refsum 's disease , also known as heredopathia atactica polyneuritiformis ( hap ) , was described by norwegian neurologist sigvald refsum in 1946 . carriers are unaffected , however they may asymptomatically exhibit slightly elevated phytanic acid levels , whereas refsum 's disease patients have markedly elevated levels ( normal < 0.70  mg / dl ) . phytanic acid is a branched - chain fatty acid ( bcfa ) , formed by bacterial degradation of chlorophyll in the intestinal tract of ruminants , invertebrates and , pelagic fish . individuals with refsum 's disease are unable to metabolize phytanic acid by the -oxidation pathway due to deficiency of the peroxisome enzyme phytanoyl - coa hydroxylase ( pahx ) [ 25 ] ( figure 1 ) . it is essential for the 3-methyl group in the -position of this bcfa to be removed by an -oxidation step , activated by pahx ( within the endoplasmic reticulum ) in order to proceed with the -oxidation pathway . peroxisomal -oxidation is the most efficient mechanism for the metabolism of phytanic acid . as a result , high levels of phytanic acid accumulate in blood and other tissues , especially adipose tissue , neural tissue , and astrocytes , where they cause oxidative stress in mitochondria and oxidative damage during chronic exposure [ 3 , 6 , 7 ] . in a subset of patients , a mutation of a second gene encoding for pex7- peroxin 7 receptor protein , involved in peroxisomal import of proteins , has been identified as a cause for the phenotype of refsum 's disease [ 2 , 5 ] . early diagnosis of hap or refsum 's disease is important because treatment is available to minimize progression . classical refsum 's disease is usually diagnosed during childhood or early adulthood when visual problems due to retinitis pigmentosa become apparent [ 1 , 8 ] . refsum 's disease leads to other sensory complications , including impaired sense of smell , usually occurring in early childhood but some times undiagnosed until other symptoms become apparent . gradual or sudden hearing loss can occur in adulthood , usually after the 3rd decade . ichthyosis , malaise , anorexia , and skeletal bone abnormalities such as bony prominences around elbows , knees and ankles and short digits of tubular bones of hands or feet ( especially the metatarsal of the fourth toe ) are also common . renal and hepatic manifestations include tubular dysfunction , aminoaciduria , and fatty degeneration [ 1 , 5 , 811 ] . humans have a secondary , less efficient pathway for phytanic acid metabolism via -oxidation , which is not affected in these patients [ 2 , 5 ] ( figure 1 ) . however the capacity of -oxidation is limited and it is only sufficient to process the reduced supply of phytanic acid associated with dietary restriction . it is reported in animal studies that fibrate drugs may induce this -oxidation pathway of phytanic acid metabolism . patients with refsum 's disease require multidisciplinary monitoring to detect cardiac , ophthalmic , and neurological manifestations . humans also convert phytol , a side chain of chlorophyll found in green leafy vegetables , to phytanic acid . management of refsum 's disease requires a diet restriction of intake of phytanic acid to < 1020  mg / day ( i.e. , about 10% of that in a normal western diet ) . these low phytanic acid ( < 10  mg / dl ) diets are very stringent . lowering of plasma phytanic acid levels by the long - term adherence to diets low in phytanic acid and phytol may be enhanced by serial plasma exchange to prevent development or progression of neuropathy , ataxia , cardiac arrhythmias , and ichthyosis [ 1 , 10 ] . it is less certain whether progression of retinitis pigmentosa , anosmia or deafness can be prevented . it is important that patients maintain body weight , since rapid weight loss releases phytanic acid stored in body tissues and increases symptoms . similarly fevers , pregnancy , and catecholamine released during plasmapheresis have been associated with acute or subacute presentations that mimic guillain - barre syndrome or chronic inflammatory demyelinating polyneuropathy . orlistat ( xenical ) is an inhibitor of intestinal lipase that blocks the digestion of triglycerides . we hypothesised that it would therefore reduce absorption of dietary branched chain fatty acids , in particular phytanic acid . orlistat is usually prescribed for weight loss and has a favourable safety profile which has contributed to the decision to make it available across the counter . side effects associated with orlistat therapy include diarrhoea , faecal incontinence following excessive fat ingestion , and a slight decrease in absorption of fat soluble vitamins . it must be noted that orlistat - induced weight loss might release adipose stores of phytanic acid , thereby increasing plasma levels . we guarded against this possibility by advising our patients to increase their calorie intake so as to maintain weight . the family comprised five children , four brothers and one sister , born of consanguineous parents . there is no clear history of a similar disorder in other generations of the family . brothers af ( 50 years ) and vf ( 48 years ) were diagnosed following the detection of the disorder in their older brother alf ( 56 years ) who was living overseas . the diagnosis of refsum 's disease was made when alf presented to an ophthalmologist with progressive visual symptoms due to retinitis pigmentosa . the family was screened , and the younger brothers af and vf were found to have elevated plasma phytanic acid levels ( af 18.536  mg / dl and vf 3341  mg / dl ) . in retrospect , brothers af and vf reported long standing symptoms of poor sense of smell , tinnitus , loss of peripheral vision , and clumsiness . examination revealed anosmia , retinitis pigmentosa , constricted visual fields , nystagmus , impaired coordination , and ataxia on heel - toe walking . af also had an episode of nonsustained cardiac arrhythmia , long - standing irritable bowel syndrome , and a characteristic deformity in his fourth toes ( figure 2 ) which was reported to be a feature in brother alf as well . the additional features in younger brother vf included hearing impairment , ichthyosis , long slender toes , and multiple bony prominences which are associated with refsum 's disease . following confirmation of the diagnosis by serum phytanic acid measurements , both brothers commenced a low phytanic diet and plasmapheresis . the plasma phytanic acid levels at base - line and with dietary treatment plus plasmapheresis are shown in figure 3(a ) . despite this intensive treatment , the two brothers continued to have progressive symptoms and incomplete control of plasma phytanic acid levels ( greater than 10 times the upper limit of normal ) . substantially lower treatment goals were recommended to minimize complications or progression of disease .   at this stage they were referred to the lipid and metabolic disorder clinic at royal prince alfred hospital in sydney for further optimisation of treatment . af and vf commenced treatment with orlistat at the standard dose of 120  mg three times a day before meals . however their compliance was incomplete and they managed only two doses per day over the first few months . they continued a suitable low - phytanic acid diet with adequate calorie intake to avoid weight loss and regular ( every 3 weeks ) plasma exchanges . the mean pre plasmapheresis phytanic acid levels were calculated for the periods before ( april 2000june 2005 ) and during ( june 2005january 2010 ) orlistat therapy , ( figure 3(b ) ) . nutritional biochemical markers including fat soluble vitamin levels were monitored at baseline and at regular intervals but supplements were not required . phytanic acid was measured by gas chromatography using a 25  m    0.32  mm i.d . sge bp-20 capillary column ; nonadecanoic acid ( 19  :  0 ) methylester was used as internal standard and calibrated against phytanic acid methyl ester ( ultra scientific , usa ) . in af , mean plasma phytanic acid level ( figure 3(b ) ) on diet and plasmapheresis every 3 weeks was 14.8  mg / dl ( sd 10  mg / dl ) , falling to 6.7  mg / dl ( sd 2.8  mg / dl ) after the addition of unblinded orlistat therapy ( p  <  0.05 on two - sample t - test ) . he reported clinical improvement in symptoms of polyneuropathy , ataxia , ichthyosis , irritable bowel syndrome , and cardiac arrhythmia . in vf , mean plasma phytanic acid level ( figure 3(b ) ) on diet and plasmapheresis was 19.0  mg / dl ( sd 13.0  mg / dl ) , falling to 8.2  mg / dl ( sd 5.5  mg / dl ) during unblinded orlistat therapy ( p  <  0.05 , two - sample t - test ) . this was associated with improvement in symptoms of ataxia , hearing loss , and pruritus . however vf continued to suffer progressive impairment of vision , which has improved following bilateral cataract surgery . during this period af and vf maintained stable weight most of the time with brief periods of weight loss associated with a slight increase in measured phytanic acid levels resolving with weight stabilisation , ( figure 3(a ) ) . early diagnosis of hap or refsum 's disease is important because early treatment will minimize accumulation of phytanic acid and progression of functional impairment [ 1 , 2 ] . we considered the use of orlistat ( xenical ) , an intestinal lipase inhibitor , hypothesising that it has the potential to reduce the bioavailability of dietary phytanic acid . this occurs because the inhibition of intestinal lipase by orlistat results in intestinal fat accumulation . lipid soluble materials such as phytanic acid are likely to partition into the triglyceride phase and remain there until excreted . indeed , significant reductions in mean pre - plasmapheresis plasma phytanic acid levels were demonstrated , ( figure 3(b ) ) in these two patients , without significant adverse effects or sustained weight loss . liberalisation of the restrictive diet or reduction in the frequency of plasmapheresis may be feasible in the setting of continued orlistat therapy . , it may be possible to intensify reduction in intestinal lipolysis by the additional inhibition of lingual lipase . this offers the prospect of greater reductions in phytanic acid absorption , but this must be balanced against the possibility that associated weight loss might release tissue stores . it has provided the most effective means of reducing phytanic acid levels and disease progression . orlistat might be useful in the treatment of other metabolic disorders in which lipid soluble materials from the intestine contribute to pathology . we have used orlistat to treat chylomicronaemia associated with massive hypertriglyceridaemia , which poses a risk of acute pancreatitis . these patients remained free of pancreatitis during orlistat therapy , but triglyceride levels and the clinical course of this condition are notoriously variable . a large - scale randomised clinical trial of the use of orlistat would be required to assess its potential for the prevention of pancreatitis in chylomicronaemia . this report of the therapeutic effect of orlistat in refsum 's disease requires confirmation in other patients . the use of orlistat to reduce plasma phytanic acid levels may permit a reduction in the intensity of diet therapy and plasmapheresis , which would result in significant benefit to the patient and reduction in the cost burden to health systems . it may also favourably modify the progression of the clinical manifestations of refsum 's disease .
refsum 's disease is an inherited metabolic disorder in which a metabolite of branched chain fatty acids accumulates due to lack of appropriate oxidative enzymes . 
 patients have elevated plasma phytanic acid levels and high concentrations of phytanic acid in a variety of tissues leading to progressive tissue damage . besides retinal degeneration or retinal dystrophy associated with adult onset retinitis pigmentosa , additional symptoms include chronic polyneuropathy , cerebellar ataxia , sensorineural hearing loss , anosmia , ichthyosis , as well as skeletal , cardiac , hepatic , and renal abnormalities . 
 current management includes avoidance of dietary sources of branched chain fatty acids and regular plasmapheresis to prevent accumulation of these compounds to ameliorate progressive neurological deficits . 
 two brothers with refsum 's disease who experienced progressive symptoms despite optimal diet and plasmapheresis were commenced on a novel therapy . 
 we report the effect of the intestinal lipase inhibitor , orlistat , which led to significant reduction ( p - value < 0.001 on 2-sample unpaired t - test ) of mean preplasmapheresis phytanic acid levels with retardation of the progression of most of their dermatological and neurological symptoms .