Refsum disease - Clinicals, Diagnosis, and Management

Neurology

Clinicals - History

Fact Explanation
Vision disturbances Refsum disease is an autosomal recessively inherited metabolic disease caused by phytanoyl-coenzyme A hydroxylase enzyme deficiency. This causes in defective alpha oxidation of phytanic acid, a branched chain fatty acid of dietary origin.
Accumulation of phytenic acid in the eyes damages the light sensing rods and cons of the retina. The ultimate retinitis pigmentosa initially manifests as blurring of vision/ night blindness. Onset of the visual problems is most commonly occurs in childhood/adolescence with a progressive course. This may eventually result in permanent blindness. Apart from retinitis pigmentosa, cataract may be the cause of visual disturbances in some patients. This may be accompanied by photophobia secondary to impaired papillary light responses.
Vision disturbances
Refsum disease is an autosomal recessively inherited metabolic disease caused by phytanoyl-coenzyme A hydroxylase enzyme deficiency. This causes in defective alpha oxidation of phytanic acid, a branched chain fatty acid of dietary origin.
Accumulation of phytenic acid in the eyes damages the light sensing rods and cons of the retina. The ultimate retinitis pigmentosa initially manifests as blurring of vision/ night blindness. Onset of the visual problems is most commonly occurs in childhood/adolescence with a progressive course. This may eventually result in permanent blindness. Apart from retinitis pigmentosa, cataract may be the cause of visual disturbances in some patients. This may be accompanied by photophobia secondary to impaired papillary light responses.
Hearing difficulties This is thought to be due to the inflammation triggered by accumulated phytenic acid in the nerves. The difficulties are insidious in the onset and progress slowly from infancy to the adolescence. Hearing difficulties
This is thought to be due to the inflammation triggered by accumulated phytenic acid in the nerves. The difficulties are insidious in the onset and progress slowly from infancy to the adolescence.
Bilateral anosmia is caused by the involvement of the phytenic acid in the olfactory nerves. Bilateral anosmia
is caused by the involvement of the phytenic acid in the olfactory nerves.
Unsteady gait Patient may have difficulties in balancing his body in the upright posture. This is thought to be due to the involvement of the cerebellum. Unsteady gait
Patient may have difficulties in balancing his body in the upright posture. This is thought to be due to the involvement of the cerebellum.
Tremors Cerebellar involvemet may present as tremors as well. These are intention tremors. Patient may find it difficult to complete some purposeful movements, like reaching to pick up an object. His or her hand will experience a very broad, slow tremor. The grasping becomes difficult because of it. Objects usually slip out of reach just as the patient completes the movement. Tremors
Cerebellar involvemet may present as tremors as well. These are intention tremors. Patient may find it difficult to complete some purposeful movements, like reaching to pick up an object. His or her hand will experience a very broad, slow tremor. The grasping becomes difficult because of it. Objects usually slip out of reach just as the patient completes the movement.
Skin lesions Accumulation of phytenic acid in the skin results in ichthyosis. These patients have dry, thickened, scaly or flaky skin that sometimes may be cracked. This can affect all parts of the body, including the face and scalp. Skin lesions
Accumulation of phytenic acid in the skin results in ichthyosis. These patients have dry, thickened, scaly or flaky skin that sometimes may be cracked. This can affect all parts of the body, including the face and scalp.
Chest pain In rare instances patients may present with chest pain that resembles a heart attack. This is due to rare involvement of heart results in Cardiomyopathy and conduction abnormalities. Chest pain
In rare instances patients may present with chest pain that resembles a heart attack. This is due to rare involvement of heart results in Cardiomyopathy and conduction abnormalities.

Clinicals - Examination

Fact Explanation
Skin lesion Accumulation of phytenic acid in the skin results in ichthyosis. There skin is appeared to be dry, thickened, scaly or flaky. Sometimes these lesions are cracked. Skin lesion
Accumulation of phytenic acid in the skin results in ichthyosis. There skin is appeared to be dry, thickened, scaly or flaky. Sometimes these lesions are cracked.
Anosmia Some patients have bilateral anosmia due to the involvement of olfactory nerve. Anosmia
Some patients have bilateral anosmia due to the involvement of olfactory nerve.
Visual signs Eye involvement is indicated by cataract. Retinitis pigmentosa can be demonstrated by fundoscopic examination. Progressive loss of photoreceptor cells may eventually lead to blindness. Atypical retinitis pigmentosa can present with progressive concentric restriction of visual fields. Tunnel vision, peripheral vision, latticework vision, aversion to glare and blurring of vision are some other findings. Visual signs
Eye involvement is indicated by cataract. Retinitis pigmentosa can be demonstrated by fundoscopic examination. Progressive loss of photoreceptor cells may eventually lead to blindness. Atypical retinitis pigmentosa can present with progressive concentric restriction of visual fields. Tunnel vision, peripheral vision, latticework vision, aversion to glare and blurring of vision are some other findings.
Hearing difficulties Neurological degeneration of the chochlear nerve result in nerve deafness. This is usually bilateral. Hearing difficulties
Neurological degeneration of the chochlear nerve result in nerve deafness. This is usually bilateral.
Ataxia Cerebellar degeneration results in some prominent cerebellar signs such as cerebellar ataxia.
This might be accompanied by dyssynergia, dysmetria, dysdiadochokinesia and dysarthria. Intension tremors can also be detected. All these signs are ipsilateral. As the disease may affect both sides of the celebellum, signs may be demonstrated bilaterally.
Ataxia
Cerebellar degeneration results in some prominent cerebellar signs such as cerebellar ataxia.
This might be accompanied by dyssynergia, dysmetria, dysdiadochokinesia and dysarthria. Intension tremors can also be detected. All these signs are ipsilateral. As the disease may affect both sides of the celebellum, signs may be demonstrated bilaterally.
Diminished deep tendon reflexes Associated polyneuropathie result in absence of deep tendon reflexes unilaterally or bilaterally. Diminished deep tendon reflexes
Associated polyneuropathie result in absence of deep tendon reflexes unilaterally or bilaterally.
Cardiovascular system findings A small portion of patients suffer from cardiomyopathy as a complication. Those may have tachypnea, tachycardia, hypertension, signs of hypoxia (cyanosis, clubbing), jugular venous distension, pulmonary edema (crackles and/or wheezes), S3 gallop
and enlarged liver.
Cardiovascular system findings
A small portion of patients suffer from cardiomyopathy as a complication. Those may have tachypnea, tachycardia, hypertension, signs of hypoxia (cyanosis, clubbing), jugular venous distension, pulmonary edema (crackles and/or wheezes), S3 gallop
and enlarged liver.

Investigations - Diagnosis

Fact Explanation
Plasma phytanic acid level Normal plasma level of phytenic acid level is less than 0.2 mg/dL. In Refsum disease it is between 10-50 mg/dL or even higher. Plasma phytanic acid level
Normal plasma level of phytenic acid level is less than 0.2 mg/dL. In Refsum disease it is between 10-50 mg/dL or even higher.
Cerebrospinal fluid analysis CSF analysis shows cellular-protein dissociation. CSF protein levels are usually elevated (100-600 mg/dL) while the cell counts are within normal range. Cerebrospinal fluid analysis
CSF analysis shows cellular-protein dissociation. CSF protein levels are usually elevated (100-600 mg/dL) while the cell counts are within normal range.
Lipid profile Low (LDL) and high-density lipoprotein (HDL) cholesterol levels are decreased as a negative feedback effect of increased phytanic acid in serum. Lipid profile
Low (LDL) and high-density lipoprotein (HDL) cholesterol levels are decreased as a negative feedback effect of increased phytanic acid in serum.
Plain X-rays Some patients with Refsum disease has Epiphyseal dysplasia which leads to characteristic shortening of the fourth toe, hammer toe, pes cavus and osteochondritis. Plain X-rays
Some patients with Refsum disease has Epiphyseal dysplasia which leads to characteristic shortening of the fourth toe, hammer toe, pes cavus and osteochondritis.
MRI scan Changes in corticospinal tracts, cerebellar dentate nuclei and corpus callosum are usually demonstrable symmetrically. MRI scan
Changes in corticospinal tracts, cerebellar dentate nuclei and corpus callosum are usually demonstrable symmetrically.
Nerve conduction studies Slow conduction velocities are found in nerve conduction studies. Nerve conduction studies
Slow conduction velocities are found in nerve conduction studies.
Electroretinogram Electroretinogram (ERG) showed retinal pigmentation abnormalities in both fundi. Electroretinogram
Electroretinogram (ERG) showed retinal pigmentation abnormalities in both fundi.
UPSIT (University of Pennsylvania Smell Identification Test) Anosmia or grossly impaired smell function can be demonstrated by this test. UPSIT (University of Pennsylvania Smell Identification Test)
Anosmia or grossly impaired smell function can be demonstrated by this test.
Electrocardiogram (ECG) Cardiac conduction defects can be detected if presents as a complication of refsum disease. Electrocardiogram (ECG)
Cardiac conduction defects can be detected if presents as a complication of refsum disease.

Investigations - Management

Fact Explanation
Neurology follow up Patient should be frequently followed up on the neurological progression of the disease. Full neurological examination has to be perform on this purpose focusing on gait abnormalities and deep tendon reflexes. Neurology follow up
Patient should be frequently followed up on the neurological progression of the disease. Full neurological examination has to be perform on this purpose focusing on gait abnormalities and deep tendon reflexes.
Ophthalmology follow up Ophthalmology follow up is important as a mild retinitis pigmentosa may progress to the blindness later on. Visual field examination, fundoscopy and Electroretinogram may play an important role. Ophthalmology follow up
Ophthalmology follow up is important as a mild retinitis pigmentosa may progress to the blindness later on. Visual field examination, fundoscopy and Electroretinogram may play an important role.
Dermatological follw up Though the skin lesion resolves with the reduction of phytenic acid in the serum, some patient may have long term sequel of icthyiosis. These patients should be treated accordingly. Dermatological follw up
Though the skin lesion resolves with the reduction of phytenic acid in the serum, some patient may have long term sequel of icthyiosis. These patients should be treated accordingly.

Management - Supportive

Fact Explanation
Patient education Patient should be educated regarding the disease and the important of the diet on controlling the disease. Patient education
Patient should be educated regarding the disease and the important of the diet on controlling the disease.
Genetic counselling / Family screening Refsum disease is inherited in autosomal recessive manner. So the siblings and relatives should be screened. Prenatal diagnosis in at-risk pregnancies is also possible. Genetic counselling / Family screening
Refsum disease is inherited in autosomal recessive manner. So the siblings and relatives should be screened. Prenatal diagnosis in at-risk pregnancies is also possible.
Urea preparations Dermatological preparations which contain urea such as Carmol and Ureacin-40 are helpful in softening the skin in case of hyperkeratosis. These topical treatments promotes hydration and the removal of excess keratin in conditions of hyperkeratosis. Urea preparations
Dermatological preparations which contain urea such as Carmol and Ureacin-40 are helpful in softening the skin in case of hyperkeratosis. These topical treatments promotes hydration and the removal of excess keratin in conditions of hyperkeratosis.
Dietary Modification Dietary modification is considered as the most effective management for Refsum disease. The main goal is to reduce dietary intake of phytenic acid containing food. Green vegetables and animal fat (Fish, beef, lamb and dairy products) have to be avoided as much as possible. Poultry, pork, fruit and other vegetables are allowed. Patient should be educated that these dietary modifications are life long and these alone can result in weight loss. TO prevent that, patient should avoid fasting and his/ her diet should include enough calories by means of much carbohydrates. Dietary Modification
Dietary modification is considered as the most effective management for Refsum disease. The main goal is to reduce dietary intake of phytenic acid containing food. Green vegetables and animal fat (Fish, beef, lamb and dairy products) have to be avoided as much as possible. Poultry, pork, fruit and other vegetables are allowed. Patient should be educated that these dietary modifications are life long and these alone can result in weight loss. TO prevent that, patient should avoid fasting and his/ her diet should include enough calories by means of much carbohydrates.

Management - Specific

Fact Explanation
Plasmapheresis Plasmapheresis is indicated in situations when the dietary management is not sufficient, the disease condition is severe and rapidly worsening. Cascade filtration is an efficient alternative for plasmapheresis and it removes the need for albumin replacement. Plasmapheresis
Plasmapheresis is indicated in situations when the dietary management is not sufficient, the disease condition is severe and rapidly worsening. Cascade filtration is an efficient alternative for plasmapheresis and it removes the need for albumin replacement.
Bilateral cochlear implantation Bilateral cochlear implantation should be implemented in severe auditory impairment. Bilateral cochlear implantation
Bilateral cochlear implantation should be implemented in severe auditory impairment.

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  1. BRITTON TC, GIBBERD FB, CLEMENS ME, BILLIMORIA JD, SIDEY MC. The significance of plasma phytanic acid levels in adults. J Neurol Neurosurg Psychiatry [online] 1989 Jul, 52(7):891-4 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/2475586
  2. CHOKSI V, HOEFFNER E, KARAARSLAN E, YALCINKAYA C, CAKIRER S. Infantile refsum disease: case report. AJNR Am J Neuroradiol [online] 2003 Nov-Dec, 24(10):2082-4 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/14625237
  3. MILLAR JH. Refsum disease--the effect of diet. Ulster Med J [online] 1985 Apr, 54(1):41-5 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/2417395
  4. SINGH I, PAHAN K, SINGH AK, BARBOSA E. Refsum disease: a defect in the alpha-oxidation of phytanic acid in peroxisomes. J Lipid Res [online] 1993 Oct, 34(10):1755-64 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7504046
  5. STEINBERG D, MIZE CE, AVIGAN J, FALES HM, ELDJARN L, TRY K, STOKKE O, REFSUM S. Studies on the metabolic error in Refsum's disease. J Clin Invest [online] 1967 Mar, 46(3):313-22 [viewed 25 September 2014] Available from: doi:10.1172/JCI105533
  6. WANDERS RJ, KOMEN J, FERDINANDUSSE S. Phytanic acid metabolism in health and disease. Biochim Biophys Acta [online] 2011 Sep, 1811(9):498-507 [viewed 25 September 2014] Available from: doi:10.1016/j.bbalip.2011.06.006
  7. WANDERS RJA, WATERHAM HR, LEROY BP, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Refsum Disease [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301527
  8. WILLS AJ, MANNING NJ, REILLY MM. Refsum's disease. QJM [online] 2001 Aug, 94(8):403-6 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11493716