Kansas Journal of Medicine 2009 Decompensation of

Decompensation of Refsum Disease Caused by Ibuprofen Intake Natacha Esber, M.D. Thomas Schulz, M.D. University of Kansas School of Medicine-Wichita Department of Internal Medicine

Introduction Refsum disease (or heredopathia atactica five sessions of plasmapheresis. During her polyneuritiformis) is an autosomal recessive last hospitalization, her phytanic level was disorder caused in most instances by 105.5umol/L (reference range : ≤ 9.88). It mutations in the gene ( PhyH ) encoding the decreased to zero after the completion of enzyme phytanoyl-CoA hydroxylase, four sessions of plasmapheresis. She took located on chromosome 10pter-p11.2. 1,2 ibuprofen 800 mg by mouth every eight These mutations lead to the accumulation of hours during her hospital stay at the other phytanic acid in affected patients. The facility. mainstay of treatment is a reduction in the The patient presented to the emergency dietary phytanic acid intake. The following department at our facility for acute case illustrates an aggressive progression of exacerbation of her disease, including retro- the disease in a patient who was compliant orbital headaches, chest pain, nausea, with the dietary restrictions. vomiting, diarrhea, urinary incontinence, diffuse muscle aches, and weakness that had Case Report increased in intensity over two weeks. A A 33-year-old white female, had a detailed history revealed that she was history of progressive loss of vision and compliant with her diet, but had a chronic hearing since the age of 20, cardiomyopathy, ibuprofen intake for recurrent tension cardiac arrhythmias, gastroparesis, urge headaches. She was never told that incontinence, decreased bone mass, bilateral ibuprofen is contraindicated in Refsum hip replacement, multiple surgical disease. The patient improved significantly interventions on the right ankle, and one after five sessions of plasmapheresis and surgical intervention on the right knee. At discontinuation of ibuprofen. the age of 27, she was diagnosed with Refsum disease by associating the Discussion shortening of the 4 th metatarsals bilaterally Branched-chain fatty acids are common and the retinitis pigmentosa, along with a in the diet and related structures are high phytanic acid level. She was started on common and occur in some drugs, such as the appropriate diet consisting of restrictions ibuprofen (Figure 1).3 The most common on green vegetables, meats from ruminating branched-chain is phytanic acid, animals, and dairy products. found in some meats and dairy products. Since the age of 30, the patient was Normally, it is metabolized by activation to hospitalized four times at another facility for its CoA ester, phytanoyl-CoA, then alpha- acute decompensation of her disease. oxidation to .4 During each hospitalization, she underwent

71 Kansas Journal of Medicine 2009 Decompensation of Refsum Disease

O CoA Phytanoyl-CoA S

α-oxidation

OH (2R,S)-Pristanic acid O S O CoA α-Methylacyl-CoA racemase

S (2S)-Pristanoyl-CoA Buprofenoyl-CoA CoA O

β-oxidation

Figure 1. Peroxisomal degradation of phytanic acid to pristanic acid. [Figure from MD Lloyd and MD Threadgill. 3]

Patients with Refsum disease are unable and plasma levels of phytanic acid of > 800 to degrade phytanic acid because of mmol. 4-7 deficient activity of phytanoyl-CoA Treatment consists of strict reduction in hydroxylase, a peroxisomal enzyme that dietary phytanic acid intake to 10-20mg/day catalyzes the first step of phytanic acid (daily average: 50-100mg).7 Plasma alpha-oxidation. 4 Consequently, they exchange can be considered if dietary accumulate significant amounts of phytanic control is inadequate.8 This approach halts acid in plasma and tissues, which are the progression of the disease, but does not thought to be the major cause of the reverse neurologic abnormalities com- pathology of the disease. 5 pletely. Ichthyosis, sensory neuropathy, and Refsum disease is characterized ataxia resolve in approximately that order, clinically by atypical retinitis pigmentosa, and electrocardiographic abnormalities may peripheral polyneuropathy, cerebellar ataxia, improve. However, treatment may not anosmia, cardiomyopathy, conduction affect retinitis pigmentosa, hearing abnormalities, icthyosis, hyperkeratosis impairment, or anosmia.7-9 plantaris and palmaris, and epiphyseal dysplasia leading to characteristic shortening References of the fourth toe, hammer toe, pes cavus, 1 Harari D, Gibberd FB, Dick JP, Sidey MC. and osteochondritis.4-6 The characteristic Plasma exchange in the treatment of findings are slow conduction velocities on Refsum’s disease (heredopathia atactica nerve conduction studies, elevated polyneuritiformis). J Neurol Neurosurg cerebrospinal fluid protein concentration Psychiatry 1991; 54:614-617. (100 to 600 mg/dl) without an increase in 2 Percy AK, Wanders RJA. Peroxisomal cells, grossly abnormal electroretinogram, disorders. UptoDate, May 2008. Accessed onion bulb formation and targetoid at: http://www.uptodate.com/online/cont inclusions in Schwann cells on nerve biopsy,

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ent/topic.do?topicKey=ped_neur/10545&s 7 Steinberg D. Refsum disease. In: CR electedTitle=1~52&source= search _result. Scriver, AL Beaudet, WS Sly, D Valle, 3 Lloyd M, Threadgill MD. Branched-chain Eds, The Metabolic Bases of Inherited fatty acid metabolism. University of Bath, Disease. 6th Edition. New York: McGraw- Department of Pharmacy and Pharma- Hill, pp. 2351-2369. cology. Accessed at: www.bath.ac.uk/ 8 Lou JS, Snyder R, Griggs RC. Refsum’s pharmacy/staff/lloyd.shtml. disease: Long term treatment preserves 4 Cruse R. Hereditary neuropathies sensory nerve action potentials and motor associated with generalized disorders. function. J Neurol Neurosurg Psychiatry UptoDate, May 2008. Accessed at: 1997; 62:671-672. http://www.uptodate.com/online/content/t 9 Komen JC, Distelmaier F, Koopman WJ, opic.do?topicKey=ped_neur/7406&selecte Wanders RJ, Smeitink J, Willems PH. dTitle=29~150&source=search_result. Phytanic acid impairs mitochondrial 5 Wills AJ, Manning NJ, Reilly MM. respiration through protonophoric action. Refsum’s disease. QJM 2001; 94:403-406. Cell Mol Life Sci 2007; 64:3271-3281. 6 Gibberd FB, Billimoria JD, Goldman JM, et al. Heredopathia atactica polyneurit- Keywords : heredopathia atactica poly- iformis: Refsum’s disease. Acta Neuro neuritiformis, Refsum disease, ibuprofen, Scand 1985; 72:1-17. case report

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