be found at times when no metabolic stress is present. Screening is relatively easy and timely diagnosis has important implications for treatment. Communicated by: Manuel SchiffPeter van Vliet and Annelies E. Berden contributed equally to this work. Electronic supplementary material:The online version of this chapter

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Disorders of Mitochondrial Fatty Acid Oxidation & Riboflavin Metabolism

Cited by 11 publications

References 50 publications

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Pancreatitis in multiple acyl CoA dehydrogenase deficiency: An underdiagnosed complication

Peripheral Neuropathy, Episodic Rhabdomyolysis, and Hypoparathyroidism in a Patient with Mitochondrial Trifunctional Protein Deficiency

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