Multiple acyl-Coa dehydrogenase deficiency: an underdiagnosed disorder in adults.

Inherited metabolic diseases, as a first presentation in adults, are an under-recognised condition associated with significant morbidity and mortality. Diagnosis is challenging because of non-specific clinical and biochemical findings, resemblance to common conditions such as neuropsychiatric disorders and the misconception that these disorders predominantly affect paediatric populations. We describe a series of patients with multiple acyl-CoA dehydrogenase deficiency (MADD)/MADD-like disorders to highlight these diagnostic challenges.

Hyperammonaemia: review of the pathophysiology, aetiology and investigation.

Acute hyperammonaemia is a medical emergency as it can progress to cerebral oedema, seizures, coma and death. Hepatic encephalopathy secondary to cirrhotic disease or portosystemic shunting are relatively well-known causes, but non-cirrhotic aetiologies of acute hyperammonaemia are less well-known, especially in the emergency department. However, an elevated ammonia is not required to make the diagnosis of hepatic encephalopathy. Although measurement of plasma ammonia is recommended for patients with acute, unexplained, altered mental status, as early identification allows early effective management which may prevent irreversible brain damage, there is currently reduced awareness among physicians of the non-cirrhotic aetiologies of acute hyperammonaemia. Furthermore, measurement of ammonia in patients with cirrhosis has been shown to have low sensitivity and specificity, and not to have altered management in the majority of cases; thus, measurement of ammonia is currently not recommended in guidelines for management of hepatic encephalopathy. We sought to describe the pathophysiology of hyperammonaemia and review the non-cirrhotic causes. This was achieved by review of MEDLINE, PubMed and Web of Science databases to include published English literature within the last 20 years. We also present a framework for investigating the acute non-cirrhotic causes of hyperammonaemia to assist both chemical pathologists and clinicians managing these often challenging cases.

Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence

Abstract Medium chain acyl-coA dehydrogenase deficiency (MCADD), the most common fatty acid oxidation disorder, has been regarded as a relatively benign condition with low risk of mortality in patients with a known diagnosis, if adequate caloric intake is met. However, inadequate energy provision, as occurs in eating disorders, significantly amplifies the risk of metabolic decompensation. This case series describes four patients with MCADD and a concomitant eating disorder and aims to raise awareness of the potentially under-recognised coexistence of these conditions. All patients were female with signs of disordered eating in adolescence and young adulthood though latency in diagnosis was apparent. Three of the patients had low body mass index (BMI) and the other was overweight. Metabolic decompensation and hospitalisation occurred in three of four patients secondary to extreme risk-taking behaviour with caloric restriction. The coexistence of MCADD and eating disorders is of significant concern, placing the patient at substantial risk of decompensation in an otherwise relatively stable metabolic condition. Awareness of disordered eating in this population is paramount, as early recognition of signs and symptoms of eating disorders in the MCADD population may facilitate prompt intervention and avoidance of morbidity and potential mortality.

Pharmacodynamics, safety, tolerability and pharmacokinetics of a single oral dose of an engineered phenylalanine ammonia-lyase in patients with phenylketonuria.

The cornerstone treatment of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) is a lifelong low-protein diet with phenylalanine (Phe) free L-amino acid supplements. However, the PKU diet has significant shortcomings, and there is a clinically unmet need for new therapeutics to improve patient outcomes. CDX-6114 is a modified phenylalanine ammonia-lyase (PAL) enzyme obtained by a mutation in the Anabaena variabilis PAL sequence. CodeEvolver® protein engineering technology has been applied to improve the degradation resistance of the enzyme. In our first phase I trial, 19 patients were given a single oral dose of CDX-6114 at 7.5 g, 2.5 g, 0.7 g, or placebo in a cross-over design. After an overnight fast, patients received a standardised breakfast of 20 g of protein, thus exceeding the dietary recommendations for a single meal in patients with PKU. Plasma levels of Phe and cinnamic acid (CA) were measured over a 5-h period following CDX-6114 dosing. During the development of CDX-6114, a stability assessment using reverse-phase high-performance liquid chromatography (HPLC) assay revealed two peaks. The second peak was identified as CA. It was not previously known that as part of the mechanism of action, the CA remained associated with the protein following the conversion of Phe. Thus, recalculating the historical PAL enzyme amounts in CDX-6114 bulk substance was necessary. An updated extinction coefficient was achieved by applying a correction factor of 0.771 to previously reported doses. Postprandial plasma levels of Phe increased in all dose cohorts over time between 10% and 30% from baseline, although the actual peak of Phe levels was not achieved within the 5-h observation. When accounting for the interquartile ranges, these concentrations were similar to the placebo. As plasma levels of Phe were no longer a reliable marker for pharmacodynamics, the consistently detectable amount of CA seen in all patients who received CDX-6114 provided proof of the enzymatic activity of CDX-6114 in metabolising gastrointestinal Phe. Peak levels of CA were seen shortly after CDX-6114 intake, with a rapid decline, and remained low compared with the plasma Phe levels. This pattern indicates a short half-life, possibly due to the liquid formulation or the inability to withstand the lower pH in the human stomach compared with animal models in earlier studies. This was the first trial in patients with PKU to establish the safety and tolerability of CDX-6114. A single dose of CDX-6114 was safe and well tolerated, with no serious adverse events or presence of anti-drug antibodies detected. Efficacy will be explored in future trials using an optimised formulation.

Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism that results in impairment of mitochondrial ß-oxidation of fatty acids. It is inherited in an autosomal recessive manner and impairs electron transfer in the electron transport chain. The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death. Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations. While late-onset MADD is suggested to have a lower mortality, the severe encephalopathic presentations may well be under-reported as a diagnosis of MADD may not be considered.MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation. The neonatal phenotype differs significantly from late-onset MADD, where diagnosis may be delayed due to heterogeneity in clinical features, atypical presentation and confounding comorbidities, together with lower awareness among physicians.This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation. Subsequent biochemical investigation revealed a diagnosis of MADD. At present, there are no national guidelines in Australia for the management of MADD. This case highlights the investigation and treatment of late-onset MADD.