Molecular Basis of Metabolic Disease: Refsum Disease

Overview 

Refsum disease (RD), also termed “heredopathia actactica polyneurotiformis (HAP),” is a rare genetic disease characterized biochemically by the build-up of phytanic acid, a branched-chain fatty acid (BCFA), in plasma and tissues. The accumulation of phytanic acid is due to the lack of appropriate oxidative enzymes. RD was first described in 1946 by Sigvald Refsum, a Norwegian neurologist (Wills et al., 2001). A variant of RD that occurs in children is called infantile RD. The disease has an autosomal recessive pattern of inheritance because of the mutations in PhyH. PhyH is a gene that encodes the defective enzyme –“peroxisomal apha-oxidation enzyme, phytanoyl-coenzyme alpha-hydroxylase (PAHX-AP1)” (Wills et al., 2001). This defective enzyme usually uses the CoA derivative as a substrate to catalyze the breakdown of phytanic acid to pristanic acid. As a result, phytanic acid starts to accumulate in the blood and other tissues. 

RD typically appears in late childhood or early adulthood. Although the disease usually appears in late childhood or early adulthood, symptoms usually do not develop until the RD patient attains 40 years and above. The disease usually follows a progressive course. The clinical manifestations of the disease include “retinitis pigmentosa, cataracts, a chronic peripheral polyneuropathy, and cerebellar ataxia among other clinical signs” (Claridge et al., 1992). The neurological symptoms are often preceded by nyctalopia and visual failure. 

Gene/Protein involved in RD 

RD is a genetically heterogeneous condition, meaning that a mix of genes causes it. Studies have identified two genes that cause RD (Van et al., 2003). According to Van et al. (2003), RD is caused by the mutations of two genes, the PhyH gene (10p13) and the peroxisomal biogenesis factor 7 (PEX7) gene (6q21-q22.2). The PhyH and PEX7 genes are involved in lipid metabolism and protein transport. According to the study carried out by Van et al. (2003), mutations in the PEX7 gene result in relatively mild RD. Patients affected by RD have elevated levels of phytanic acid due to a deficiency of PhyH. 

The novel protein PAHX-AP1, which is often associated with PAHX, is involved in RD (Perera et al., 2010). The PhyH gene provides instructions for making a PAHX enzyme. PAHX is critical for the normal function of peroxisomes. These sac-like compartments contain enzymes needed to break down fatty acid and certain toxic compounds. Phytanic acid is one of these compounds that is broken down during this process. This type of fatty acid is usually obtained from diets, particularly beef and dairy products. PAHX-AP1 is responsible for one of the steps involved in breaking down this acid through a process called alpha oxidation (Perera et al., 2010). 

PAHX-AP normally catalyzes the second step in the breakdown of phytanic acid to pristine acid. More specifically, PAHX-AP1 is responsible for activating the second step of removing BCFA during the alpha oxidation (Perera et al., 2010). Deficiency of PAHX-AP results in defective alpha oxidization of phytanic acid. This results in RD. RD patients exhibit markedly elevated phytanic acid levels due to their inability to metabolize phytanic acid because of the deficiency of PAHX-AP1. Generally, PAHX-AP1 is involved in RD because of its association with PAHX, an RD gene product. 

The mutation that leads to RD 

A specific mutation that leads to RD is the mutation of the PhyH gene (10p13). The mutation of this gene causes 90% of all the cases of RD (Wanders et al., 2015). Studies have identified about 30 mutations in this gene. PhyH gene is localized in chromosome 10p. A study carried out by Jansen et al. (2000) identified mutations in the PhyH gene. The author identified the PhyH complementary DNA of several patients with RD was as a result of either 1 or 2 different mutations that occurred in the same splice acceptor site. These mutations resulted in the skipping of an exon, which led to an enzymatically inactive PhyH protein. These mutations alter the structure or the production of PAHX, which reduces the enzyme’s activity. A deficiency of this enzyme disrupts the breakdown of phytanic acid in peroxisomes. This results in the accumulation of phytanic acid and other compounds. The build-up of this acid in the body’s tissues is toxic to cells. 

Current Treatment for RD 

RD is treatable because phytanic acid is not produced by the body. The acid is obtained from dietary intakes, particularly beef, dairy products, and fatty fish. RD is mainly treated through dietary restrictions (Baldwin et al., 2010). Phytanic acid is almost entirely of exogenous origin. Thus, avoiding diets that contain phytanic acid, such as beef and dairy products as well as fatty fish, is considered the primary treatment of ARD. According to Wills (2001), it is less likely to achieve a diet that is totally free of phytanic acid. On average, an individual takes 50 to 100 mg of phytanic acid per day. Ideally, this ought to be reduced significantly. In order to manage the disease, patients are required to restrict the intake of phytanic acid to <10-20 mg/day (Wills et al., 2001). According to Will et al. (2001), these low phytanic acid diets are very stringent. 

Another treatment option for RD is plasmapheresis, which refers to plasma exchange. During plasmapheresis, blood is drawn from the patient with RD. The blood is then filtered and reinfused back into the body. This process helps treat RD by controlling the accumulation of phytanic acid in blood (Cortese & Cornblath, 2013). Plasmapheresis produces a rapid clinical improvement compared to dietary restriction. Thus, plasmapheresis ought to be considered where dietary control is inadequate. 

With treatment, most of the symptoms of RD disappear. Some of the symptoms that disappear include muscle weakness, numbness, and dry and scaly skin. However, other symptoms of the disease may persist, such as vision, hearing problems, and a sense of smell. If the disease goes untreated, it can result in sudden death, which is often caused by heartbeat abnormalities. 

RD is a disease biochemically characterized by the build-up of phytanic acid in the body. The disease has an autosomal recessive pattern because of the mutations in PhyH. RD is caused by the mutations of two genes, the PhyH gene (10p13) and the peroxisomal biogenesis factor 7 (PEX7) gene (6q21-q22.2). PhyH gene (10p13) accounts for about 90 percent of all cases of RD, while PEX7 accounts for the remaining 10 percent. The novel protein PAHX-AP1 is involved in RD. PAHX-AP normally catalyzes the second step in the breakdown of phytanic acid to pristine acid. Deficiency of PAHX-AP results in defective alpha oxidization of phytanic acid. This results in the accumulation of phytanic acid in the body, which in turn results in RD. The current treatment options for RD include dietary restrictions of food rich in phytanic acids and plasmapheresis. 

References 

Baldwin, E. J., Gibberd, F. B., Harley, C., Sidey, M. C., Feher, M. D., & Wierzbicki, A. S. (2010). The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease.  Journal of Neurology, Neurosurgery & Psychiatry ,  81 (9), 954-957. 

Claridge, K. G., Gibberd, F. B., & Sidey, M. C. (1992). Refsum disease: the presentation and ophthalmic aspects of Refsum disease in a series of 23 patients.  Eye ,  6 (4), 371-375. 

Cortese, I., & Cornblath, D. R. (2013). Therapeutic plasma exchange in neurology: 2012.  Journal of clinical apheresis ,  28 (1), 16-19. 

Jansen, G. A., Hogenhout, E. M., Ferdinandusse, S., Waterham, H. R., Ofman, R., Jakobs, C., ... & Wanders, R. J. (2000). Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum’s disease.  Human molecular genetics ,  9 (8), 1195-1200. 

Perera, N. J., Lewis, B., Tran, H., Fietz, M., & Sullivan, D. R. (2010). Refsum’s Disease—Use of the Intestinal Lipase Inhibitor, Orlistat, as a Novel Therapeutic Approach to a Complex Disorder.  Journal of obesity ,  2011 . 

Van Den Brink, D. M., Brites, P., Haasjes, J., Wierzbicki, A. S., Mitchell, J., Lambert-Hamill, M., ... & Wanders, J. R. (2003). Identification of PEX7 as the second gene involved in Refsum disease.  The American Journal of Human Genetics ,  72 (2), 471-477. 

Wanders, R. J., Waterham, H. R., & Leroy, B. (2015). Refsum disease. In  GeneReviews® . University of Washington. Seattle 

Wills, A. J., Manning, N. J., & Reilly, M. M. (2001). Refsum’s disease. QJM : An International Journal of Medicine  94 (8 ), 403-406. DOI: https://doi.org/10.1093/qjmed/94.8.403