Preface: Knowledge of Adult Refsum Disease (ARD) is limited and therefore as new information becomes available the advice and opinions presented in this Question and Answer summary may change. Each patient is an individual and therefore the advice for each person with ARD will need to be adapted for that person and their personal health situation. This requires the help of a doctor and dietician who knows them and has been informed about ARD.

Topic 1 - Disease management – diet & apheresis

Diet

1.              In following a phytanic acid reduced diet we may not be getting all the essential nutrients required for a healthy diet. Should/can our diet be supplemented in any way?

·        There is no blanket recommendation for supplementary nutrition as it largely depends on how a patient translates the diet. For example, for a woman with high menstrual loss who translates the diet in a way that she did not have any significant sources of iron, an iron supplement would be recommended. If a person was not using any skimmed milk or calcium fortified products a calcium supplement would be given. The need for supplements largely depends on an individual’s nutritional requirements. Low fat/skimmed milk products are considered to provide sufficient amounts of calcium.

2. People with age related macular degeneration (AMD) are advised to take anti-oxidants or to eat food high in their content and to eat fish at least 3x week. These foods are also recommended for heart care. As heart problems can be a factor in our condition and our retinas are deteriorating should we be increasing our intake of anti-oxidants? Could we introduce fish that has white flesh? Is there any new research available to show that fish is safe for Adult Refsum Disease patients?

· Fish is a significant source of phytanic acid according to previous diet analysis. White fish and crustaceans have a low fat content and thus are minimal sources of phytanic acid. Not all forms of fish have been analysed but currently it is not recommended to consume fish regularly.

· No studies have demonstrated the improvement of cardiovascular risk with the use of antioxidants.

· C&W does not currently advocate a restriction of fruit and vegetable intake which is a significant source of antioxidants.

· Patients with retinitis pigmentosa (RP) should not follow guidelines put forward for other diseases like AMD.

· The general advice given to RP patients to eat foods with a high docosahexaenoic acid (DHA) content is to be regarded with extreme caution by ARD patients: DHA is specifically found in fatty fish, which also contains high amounts of phytanic acid.

3. Does cooking vegetables really release phytol thus becoming a further exogenous source of phytanic acid?

· No, phytol does not break off the chlorophyll with cooking. Caution should be exercised with some Japanese foods with fermented vegetables (kimshi should be avoided)

· Vegetables should not be overcooked in order to retain their water soluble vitamins.

4. Are there any vegetables in particular that should be avoided? Is there still consensus that green vegetables are permissible?

· Yes, all vegetables are permissible. Even spinach can be safely eaten.

5.              What about legumes and soy products like tofu and soy milk? Is olive oil recommended?

·        In the UK soy products are used extensively by ARD patients. From a coronary artery disease point of view olive oil or rapeseed oil is the recommended choice of oils. Walnut oil should be avoided since walnuts have been shown to contain phytanic acid.

6. Does horsemeat belong to the group of permissible food items?

· C&W has never investigated horsemeat however although horses are non-ruminants horsemeat is not considered safe.

· Explanatory note: In ruminant animals, the rumen is their “first” stomach and with bacteria, is involved with the digestion of chlorophyll resulting in the release of phytol and the formation of phytanic acid. Other herbivores, which are not ruminants do not have a rumen. Some of these other herbivores, but not all, are able to digest chlorophyll in their gastrointestinal system with the help of bacteria. Examples of these are horses and rabbits which digest chlorophyll in their diet. Their fat will contain phytanic acid when they feed on grass and other green foods.

7. Are there any plans to measure phytanic acid contents in new food items recent to the market? Is there any new development in assays available to measure phytanic acid content in food?

· Presently 1000 samples are available for new analysis so the hope is to have a much more comprehensive database available towards the end of 2005. C&W are interested in suggested food items in particular from the international community for investigation. Not all processed products can be measured individually in detail so an average assessment will be given. Seasonal variations in phytanic acid are seen over different countries and content in food. For example, cows out to pasture will produce milk with a higher phytanic acid content than grain feed cows.

8. Is there a newer diet plan available since the last one published in 1993? If so is it possible to keep it up to date and make it available to everybody?

· The diet plan has been updated and the amended version will be emailed to Susan Kuranoff who will make it available via the web and to the German Refsum group.

9. It appears that ARD patients don’t all follow the same dietary regulations. I follow a complete vegan diet and avoid all animal products.

Has it ever been studied whether ARD patients convert chlorophyll to phytanic acid? Should patients avoid consuming chlorophyll containing food?

· See above. According to studies conducted, chlorophyll does not seem to present a problem. A blanket recommendation is difficult since patients translate them in a different way. Your own diet should be reviewed on a regular basis to ensure its appropriateness.

10. Is it recommended to substitute one/several meals a day with SIP feeds (liquid supplements)?

· It is not recommended as a general measure as flavor fatigue can occur very quickly. SIP feeds are valuable in situations where an oral intake cannot be maintained or as supplements during the course of the day. They can be very useful when travelling as a meal substitute or to avoid long breaks between meals.

Apheresis

Editor’s note: The answers provided for questions 11 – 16 solely represent the German approach to apheresis. In the UK apheresis is not commonly practiced as there is not substantial evidence of benefit in patients with stable ARD.

11.       Which procedure is better and recommended – plasmapheresis or apheresis (cascade filtration)? What is the difference and how does cascade filtration function? What frequency is recommended and does it differ for younger and older patients?

·        Current state of the art according to the German Society of Nephrology recommends closed circuit apheresis. Historically plasmapheresis was practiced but is now replaced by cascade filtration which is one of the best and efficient treatments available in case pheresis is needed.

·        There is no difference in format/frequency between the young and old.

12. Can an assessment be made of ongoing new mini regular plasmapheresis performed at 6 to 8 weeks intervals. Also, is it felt that regular plasmapheresis treatment is beneficial in reducing neuropathy?

· Mini-apheresis is suggested when regular/intensive apheresis has been used previously (approximately 14-day intervals). An improvement in clinical symptoms is expected.

13. What neurological, nephrological and ophthalmologic symptoms can be expected to present when long term apheresis (13 year period) is suddenly discontinued?

· Severe consequences and complications are expected to occur within 6 months after cessation.

14. Is there any understanding of the damage which may occur when plasmapheresis is discontinued for a period of ¾ of a year?

· Phytanic acid levels increase and symptoms appear to be worse than before the introduction of apheresis (this is known as a re-bound effect).

15.         Is there a cut-off level as from when a plasma exchange is recommended? 20/d is the recommendation from the Bundesausschuss (German expert committee)– how should this number be understood?

·        There is no pre-defined level as to when apheresis should be introduced to manage the condition. Initiation of apheresis should be dependent on the clinical picture and not necessarily the phytanic acid level. It should be considered in the presence of increased poly-neuropathy, possibly in the progression in retinal dystrophy, and cerebral neurological symptoms (for example, stroke).

·        It is not clearly understood what 20/d implies.

16.       Apart from phytanic acid, what other elements are removed from the body during a plasma exchange?

·        Other toxic and oxidized LDL cholesterols as well as pristanic and pipecolic acids (derived from lycine) are removed. Alpha 2 mcacroglobulin is reduced as well as fibrinogen. This results in the lowering of blood viscosity.

17.       Is the presence of clinical symptoms alone sufficient to proceed with apheresis?

·        C&W says no. Over the last several years the Refsum Clinic in London has not had the need to use apheresis to bring down phytanic acid levels since dietary management alone has been successful in sustaining low phytanic acid levels over time. The only clear indication for apheresis is acute neuropathy and myopathy. There is not substantial evidence of benefit in stable ARD.

18.       Are there any ongoing or planned studies in plasmapheresis?

·        It is an area that researchers are interested in and it has already been seen that disease management appears to differ between Germany and the UK. Collaboration on a multi-national level is recommended in the context of comparison and data sharing to monitor baseline parameters (diet and phytanic acid levels) prior treatment. How fast phytanic acid comes down by diet compared to apheresis should be looked at to determine in which countries too much or too little apheresis is presently being done. More studies are needed and for this a ARD network is needed as well as financial and human resources.

Other treatment:

19. Is there anything available to improve muscle function due to ARD? Is there any treatment for poly-neuropathy? Are supplements such as magnesium beneficial?

· The best method is to reduce phytanic acid levels. It does not help to give specific treatment to target the muscle. No additional diet supplements are advocated to help muscle function.

· ARD patients should exercise as much as possible to use their muscles but to avoid feeling weak never overexert yourself.

· Non-steroidal anti-inflammatory drugs (NSAIDs), with the exception of Ibuprofen is advocated to treat muscle aches and joint pain. Ibuprofen should be avoided as it is metabolized to one of the enzymes of the alpha-oxidation pathway.

20. I’ve heard about a drug available in US known as E100 that is effective in regenerating damaged hearing nerves. Is it available in Germany and can it be used here?

·        E100 is ascorbic acid (vitamin C) and is available in Germany.

21. To what extent has acupuncture been studied as a treatment for auditory and optic nerves? Could acupuncture help preserve the optical nerve so that once progress in treating RP is available, sight may be regained? Any studies available in treatment of cataracts with acupuncture?

·        It is not thought that acupuncture can treat either a cataract or the retina.

·        The optic nerve is part of the central nervous system. There are no primary relevant changes in the central nervous system in ARD, however there are secondary changes probably resulting from a variety of factors. Although the visual nerves may show secondary changes the primary changes for vision are in the sensory end organ, the retina, not the visual nerve. The situation for hearing and smell is less clear. The relationship between these sensory end organs and the nerve is complex. The structures of these special sensory end organs and their pathways are intricate.

22. Can the nervous system be regenerated?

·        Myelin can be which is why peripheral neuropathy gets better. Axons can re-grow and if de-myelination occurs Schwann cells can recover and lay down new myelin but conduction speed never completely recovers. If the axon is no longer intact myelin will not be able to regenerate.

·        Neurons within the central nervous system cannot be regenerated but current investigational work being done in transplants and injections may address this problem in the future.

Topic 2 - Disease progression & its measurement

23. Is there a template or questionnaire that we could present to our GP for them to compare our individual symptoms with the broader spectrum of ARD symptoms? This could serve as a summary of our medical history and provide an overview of our condition.

· A questionnaire has been developed to primarily help with the compilation of a registry but is not intended for GP use.

24. What impact does early diagnosis have on the progression of the characteristic symptoms of ARD ie: RP, anosmia and hearing loss? Can early introduction of disease management prevent further deterioration?

· Yes, it is firmly believed that early intervention can be beneficial. There may be a 10-15 year delay between the diagnosis of an eye problem and the correct diagnosis of ARD. Eye doctors need to be re-educated to help to reduce this timeline and properly diagnose the condition in order to intervene and slow the course of the disease.

25. Is there a specific form of RP linked directly to ARD? Can we exclude total blindness as a prognosis for ARD patients?

· No, there is no easy way to distinguish between RP in ARD patients and isolated RP. If patients are diagnosed early it is expected that some sort of vision can be preserved at the end of a normal life span.

26. The lab that does my phytanic acid level reading uses a method known as GC/MS – gas chromatography-mass spectrometry. Do all laboratories use this method and if not what other methods are in place? Is there a consensus which technique is the best? How much lab inter-variability can be expected with this method?

· GC/MS is the recommended technique for all labs but some labs still use GC technique which is outdated and should not be used. Quality control schemes are slowly starting to become mandatory implying the labs deliver consistent and quality results.

· 600% difference within the same sample depending on the laboratory was seen prior the introduction of the scheme, variability has now been reduced to 50%.

· A new technique is available known as GC tandem mass spectrometry which will bring variability down to less than 2%.

· A list of the 10 biggest European laboratories presently in the quality control scheme offering specialist tasks is available on the Society for the Study of Inborn Metabolism Errors web page: www.ssiem.org/uk. From there click through to Links then Diagnostic Centres and Assay Finder Services or contact the national society.

27. Do any statistics exist documenting the progression of the disease?

· There is no statistical information available about disease progression. Several articles have been published but none of them contain statistical results. The nearest to this which has been done is to look at the endpoint of phytanic acid and these results will soon be published. Statistical analysis is difficult within a clinical setting when variations within patients are so large in a small patient group like ARD.

28. Early recognition of ARD does not only happen at the ophthalmologist or paediatrician – more awareness needs to happen. What can we as patients do to educate our caregivers?

· ARD patients need to tell their caregivers about their disease and essential symptoms to help redefine the clinical picture as perceived by the doctors. Patients need to understand that their GP will likely not possess the knowledge required to make an ARD diagnosis. Instead, more focus should be aimed at re-educating the ophthalmologists as they are the ones likely to see the first signs of ARD and play an instrumental role in making an early diagnosis.

· A scientific consensus statement resulting from this workshop will be published in Ophthalmology journals to increase disease awareness among ophthalmologists.

29. My daughter who has ARD, was very young (4-6 years old) when she started to show signs of RP. Was she born with a damaged retina or did deterioration first start during her early years?

· This is a difficult question and cannot be answered with certainty. It would depend very much on plasma phytanic acid levels early on in life. It can be assumed the retina must have been pretty normal at birth. Probably part of the damage done by the age of 6 could have been prevented if an early diagnosis of ARD had been made.

Topic 3 - Clinical picture and its relationship to genetics, environment and phytanic acid

30. How high can phytanic acid levels rise before irreversible damage such as tremor, heart attack or stroke is expected to occur?

· There is no such thing as an acceptable elevated phytanic acid level. At what level a person will develop symptoms and signs is not known. RP probably occurs before phytanic acid is highly elevated. The aim of disease management should always be to get and keep phytanic acid levels down to normal.

· Strokes are not a feature of ARD and are not expected more frequently than in the normal population. Tremor is a feature of the ataxia (unsteadiness and incoordination). Heart disease is rare expect in patients whose phytanic acid level is very high and not controlled (see question 32)

31. Is PA an indicator of or the cause for the disease?

·        It is both a measure and indicator of the condition. The origin of the disease is the genetic abnormality which leads to the enzyme abnormality which leads to the rise in phytanic acid levels. It is known that at least two genes are responsible for the condition and result in very different presentations of the disease. The phytanic acid level is a measurable indicator of how seriously the metabolism is affected. A raised phytanic acid level is a cause of most of the acute symptoms, but probably not all the chronic symptoms. For example it has not been proven that phytanic acid is responsible for hearing loss or anosmia. Phytanic acid is part of the syndrom and it is known for instance that people with neuropathy have elevated phytanic acid levels.

32.       Is there any evidence that heart problems are linked to ARD and if so, which ones?

·        Yes, but heart problems are rare. Heart problems do not occur in people who have their condition well controlled. ECGs in people with well controlled disease seem to be normal and will change only when a patient is very ill. Cardiac myopathy leads to an arrhythmia and if bad enough can lead to ventricular dysfunction which can cause heart failure. Asystole can lead to sudden death.

33. Can it be assumed the monozygotic twins will experience the same disease progression?

· No, the expectation is that their progression will be very similar but not absolutely identical. While their genetic background is identical, differences in disease progression will be due to external factors such as the environment and diet.

34. Is there a correlation between memory/forgetfulness and phytanic acid levels?

· No, cerebral function appears to remain normal therefore there is probably no correlation. Because of concurrent illness patients may experience forgetfulness secondary to ARD.

35. Is there any research on the correlation of stress and ARD?

· No, but some patients have experienced considerable deterioration during traumatic experiences due to substantial weight loss.

36. How does passive or active smoking affect the course of disease progression? What about alcohol?

· Cyanide in cigarette smoke is a bad thing and adds toxicity at the level of the optic nerve plus it is a cardiac risk. It is suggested to refrain from smoking.

· Alcohol consumption should be kept modest. Alcohol does not affect the retina in moderate amounts. The retina and the optic nerve however can be affected by large amounts of alcohol consumption.

37. It’s been observed that ARD patients have difficulty with long breaks between meals. Is phytanic acid released during meal breaks? Is there an explanation why ARD patients feel hungry again very quickly after a meal?

· Patients are advised not to have long breaks between meals. Breakfast, lunch and dinner are recommended with snacks in between as well as a bedtime snack in the case of a late bedtime.

This balanced food intake profile is also likely to reduce post-eating excursions in phytanic acid levels. Hunger after meals could be simply an expression that somebody is dissatisfied with what they are eating and are

bored with their food combinations as opposed to being a real question of satiety.

38. To what extent is genetic counselling in necessary for ARD patients considering having a family? What about family planning for offspring of a ARD patient? Is genetic counselling reimbursed by national health insurance programs? Do we have an idea what this costs in Germany?

· Advice worth giving to somebody with ARD or a member of the family is not to marry a blood relative as this will increase the chances of the disease. The chances of marrying someone who is a the carrier of a bad copy of the ARD gene are very small. The surveys for ARD and the abnormal genes are not extensive and the incidence and prevalence of ARD is inadequately estimated. These figures could vary within Europe and the word but carrier frequency is estimated to about 1/500 and prevalence is estimated to 1/1,000,000.

· Genetic counselling is available in Germany and is covered by the German health insurance. This is also true for most European countries.

Topic 4 – Research; future prospects and participation

39. Is there an Australian component in the current research and if so how can a patient get involved?

· Letters have been sent by Dr. R. Wanders to his colleagues in Australia asking patient participation. Australian patients may approach their caregivers with the RDDPT questionnaire available from Dr. M. Horn.

40. We are aware that a French research unit is linked to the RDDPT project. What is their role and why is there so little known about their involvement?

· There is one French unit (Dr. Patrick Aubourg) who is involved through Dr. R. Wanders’ lab. The unit has to do with one of the first French patients who presented with a severe picture from a very early age in whom it is thought the gene is completely absent. French involvement is limited because of logistical reasons since there is no single centre caring for the French patients although there is a cluster of patients in northern France. It is hoped to re-activate the relationship with the French and include French patients in the research project.

41. We’d like to learn more about the development of the Refsum mouse model.

So would the researchers!

Two models exist of different aspects:

· 1) Carrier protein minus mouse (SCP2 knock-out) – This mouse has a severe phenotype and presents with a severe form of the condition. The mouse presents with several symptoms of ARD, but it does not fit the complete picture as it doesn’t develop the eye problems.

· 2) Refsum mouse – hydroxylase protein is knocked out. The mouse has been seen to be remarkably well until it is fed phytol and then dies very quickly of weight loss. The mouse does not develop eye-changes by the time they die probably because they were receiving too much phytol (2%) and dying before the full clinical picture could develop. Further studies are ongoing whereby the mouse will be fed smaller quantities of phytol to better mimic the progression in humans.

42. What is the status of research with retina implants?

· Several lines of thought prevail in therapies for inherited retinal dystrophies:

1) Gene therapy – effective but not applicable to ARD.

2) Retinal transplants – still in the early experimental days

3) Retinal implants – initial results are hopeful but it is not a therapy which will be applied in the near future.

43. Monitoring disease progression requires an interdisciplinary approach from several specialists which in turn requires the establishment of specialty services within the clinics. Should we not establish ARD special care units in Germany within the national health legislation?

· Yes, it makes sense to establish such centers for treatable diseases. Efforts and discussions are ongoing but because of the disjointed health system it’s a slow process.

· It is suggested to establish several specialty centers per country along the lines of one unit per 10 mio people.

44. Is it possible to counteract a genetic defect by transplanting an organ such as the liver? I was told by a physician that my ARD could be healed simply by obtaining a new liver since the enzyme for PA resides in the liver?

· This has been done in one case in Italy but details are not well known. Liver transplantation is difficult because of immunosuppressive problems and once having had one liver transplant it’s difficult to have a second. The risk associated with a liver transplantation is still quite considerable. The UK is looking at infusing liver cells as a treatment for genetically inherited liver disease however the research is at a very early stage. Problem exists with cell survival without repressing the immune system too much.

Topic 5 - Other

Genetics

45. Is there any evidence indicating that ARD may a dominant genetic disease as apposed to autosomal recessive?

· No, there is nothing in the pathway that looks like it can be a dominant disease. Carriers may have a slightly raised phytanic acid level but won’t express symptoms of the condition.

· The approximate chance that a ARD patient will have a child with ARD disease provided she has not married a family member is estimated to about 1/1000.

46. Within a family of affected siblings, is it possible that one child may express only one characteristic of the disease i.e. RP, while the others show a full blown syndrome?

· Families showing considerable variation of the disease have been seen and it is not unusual. External factors such as health, food, lifestyle play an important role in disease expression and may explain variation.

47.       Can physiotherapy be beneficial to a ARD patient?

·        Active physiotherapy can help as long as you don’t exercise to a degree that doesn’t leave you exhausted the next day.

48.       Diagnostics – are there any general recommendations for testing that an ophthalmologist should apply? What regular controls should a neurologist perform?

·        An ophthalmologist should do a full ophthalmologic examination including a visual field plus an ISCEV (International Society of Clinical Electrophysiology of Vision) standard full-field flash electro-retino-gram (ERG). Follow-up visits are advisable at 3 year intervals or more frequently if the patient so desires. A good prognostic factor of vision is good visual acuity together with a well preserved pattern ERG. This is a measure of central retinal or macular function with some prognostic value as to visual acuity.

·        Asking an ophthalmologist to measure phytanic acid in all patients with RP is a tall order, however if the patient with RP had neurological symptoms, loss of smell or skeletal deformities it is very important to measure the phytanic acid level. However, asking to see a patient’s hands and feet is easily done and enquiring whether the sense of smell is perceived as impaired is equally easy.

·        Neurologist should always be on the look out for ARD if a patient presents with peripheral neuropathy. They should do a full neurological examination and check smell and consider RP.

49.       A mother strongly influences the metabolism of an unborn child. Once an unborn child’s metabolism becomes active during the last months of pregnancy is there a possibility to positively influence the mother’s and her ability to metabolize phytanic acid?

·        It is not certain but the feeling is that pregnancy does not have a beneficial influence on the disease progression.

50.       What role do stem cells have as potential treatment in ARD?

·        Stem cells are great hope of medicine and appear to work in the short term in some conditions but it is an early technique at the moment. Stem cells to repopulate the blood will probably be easier than repopulating the retina however there is still a long way to go before this is possible.

Round Table Questions & Answers

ECHOO Conference Translators, Berlin

Topic 1 - Disease management – diet & apheresis

Topic 2 - Disease progression & its measurement

Topic 4 – Research; future prospects and participation

Topic 5 - Other