Infantile Refsum Disease: Influence of Dietary Treatment on Plasma Phytanic Acid Levels

Abstract

Infantile Refsum disease (IRD) is one of the less severe of Zellweger spectrum disorders (ZSDs), a group of peroxisomal biogenesis disorders resulting from a generalized peroxisomal function impairment. Increased plasma levels of very long chain fatty acids (VLCFA) and phytanic acid are biomarkers used in IRD diagnosis. Furthermore, an increased plasma level of phytanic acid is known to be associated with neurologic damage. Treatment of IRD is symptomatic and multidisciplinary.

The authors report a 3-year-old child, born from consanguineous parents, who presented with developmental delay, retinitis pigmentosa, sensorineural deafness and craniofacial dysmorphisms. While the relative level of plasma C26:0 was slightly increased, other VLCFA were normal. Thus, a detailed characterization of the phenotype was essential to point to a ZSD. Repeatedly increased levels of plasma VLCFA, along with phytanic acid and pristanic acid, deficient dihydroxyacetone phosphate acyltransferase activity in fibroblasts and identification of the homozygous pathogenic mutation c.2528G>A (p.Gly843Asp) in the PEX1 gene, confirmed this diagnosis. Nutritional advice and follow-up was proposed aiming phytanic acid dietary intake reduction. During dietary treatment, plasma levels of phytanic acid decreased to normal, and the patient’s development evaluation showed slow progressive acquisition of new competences.

This case report highlights the relevance of considering a ZSD in any child with developmental delay who manifests hearing and visual impairment and of performing a systematic biochemical investigation, when plasma VLCFA are mildly increased. During dietary intervention, a biochemical improvement was observed, and the long-term clinical effect of this approach needs to be evaluated.

Competing interests: None declared

Appendices

Synopsis

In spite of being a peroxisomal biogenesis disorder, infantile Refsum disease may have residual peroxisomal activity once we obtained a decrease of phytanic acid plasma levels, along with a low phytanic acid diet, in a 3-year-old child with the common pathogenic p.(Gly843Asp) mutation in the PEX1 gene.

Compliance with Ethics Guidelines

Conflict of Interest

Maria João Nabais Sá, Júlio C. Rocha, Manuela F. Almeida, Carla Carmona, Esmeralda Martins, Vasco Miranda, Miguel Coutinho, Rita Ferreira, Sara Pacheco, Francisco Laranjeira, Isaura Ribeiro, Ana Maria Fortuna and Lúcia Lacerda declare that they have no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the patient’s parents for being included in the study. Proof that informed consent was obtained is available upon request.

Details of the Contributions of Individual Authors

Maria João Nabais Sá, Júlio C. Rocha and Lúcia Lacerda contributed pertinent aspects of the planning, conducting and reporting of the work described in the article. Maria João Nabais Sá wrote the first draft of this manuscript. All the authors critically revised the original draft manuscript for intellectual content and approved the version submitted for publication.

Maria João Nabais Sá made the clinical diagnosis, requested and interpreted the necessary diagnostic procedures, conducted the biochemical investigation, is in charge of the follow-up of the patient, performed the family screening and counselling, collected the protocol baseline and historical and follow-up clinical data of the patient and performed and selected the corresponding photographs, included in Fig. 1a of this manuscript.

Lúcia Lacerda supervised the diagnostic biochemical and molecular studies of the peroxisomal biogenesis disorder and was responsible for their interpretation and reporting.

Esmeralda Martins, Vasco Miranda and Miguel Coutinho did the necessary diagnostic procedures, namely, the biochemical investigation, ophthalmologic evaluation and audiological evaluation, respectively, are in charge of the follow-up and treatment of the patients and collected the protocol baseline and historical and follow-up clinical data of the patient.

Vasco Miranda performed and selected the photographs included in Fig. 1b of this manuscript.

Júlio C. Rocha and Manuela F. Almeida are in charge of the nutritional follow-up and treatment of the patient.

Carla Carmona conducted the psychomotor development assessment of the patient and designed the bar chart included in Fig. 1c.

Rita Ferreira, Sara Pacheco and Isaura Ribeiro performed the biochemical assays and were responsible for their interpretation and reporting. Isaura Ribeiro performed and selected the photograph included in Fig. 2 of this manuscript.

Francisco Laranjeira performed the molecular analysis of the PEX1 gene and was responsible for its interpretation and reporting.

Ana Maria Fortuna supervised the clinical and laboratory content of this manuscript, as Head of the Department of Medical Genetics, Centro de Genética Médica Dr. Jacinto de Magalhães/Centro Hospitalar do Porto, Porto, Portugal.