What Is Refsum Disease

  • Tanvi Shukla Master of Pharmacy - MPHARM, Nirma University

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There are currently a myriad of known genetic disorders that affect humans. Some of them are well understood and have been studied and reported for millenia, while others have been discovered only recently, and are still puzzling. Refsum disease is a recent discovery, being reported in the late 20th century by Norwegian neurologist Sigvald Bernhard Refsum.¹

Refsum disease is a genetic disorder that affects peroxisomes, an organelle part of our cells that is a key part of our metabolism of fats¹. Defective peroxisomes are unable to metabolise phytanic acid, and the accumulation of this molecule causes neurological damage in patients.² In order to better understand this disorder, let’s dive deep into the different types of Refsum disease and what causes it, and what implications this diagnosis has to a patient.

The two types of refsum disease

Refsum disease is commonly divided into two types: classic or adult Refsum disease (also known as hereditary motor and sensory neuropathy IV, or as heredopathia atactica polyneuritiformis) and infantile Refsum disease.²

Both adult and infantile Refsum disease present similarly, but there are a few key differences that make them both distinct diseases: first of all, the cause; although both are genetic disorders, the genes mutated that result in classic Refsum disease (CRD) are different from the genes that cause infantile Refsum disease (IRD).² Because of this, different enzymes are mutated, therefore different metabolites (side products) are generated in each disease, causing a similar outcome through different pathways.²

Another significant difference is the onset: IRD typically presents very early on, during the sixth month of infancy, and it has severe consequences that might be fatal if left untreated.² CRD, however, only presents during the late childhood or early teen years, but cases of adult onset have been reported as well, with slower progression when compared to IRD.²

Causes

Adult Refsum disease is caused by two mutations: most commonly in the PHYH gene, or alternatively, in the PEX7 gene.³

The PHYH gene encodes the phytanoyl-CoA hydroxylase enzyme: this enzyme is responsible for degrading phytanic acid through oxydation.³ Although not produced by our bodies, phytanic acid is present in our diets in animal products, as it comes from the metabolism of ruminating animals (since they consume leaves and transform the chlorophyll into phytols).² In an individual with a mutated PHYH gene, the defective enzyme cannot degrade phytanic acid and it accumulates in tissues rich in fat like the brain, myelin sheath of nerves, kidneys and liver, causing many problems.²

The PEX7 is associated with more severe peroxisomal disorders like rhizomelic chondrodysplasia punctata type 1, but there is a wide range of variation of this genetic mutation that can also result in mild forms of CRD³. PEX7 is responsible for the production of peroxin 7 protein, which transports phytanic acid into the peroxisome for oxidation; with a defective peroxin 7, transportation is poor or absent, and the body cannot process phytanic acid.³

On the other hand, infantile Refsum disease (IRD) is associated with an array of mutations: some of the most common ones involve the genes PEX1, PEX2 and PEX26.² These genes are responsible for metabolising very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA), including phytanic acid but not limited to it; many other molecules like pipecolic acid and cholesterol derived molecules are also affected by IRD.⁴

Although both IRD and CRD are genetic recessive autosomal disorders, and both affect metabolism of phytanic acid, their differences make them distinct disorders.² Adult Refsum disease is a defect in phytanic acid metabolism alone, and it is considered a disorder of enzyme and transporter defect in peroxisomes.⁵ Meanwhile, IRD is a peroxisome biogenesis disorder (PBD) that is part of the Zellweger spectrum, along with Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD), and it causes a defect in the metabolism of all fatty acids, including phytanic acid.⁵ 

Signs and symptoms

CRD often presents later during childhood or adolescence, or even during adulthood, with neurological and ocular symptoms². Some of the most common signs and symptoms of adult Refsum disease are:

  • Vision deterioration: night blindness is usually one of the first signs of CRD, but with age, other symptoms such as reduced visual field, cataracts and miosis (pupil constriction) can present²
  • Shortening of the metacarpals or metatarsals bones²
  • Hearing loss²
  • Muscular atrophy and weakness, and loss of sensation of the members: initially affecting the lower members, this form of neuropathy can slowly progress and affect the entire body²
  • Anosmia (loss of the sense of smell)²
  • Raised cerebrospinal fluid²
  • Cerebellar ataxia: resulting in unsteady gait²
  • Proteinuria (protein present in urine)²
  • Ichthyosis (scaly skin)²
  • Kidney and heart malfunction due to high levels of phytanic acid²
  • Psychiatric disorders²

IRD usually has early onset during infancy (six months onward), and common signs and symptoms include:

  • Visual impairment²
  • Hearing loss²
  • Anosmia²
  • Mental development issues²
  • Neurological deterioration resulting in muscle weakness, hypotonia (loss of muscular tonus), and cerebellar ataxia²
  • Craniofacial dysmorphism²
  • Hepatomegaly (augmented liver) with cirrhosis²
  • Sporadic bleeding²
  • Gastrointestinal symptoms: vomiting, diarrhoea and malabsorption²

Diagnosis

Diagnosis of Refsum disease is made through clinical evaluation of the patient, genetic testing, phytanic acid levels in blood, and biochemical analysis of peroxisomal enzyme.²

If there is suspicion of CRD or IRD, a physician should perform a few tests to evaluate the senses (vision, hearing and smell) of the patient, as well as performing a neurological assessment to understand if there is impairment and to which extent.²

  • Ocular examination with an ophthalmologist is used to assess vision loss and impairment; determining the visual field of the patient and whether or not there is macular or retinal degeneration is important in ruling out CRD or IRD²
  • Audiology tests can be performed to assess hearing loss and determine its cause; some of the most common tests are audiometry, otoacoustic emission testing, and in some cases a brainstem auditory evoked response test can be performed if other hearing tests are inconclusive²
  • Anosmia: a smell test to assess loss of the sense of smell can be performed²
  • Neurological evaluation: patients with CRD and IRD don’t have intellectual disabilities, even though they might present with motor difficulty²

Biochemical tests to determine enzyme activity can confirm the diagnosis of Refsum disease: a liver sample of a patient with CRD usually has undetectable levels of the phytanoyl-CoA hydroxylase enzyme, confirming diagnosis.² In patients with CRD, levels of phytanic acid in blood are extremely high, but only phytanic acid levels; meanwhile, IRD patients have elevated levels of long fatty acids, which include phytanic acid but are not limited to it.²

Genetic testing to confirm mutations of genes PHYH, PEX7, PEX1, PEX2 and PEX26, among others, can be performed.²

Other tests can be done depending on an individual basis. X-rays of the hands, feet and knees can be taken to detect shortening of the metacarpal and metatarsal bones.² An electrocardiogram and ultrasound can detect heart problems like arrhythmias and cardiomyopathy.² A biopsy and histopathological evaluation of the sample is not necessary to confirm diagnosis, but can give important clues: in CRD, there is hypertrophy (excess growth) of the peripheral nerves that can be observed microscopically, while in liver samples of IRD patients contain no peroxisomes at all, and IRD patients also have complete degeneration of the retina.²

All these tests can be performed in order to confirm a diagnosis, as other disorders can present similar symptoms to Refsum disease. Some of the differential diagnosis are:

  • Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD): both, along with IRD, are part of the Zellweger spectrum, and have similar symptoms but different levels of severity¹
  • Rhizomelic chondrodysplasia type 1: is caused by a mutation of the PEX7 gene, but is generally more severe than CRD³
  • Retinitis pigmentosa: can cause vision loss²
  • PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) can cause similar symptoms to CRD, but it is caused by a mutation in a different gene¹
  • Alstrom syndrome: causes similar symptoms to Refsum disease, but is caused by a different genetic mutation²
  • Bardet-Bidel syndrome can cause a few similar symptoms, but other manifestations of this syndrome like diabetes melitus, obesity and hypogonadism are distinctive from CRD²
  • Kearns-Sayre syndrome: this syndrome can cause vision and hearing loss, but does not cause motor symptoms, unlike Refsum disease²
  • Friedrich ataxia: is a type of progressive motor dysfunction that can cause hearing loss, but isn’t associated with ocular symptoms²

Management and treatment

There is no cure for Refsum disease.¹ CRD is a milder form of Refsum disease with better prognosis, and patients can live up to their forties or fifties with proper medical care, appropriate diet and plasmapheresis². A diet free from phytol-rich foods, eliminating meat or fats from ruminating animals (cow, lamb, certain fishes) and animal products like butter, milk and cheese, can limit phytanic acid intake². Besides avoiding phytanic acid, a high calorie diet that avoids fasting is essential in preventing lipolysis (burning fat), which worsens the condition.²

Medications that affect phytanic acid metabolism should be avoided as well: drugs that increase thyroxine levels, like ibuprofen and amiodarone, can worsen Refsum disease.²

Plasmapheresis, which is the therapeutic exchange of blood plasma, can be performed in patients that need rapid reduction of phytanic acid levels, such as those with rapidly worsening symptoms.²

IRD has a worse prognosis, and many patients only live into late childhood, with few of them reaching adulthood.² Diet and plasmapheresis have been helpful for IRD patients, as well as symptomatic treatment with medication: urea, ammonium lactate and mineral oil have been used to relieve skin thickening and excess keratin production.² Complications like cardiomyopathy, arrhythmia and kidney damage can lead to premature death.²

Epidemiology

Refsum disease affects 1 in every 1.000.000 people, with no preference between sexes.² As it is a recessive genetic disorder, many can be carriers of the gene without knowing: therefore, genetic counselling is important before pregnancy, in order to assess risk of having a child with Refsum disease, especially if there are cases in either family.²

Summary

Refsum disease is a recessive autosomal genetic disorder that affects the metabolism of long fatty acids like phytanic acid, resulting in their accumulation in tissues rich in fat and subsequent damage. The adult variant affects only phytanic acid metabolism, while the infantile Refsum disease affects all types of long fatty acids, being more severe. Common signs and symptoms include vision loss, hearing loss, muscle weakness and nerve damage, but other presentations like heart and kidney problems can also be present. Diagnosis is made through a combination of clinical tests including vision, smell, hearing and neurological tests, genetic testing, and biochemical analysis of liver cells, but other exams like an electrocardiogram, ultrasound, X-rays of the hands and feet, among others, can be performed depending on an individual basis. Management and treatment is based on dietary changes and plasmapheresis, with a better prognosis for the adult variant. It is a rare disorder that affects one in every 1,000,000 people, and many are carriers of the gene without knowing it.

References

  • Refsum Disease - NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). NORD; 2019. Available from: https://rarediseases.org/rare-diseases/refsum-disease/
  • Kumar R, De Jesus O. Refsum Disease [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560618/
  • van, Brites P, Haasjes J, Wierzbicki AS, Mitchell JC, Lambert-Hamill M, et al. Identification of PEX7 as the Second Gene Involved in Refsum Disease. 2003 Feb 1;72(2):471–7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC379239/
  • Krause C, Rosewich H, Thanos M, Gärtner J. Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients. Human Mutation. 2006 Nov;27(11):1157–7.
  • Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Zellweger Spectrum Disorder [Internet]. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, et al., editors. PubMed. Seattle (WA): University of Washington, Seattle; 1993. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1448/ 

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Isabela Araújo Rosa

Doctor of Dental Surgery - DDS, Universidade Federal de Goiás, Brazil

Isabela is a board certified dentist in Brazil, with a background in Oral and Maxillofacial Pathology, Bioethics and Oral Medicine, and previous experience with medical writing and medical communication.

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