VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria
Introduction
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Based on clinical presentation, three phenotypes of VLCAD deficiency have been identified: an early onset insidious type that causes a potentially lethal cardiomyopathy, a later onset type that presents with hypoketotic hypoglycaemia and an adult onset type that mainly causes muscular symptoms [1]. The inclusion of VLCAD deficiency in newborn screening programs enables early initiation of treatment and improved outcome [2], altering the natural history of this disorder, at least in those patients who would have presented in childhood. On the other hand, “patients” who may never need treatment may be identified, making the decision of whether to treat or not, and how, complex.
Treatment practices of VLCAD deficiency have changed somewhat over the past 10–15 years since this disorder was included in newborn screening programs and the number of diagnosed patients has risen dramatically [2], [3]. Concerns regarding hypoglycaemia led to a general recommendation to avoid prolonged fasting and, at times, to prescribing carbohydrate-rich drinks to patients. The early practice of prescribing medium chain triglyceride (MCT) supplementation on a regular basis and chronically [2] has been revisited. In a multi-centre collaborative study that focused on management and outcome of patients with VLCAD deficiency there were 32 patients (18 identified by newborn screening and treated from infancy) who were asymptomatic [4]. These asymptomatic infants were treated with fat-modified diet, either a combination of breast-milk and MCT-rich formula or a formula low in long- chain triglycerides (LCT) and high in MCT [4]. Current recommendations include prevention of fasting for long periods of time, a diet that is low in LCT, and MCT supplementation at times of physical activity [5]. Some centres include carnitine, but this has not been shown to make any improvements to clinical outcome [6], [7].
Our practice in the management of VLCAD deficiency has also changed over the years in parallel with the changes noted in the literature [5]. In 2013 we formalised our approach to treatment based on the published consensus papers from 2009 [4], [5] and our own experience. The purpose of this study was to review our experience with the management of patients with VLCAD deficiency from birth to their current age. We also wished to assess the patients' outcome in light of their mutations, in order to evaluate a possible prognostic value of mutation testing beyond the actual confirmation of the diagnosis. Clinical outcome parameters included: 1) metabolic stability, as measured by the number and type of admissions as well as the patients' symptoms; 2) growth; and 3) body composition. The neuropsychological outcome of some of our patients has been previously reported [8].
Section snippets
Methods
We conducted a retrospective review of all health records, including dietary records, of all patients with VLCAD deficiency diagnosed and treated at our centre since the implementation of the expanded newborn screening program in 2002. Data were collected in VICIEM, a RedCap-based in-house databank for patients with metabolic disorders. Ethics approval for collection of data in the databank (HREC #30066B) and specifically for publication (HREC #DA005-2015-11) was granted from the RCH Human
Results
There were 23 patients (13 male/10 female). All patients were picked up by newborn screening and their diagnosis was confirmed by mutation analysis (Table 2). Patient 18 is a sibling of patient 17 and patient 21 is a sibling of patient 20. Follow up period ranged from 14 months to 16 years and 7 months (median: 104 months).
Discussion
The identification of patients with VLCAD deficiency through newborn screening poses questions regarding the optimal treatment for these patients, particularly since prediction of severity of disease and outcome are difficult. There are hardly any biochemical predictive markers that can be used to suggest who would need treatment and who wouldn't. Not surprisingly, the newborn screening blood results in our patients were not predictive of symptomatology, either in the neonatal period or later.
Conclusions
There are currently no biochemical markers for prediction of disease severity and for the need for treatment in VLCAD deficiency. Mutation analysis may offer predictive value but this may not be robust enough for a large proportion of those mutations that have not been previously reported in clinically affected patients. Following the current guidelines for treatment of patients with VLCAD deficiency as per the European consensus paper [5] seems effective and safe during childhood. We propose
Conflict of interest
Maureen Evans, Brage S. Andresen and Avihu Boneh have no conflict of interest to declare. Judy Nation is currently an employee of Vitaflo but was employed by the Royal Children's Hospital, Melbourne, at the time of data collection and has no conflict of interest to report.
Acknowledgements
We are grateful to the patients and their parents for their enthusiastic participation in the study, and to Drs Peters and Lee, and the many metabolic fellows and dietitians who participated in managing our patients through the years described in the paper. We thank Helle Highland Nygaard and Margrethe Kjeldsen, Research Unit for Molecular Medicine, Skejby Sygehus for expert technical assistance with the mutation analysis. Study data were collected and managed using REDCap electronic data
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