Refsum's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

Differential diagnosis

Refsum’s disease must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases	Type of motor abnormality				Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
Diseases	Spasticity	Hypotonia	Ataxia	Dystonia	Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
Leigh syndrome	–	–	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	–	–	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	–	+	+	–	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels	—
Adrenoleukodystrophy	+	–	–	–	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	—
Zellweger syndrome	–	+	–	–	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for mutations in the PEX1 or PEX6 genes	—
Pyruvate dehydrogenase deficiency	+	+	+	–	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	—
Arginase deficiency	+	–	–	–	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	—
Holocarboxylase synthetase deficiency	–	+	–	–	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	—
Glutaric aciduria type 1	–	–	–	+	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20 percent) Cognitive function is preserved	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	–	–	+	–	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	—
Pontocerebellar hypoplasias	–	+	–	–	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	–	+	+	–	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	—
Pelizaeus-Merzbacher	+	–	+	–	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	–	–	+	–	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations	—
Rett syndrome	+	–	–	+	Occurs almost exclusively in females Normal development during first six months followed by regression and loss of milestones Loss of speech capability Stereotypic hand movements Seizures Autistic features	Clinical diagnosis Genetic testing for MECP2 mutations	—
Lesch-Nyhan syndrome	+	–	–	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	—
Miller-Dieker lissencephaly	+	+	–	–	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	Cytogenetic testing for 17p13.3 microdeletion	—
Dopa-responsive dystonia	+	–	–	+	Onset in early childhood Symptoms worsen with fatigue and exercise	Positive response to a trial of levodopa	—

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

References

↑ S. Refsum: “Heredoataxia hemeralopica polyneuritiformis – et tidligere ikke beskrevet familiært syndrom? En foreløbig meddelelse.” Nordisk Medicin,1945, 28: 2682-2686 (in norwegian).
↑ 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.
↑ National Institutes of Health. “Synonym(s): Phytanic Acid Storage Disease, Heredopathia Atactica Polyneuritiformis <Internet>”. Retrieved 8 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
↑ 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 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
↑ Snyder, Mark J. “Cytochrome P450 enzymes belonging to the CYP4 family from marine invertebrates <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
↑ Rewitz, Kim F. “Marine invertebrate cytochrome P450: Emerging insights from vertebrate and insect analogies <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
↑ Raucy, Judy L. “Regulation of CYP2E1 by Ethanol and Palmitic Acid and CYP4A11 by Clofibrate in Primary Cultures of Human Hepatocytes <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
↑ “Atromid-S: Indication & Dosage <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

Template:PNS diseases of the nervous system Template:Peroxisomal disorders

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[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.

[ARD-3] National Institutes of Health. “Synonym(s): Phytanic Acid Storage Disease, Heredopathia Atactica Polyneuritiformis <Internet>”. Retrieved 8 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

[CYP4-4] 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 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

[P450-5] Snyder, Mark J. “Cytochrome P450 enzymes belonging to the CYP4 family from marine invertebrates <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

[miP450-6] Rewitz, Kim F. “Marine invertebrate cytochrome P450: Emerging insights from vertebrate and insect analogies <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

[CYP4A11-7] Raucy, Judy L. “Regulation of CYP2E1 by Ethanol and Palmitic Acid and CYP4A11 by Clofibrate in Primary Cultures of Human Hepatocytes <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

[ASID-8] “Atromid-S: Indication & Dosage <Internet>”. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

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