Refsum disease is one of the four major peroxisomal biogenesis disorders. Peroxisomes are multiple membrane-bound intracellular organelles involved in catalyzing various functions of cellular metabolism and biosynthesis including beta-oxidation of very-long-chain-fatty-acids (VLCFA); alpha oxidation (strictly peroxisomal); catabolism of branched-chain fatty acids, amino acids, and ethanol; and biosynthesis of cholesterol, bile acids, and plasmalogens phospholipids found in the brain’s white matter.[1]
Due to such a central role of peroxisomes in the various cellular mechanisms, numerous peroxisomal disorders are known today. With ever-increasing advances, it is an expanding class of genetic disorders due to an impairment in either peroxisome biogenesis or one of the metabolic functions. The four most common peroxisomal biogenesis disorders are:
Refsum disease is classified into two subgroups, based on differences of the enzymes affected, metabolites accumulated, genetics, clinical presentations, and treatment.
Classic/adult Refsum disease is also known as hereditary motor and sensory neuropathy IV or heredopathia atactica polyneuritiformis.
The etiology for Refsum disease primarily depends on the presence of aberrant genes for specific enzymes. Both are autosomal-recessive in inheritance.
Classic/adult Refsum disease
Infantile Refsum disease
Refsum disease is a very rare disease. No exact estimates of Refsum disease prevalence are known. Most cases described in the literature are from the United Kingdom and Norway, where there is slightly more awareness as well.[1] No racial association is known. Refsum disease affects both sexes equally. CRD manifests later in life compared to IRD. CRD can be diagnosed as early as 2-7 years, but it usually gets delayed until early adulthood. IRD is evident in early infancy.[4]
Classic/adult Refsum disease
Infantile Refsum disease
In both presentations, due to high phytanic acid levels that interfere with vitamin A esterification occurring in the retinal pigment epithelium, progressive visual failure occurs that helps to obtain an early diagnosis.[7]
Classic/adult Refsum Disease
Infantile Refsum Disease
Symptoms are abundant, many of which overlap; therefore, it is particularly essential to assess the chronology of symptoms to distinguish between other peroxisomal biogenesis disorders and between CRD and IRD. The clinical findings, correlated along with a series of biochemical tests and genetic profiles, are the mainstay of accurate diagnosis.
Classic/adult Refsum Disease
Infantile Refsum Disease
Establishing the diagnosis depends on a three-pronged approach: clinical manifestations, biochemistry analysis of peroxisomal enzyme, phytanic acid concentration in plasma, and molecular genetic testing. Reaching an early diagnosis is essential for Refsum disease management, especially CRD, as it is the only peroxisomal disorder that has a good prognosis with dietary modifications coupled with plasmapheresis.
Classic/adult Refsum Disease
1. Clinical Examination:
2. Genetic Profiling:
3. Biochemistry:
4. Histopathology:
Infantile Refsum Disease
1. Biochemistry:
2. Histopathology:
Classic/adult Refsum Disease
A. Diet:
B. Plasmapheresis: Therapeutic plasma exchange (TPE)
Infantile Refsum Disease
A. Diet:
B. Symptomatic treatment:
1. Zellweger syndrome: A peroxisomal biogenesis defect also characterizes caused by PEX gene mutations. Zellweger syndrome can be precisely differentiated from Refsum disease by its clinical presentation.[7]
2. Neonatal adrenoleukodystrophy: It is an autosomal recessive peroxisomal biogenesis disorder resulting from mutations in the PEX gene. Patients usually have a severe psychomotor delay and die several months after birth, usually before the 7th month. Patients who survive further are severely mentally disabled with sensorineural deafness and are blind due to retinopathy. Fibroblasts isolated from patients are impaired in their ability to oxidize phytanic acid and VLCFA and to synthesize plasmalogens.[20]
3. Rhizomelic chondrodysplasia: Due to abnormal variants of PEX7. Refsum disease can be differentiated from rhizomelic chondrodysplasia type 1 clinically, although, in few patients with a moderate variant, a Refsum disease-like phenotype has been described.[2][30]
4. Alpha-methyl acyl-CoA racemase deficiency: Can be distinguished by screening for peroxisome metabolites in the plasma, followed by fibroblast studies and genetic testing.
5. Retinitis pigmentosa: Progressive loss of vision and anosmia are typically one of the initial presenting symptoms in Refsum disease. Hence, it is advisable to measure plasma phytanic acid in anyone presenting with retinitis pigmentosa, particularly when coupled with other manifestations such as early-onset visual and sensorineural hearing loss, ataxia and ichthyosis which are suggestive of Refsum disease.
6. Alstrom syndrome: Has clinical features very similar to Refsum disease, such as dystrophy of rods and cons cells, progressive loss of hearing (sensorineural), obesity, dilated and hypertrophic cardiomyopathy, cirrhotic liver and even multiple organ collapse. All due to bi-allelic pathogenic variants in ALMS1 with autosomal recessive inheritance pattern. It can be differentiated from Refsum disease by biochemical and genetic profile.
7. Bardet-Bidel syndrome: Also marked by retinal cell dystrophy and retinitis pigmentosa, obesity, limbic deformities such as postaxial polydactyly, sensorineural type hearing loss, diabetes mellitus, mental issues, and hypogonadism. The retinitis pigmentosa in these patients is more severe than what we see in patients of Refsum disease. Pathogenic mutations are described in at least eighteen genes.
8. Kearns-Sayre syndrome: Chararectrised by pigmentary retinopathy along with progressive ophthalmoplegia, which usually occurs before the second decade of life. Patients present at least one of the following anomalies: cardiac conduction block, CSF protein concentration >100 mg/dL, or cerebellar ataxia. Sensorineural hearing loss is also commonly seen. This syndrome is mainly sporadic and propagates due to mitochondrial DNA deletion caused by genetic aberrations exclusively from the maternal end.
9. Friedrich ataxia: Defined by gradually progressive ataxia with onset as early from 10 years of age, usually before 25 years. It shows symptoms like dysarthria, muscle weakness with spasticity in lower limbs with absent deep tendon reflexes, proprioception, and vibration sense. Patients also might have scoliosis, bladder dysfunction, and hearing loss. Caused by bi-allelic pathogenic variants in FXN.
Survival for IRD is generally 5-13 years and maybe until adulthood. Survival for CRD is until the 4th-5th decade. The prognosis is poor in untreated or non-compliant patients. The progressive degeneration of myelinated nerve fibers and the cardiac electro-conduction pathways lead to central and peripheral neuropathic symptoms, cardiac arrhythmias, impaired vision, and hearing loss. Arrhythmias are a frequent cause of death.
A relapse-free period and a good prognosis can be achieved with strict diet control augmented with TPE. Patients who are diagnosed early and are treated promptly have demonstrated that decreasing phytanic acid is always followed by an improvement of ichthyosis and, to some extent, the resolution of neurological manifestations such as cardiac arrhythmias, paraesthesia, loss of muscle tone and ataxia. Hearing and visual loss are not reversible, but the progression gets slowed. Even with complications, as long as patients are compliant with their treatment, comfortable life is expected.
1. Due to excessively high plasma levels of phytanic acid and with added high levels of VLCFA, di- & tri-hydroxycholestanoic acid, and pipecolic acid in IRD, if left untreated or if the patient is poorly complaint, phytanic acid accumulates in myelin sheaths, adipose tissue liver, and kidneys where damage may result in following complications:
2. The exact mechanism has not been clarified yet. However, it is thought that under a molecular distortion hypothesis, that phytanic acid and other metabolites penetrate and disrupt the structural integrity of the retinal cell membrane, cardiac Purkinje cells, ciliary ganglion cells, oligodendrocytes, Schwann cells, osteoblasts and insulin receptors leading to various symptoms and long term manifestations of Refsum disease.[6][31][32]
3. Structural similarities between phytanic acid and vitamin A and E have also been implicated for the ocular complications.[7][10]
4. A calcium driven apoptotic damage is implicated for cardiac and neuropathic disorders such as arrhythmias, peripheral neuropathies, hearing and vision loss, and ataxia.[10][30]
Genetic counseling plays a pivotal role in Refsum disease by educating patients and their family members through an in-depth discussion of the inheritance, to help them make informed medical and personal decisions, such as having children.
1. Parents
2. Siblings
3. Offspring
Dietary restriction is encouraged to eliminate phytol-containing foods, such as meat or fats, from ruminating animals (lamb, beef, and certain fish), baked goods containing animal fats, and dairy products such as butter and cheese.
The patient should avoid rapid weight loss or fasting because they cause a rapid mobilization of phytanic acid from hepatic lipid and body adipose stores.
Drugs like amiodarone and ibuprofen should not be used.
Refsum disease is a rare and complex disease. Managing this disease requires an interprofessional team of healthcare professionals that includes nurses, laboratory technologists, dietitians, and physicians in different specialties. While the internist is almost always involved in the care of patients, it is important to consult with an interprofessional team of specialists that include an ophthalmologist, neurologist, geneticist, nephrologist, dermatologist, cardiologist, and audiologist. Frequent plasma levels of phytanic acid should be measured. Routine ophthalmological and cardiological evaluations are done to identify visual and cardiac problems.
Collaboration shared decision making and communication are essential factors for best patient care outcomes. The interprofessional care given to the patient must have an integrated care approach compounded with an evidence-based strategy to evaluate and manage the patient with Refsum disease.
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