Refsum's disease

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(medicine) A familial disorder characterized by visual disturbances, ataxia, neuritic changes, and cardiac damage, associated with high blood level of phytinic acid.

Definition

Refsum disease is one of several inherited disorders that are collectively called leukodystrophies. Refsum disease results from defects in the formation of the myelin sheath, a fat covering that protects the nerves in the brain and spinal cord.

Description

Refsum disease has also been called Refsum-Thiébaut disease and Refsum-Thiébaut-Klenk-Kahlke disease since Drs. W. Kahlke, E. Klenk, M.F. Thiébaut, and Sigvald Bernhard Refsum all contributed to the identification and clinical characterization of the disorder. The Norwegian neurologist, Sigvald Refsum first described the disorder in 1946.

Refsum disease is a rare genetic disorder that affects the ability of the body to breakdown fats, a process called fatty acid oxidation. As a result, a metabolite called phytanic acid accumulates in the blood as well as other tissues. Phytanic acid is not produced by the human body but is obtained from meat, dairy, and fish products. Phytanic acid is a branched chain fatty acid. The accumulation of this compound in the blood was detected by the German scientist Klenk and Kahlke around 1963. Phytanic acid can also be produced through the breakdown of a substance that is found in green leafy vegetables called phytol.

Refsum disease is inherited as an autosomal recessive disorder, which means that two unaffected carrier parents have a 25% chance of having an affected child in every pregnancy. Other less commonly used synonyms for Refsum syndrome include: ataxia hereditaria hemeralopia polyneuritiformis, hemeralopia heredotaxia polyneuritiformis, hereditary motor sensory neuropathy type IV, heredopathia atactica poluneuritiformis, and phytanic acid storage syndrome.

Demographics

Refsum disease is an extremely rare disorder that affects males and females with equal frequency. It has been observed in Norwegian populations as well as others.

Causes and symptoms

One of the earliest symptoms in Refsum disease that the patients develop is night blindness. The age of onset of all clinical manifestations tends to occur during childhood and usually develop before 50 years of age. It is a progressive disorder characterized by periods of subtle worsening and often appears to be in remission.

People with Refsum disease typically experience progressive hearing loss due to nerve damage that occurs early during development. They can develop a progressive degeneration of the eye leading to blindness due to an atypical form of retinitis pigmentosa, a degenerative condition associated with night blindness and pigment changes in the retina. The visual loss involves progressive constriction of the visual fields and these patients can develop nystagmus (an involuntary oscillation of the eyeball) as well as cataracts.

Cerebellar ataxia (brain-damage-related loss of motor coordination) can also occur with Refsum disease, leading to an unsteady gait. They can have syndactyly of the fingers, where two fingers appear fused due to a failure to separate during embryo formation. The neurological damage appears to be localized toward the head and trunk of the body (rather than the limbs). A fetus with Refsum disease often develops heart disease and can also be born with skeletal abnormalities in bone formation. It is also common for people with Refsum disease to lose their sense of smell. Finally, changes in the skin can also occur with Refsum disease.

Refsum was the first genetic disorder identified to be caused by defects in lipid (fat) metabolism. It is currently felt to be caused by mutations in a gene (PAHX) that encodes a protein called phyanoly-CoA hydroxylase and is important for metabolizing phytanic acid.

Diagnosis

The diagnosis for Refsum disease is made based on the development of clinical manifestations and biochemical analysis detecting elevated phytanic acid in the blood.

Treatment team

There are several specialists that are helpful in the diagnosis, treatment, and long-term care of patients with Refsum disease. A neurologist is helpful initially in diagnosing the disorder, as well as providing the appropriate follow-up studies and treatment regimen. A genetic counselor is helpful in explaining the recurrence risks to the family, especially if they are considering reproductive implications.

Treatment

Dietary treatment involving the restriction of foods that contain phytanic acid began in Norway in 1966 by Professor Lorentz Eldjarn, the Head of the Central Laboratory and Institute for Clinical Biochemistry at the Oslo University Hospital, Rikshospitalet. This treatment continues today. Additionally, plasmapheresis or the removing of plasma from the patient's blood may also be helpful and necessary.

Recovery and rehabilitation

Recovery with treatment is often possible for many of the symptoms, although treating patients with Refsum disease cannot reverse damage to the eyesight and hearing.

Clinical trials

The National Institute for Neurological Diseases and Stroke and the National Institutes of Health supports research to help increase understanding and awareness or Refsum disease, as well as to find new prevention, treatments, or a cure for this disorder. One study, which is aimed at determining the effectiveness of an oral bile acid therapy regimen is currently recruiting patients with the infantile form of Refsum disease. (Contact information: Kenneth Setchell, Study Chair, Children's Hospital Medical Center, Cincinnati OH; (513) 636-4548).

Prognosis

The prognosis for Refsum disease is highly variable. Without treatment, the prognosis is poor. In patients who are treated appropriately, many neurological symptoms and ichthyosis (scaly, dry skin) generally disappear.

Resources

BOOKS

Iocn Health Publications. The Official Parent's Sourcebook on Refsum Disease: A Revised and Updated Directory for the Internet Age. San Diego: Icon Group International, 2002.

PERIODICALS

Richterich, R., P. van Mechelen, and E. Rossi. "Refsum's disease (heredopathia atactica polyneuritiformis): An inborn error of lipid metabolism with storage of 3,7,11,15-tetramethylhexadecanoic acid." Am J Med 39: 230–41.

OTHER

"NINDS Refsum Disease Information Page." National Institute of Neurological Disorders and Stroke. (March 10, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/refsum_doc.htm.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). P.O. Box 1968 (55 Kenosia Avenue), Danbury, CT 06813-1968. (203) 744-0100 or (800) 999-NORD (6673); Fax: (203) 798-2291. orphan@rarediseases.org. http://www.rarediseases.org.

National Tay-Sachs and Allied Diseases Association. 2001 Beacon Street Suite 204, Brighton, MA 02135. (617) 277-4463 or (800) 90-NTSAD (906-8723; Fax: (617) 277-0134. info@ntsad.org. http://www.ntsad.org.

Bryan Richard Cobb, PhD

A rare inherited metabolic disorder characterized by a buildup of phytanic acid in tissues and a manifestation of such conditions as retinitis pigmentosa, polyneuritis, deafness, and nystagmus.

Refsum's disease
Classification & external resources

Phytanic acid
ICD-10	G60.1
ICD-9	356.3
OMIM	266500
DiseasesDB	11213
eMedicine	derm/705
MeSH	D012035

Refsum's disease (Refsum-Thiébaut disease, Refsum-Thiébaut-Klenk-Kahlke disease), named after Norwegian neurologist Sigvald Bernhard Refsum (1907-1991),^[1][2] is neurological disease that results in the malformation of myelin sheaths around nerve cells. It is a peroxisomal disorder.

Causes

Refsum's disease is caused by faulty enzymes during the alpha-oxidation of phytanic acid resulting in buildup of phytanic acid and its unsaturated fatty acid derivatives in the plasma and tissues.

This in turn can be due to deficiencies of phytanoyl-CoA hydroxylase (chromosome 10) or peroxin-7 (chromosome 6).

Presentation

Patients with Refsum's Disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy. Onset is most commonly in childhood/adolescence with a progressive course, although periods of stagnation/remission occur.

Treatment

The most effective therapy in the classic Refsum disease is dietary treatment with a phytanic acid-restricted diet, such as exclusively avoiding consumption of beef, lamb, fatty fish such as tuna, cod, and haddock ^[3]. Recent research has shown that CYP4 isoform enzymes could eliminate the phytanic acid storage in vivo ^[4] and patients could try alternative natural remedies with either eatable marine invertebrates or with clofibrate supplement of which the component is usually rich in the excretion of high plant ^{[5], [6], [7]}. Currently, there is no clinical data to approve using this xenonbiotic drug for the treatment, perhaps due to its serious adverse effect ^[8]and the major medical treatment of the disease only relies on the plasmapheresis.

Reaction

Phytol (from chlorophyll in plant foods) ---> phytanic acid -x-> pristanic acid ---> propionyl CoA

See also

• The Myelin Project

References

1. ^ S. Refsum: "Heredoataxia hemeralopica polyneuritiformis - et tidligere ikke beskrevet familiært syndrom? En foreløbig meddelelse." Nordisk Medicin,1945, 28: 2682-2686 (in norwegian).
2. ^ S. Refsum: "Heredopathia atactica polyneuritiformis. A familial syndrome not hitherto described. A contribution to the clinical study of hereditary diseases of the nervous system". Acta psych. neur., 1946. Suppl.38: 1-303.
3. ^ National Institutes of Health. Synonym(s): Phytanic Acid Storage Disease, Heredopathia Atactica Polyneuritiformis <Internet>. Retrieved on 8 July, 2007.
4. ^ Xu, Fengyun et al.. CYP4 Isoform Specificity in the {omega}-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease <Internet>. Retrieved on 11 July, 2007.
5. ^ Snyder, Mark J.. Cytochrome P450 enzymes belonging to the CYP4 family from marine invertebrates <Internet>. Retrieved on 11 July, 2007.
6. ^ Rewitz, Kim F.. Marine invertebrate cytochrome P450: Emerging insights from vertebrate and insect analogies <Internet>. Retrieved on 11 July, 2007.
7. ^ Raucy, Judy L.. Regulation of CYP2E1 by Ethanol and Palmitic Acid and CYP4A11 by Clofibrate in Primary Cultures of Human Hepatocytes <Internet>. Retrieved on 11 July, 2007.
8. ^ Atromid-S: Indication & Dosage <Internet>. Retrieved on 11 July, 2007.

Nervous system pathology, primarily PNS (G50-G99, 350-359)
Nerve, nerve root and plexus disorders	cranial nerve: V (Trigeminal neuralgia) - VII (Facial nerve paralysis, Bell's palsy, Melkersson-Rosenthal syndrome, Central seven) - XI (Accessory nerve disorder) nerve root and plexus: Brachial plexus lesion - Thoracic outlet syndrome - Phantom limb mononeuropathy: Carpal tunnel syndrome - Ulnar nerve entrapment - Radial neuropathy - Causalgia - Meralgia paraesthetica - Tarsal tunnel syndrome - Morton's neuroma - Mononeuritis multiplex
Polyneuropathies and other disorders of the PNS	Hereditary and idiopathic (Charcot-Marie-Tooth disease, Dejerine Sottas syndrome, Refsum's disease, Morvan's syndrome) - Guillain-Barré syndrome - Alcoholic polyneuropathy - Neuropathy
Diseases of myoneural junction and muscle	Myasthenia gravis - Primary disorders of muscles (Muscular dystrophy, Myotonic dystrophy, Myotonia congenita, Thomsen disease, Neuromyotonia, Paramyotonia congenita, Centronuclear myopathy, Nemaline myopathy, Mitochondrial myopathy) - Myopathy - Periodic paralysis (Hypokalemic, Hyperkalemic) - Lambert-Eaton myasthenic syndrome
Autonomic	Familial dysautonomia - Horner's syndrome - Multiple system atrophy (Shy-Drager syndrome, Olivopontocerebellar atrophy)

Peroxisomal disorders
Acatalasia - Adrenoleukodystrophy - Refsum's disease - Rhizomelic chondrodysplasia punctata - Zellweger syndrome

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