Refsum Disease

Refsum Disease

Table of Contents

Alternate Terminology for Refsum Disease

What are various terms and acronyms used to refer to Refsum Disease?

Refsum Disease, a distinct medical condition, is known by several other names, including:

– Adult Refsum Disease (ARD)

– Classic Refsum Disease (CRD)

– Hereditary Motor and Sensory Neuropathy Type IV

– Heredopathia Atactica Polyneuritiformis


– Phytanic Acid Storage Disease

– Refsum Syndrome

– Refsum’s Disease

In vitro fertilization (IVF) and preimplantation genetic testing (PGT) are significant advancements in the realm of reproductive medicine and genetics, particularly for individuals at risk of transmitting genetic disorders like Refsum Disease. For couples with a known risk of passing on Refsum Disease to their offspring, IVF coupled with PGT offers a proactive approach. In this process, eggs are fertilized in a lab setting, and the resulting embryos are screened for the specific genetic mutations associated with Refsum Disease. This enables the selection of embryos without the disorder for implantation, significantly reducing the likelihood of the child inheriting Refsum Disease. Thus, IVF and PGT provide a powerful combination for family planning, particularly for those with a genetic predisposition to this condition, allowing them to minimize the risk of genetic transmission while achieving pregnancy.

Refsum Disease and Its Types

What is Refsum Disease and what are its different forms?

Refsum Disease is a key peroxisomal biogenesis disorder, linked to the dysfunction of peroxisomes, which are crucial for various cellular metabolic processes. These include the beta-oxidation of very-long-chain-fatty-acids (VLCFA), alpha oxidation, and biosynthesis of vital substances like cholesterol and plasmalogens.

The disease is categorized into two main types based on enzyme abnormalities, accumulated metabolites, genetic factors, clinical manifestations, and treatment approaches:

  1. Classic/Adult Refsum Disease (CRD): Also known as hereditary motor and sensory neuropathy IV or heredopathia atactica polyneuritiformis, CRD typically begins in late childhood or early adulthood. It primarily causes peripheral neuropathy, progressive night blindness (retinitis pigmentosa), and can lead to significant heart complications later in life.
  2. Infantile Refsum Disease (IRD): Falling under Zellweger spectrum disorders, IRD presents more severe symptoms than CRD. It affects infants and young children with symptoms like hypotonia, feeding difficulties, seizures, developmental delays, and liver disease. IRD generally has a more severe prognosis and is eventually fatal.

In addition to Refsum Disease, other common peroxisomal biogenesis disorders include Zellweger syndrome, neonatal adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata.

Genetic Origins of Refsum Disease

What are the genetic causes of Refsum Disease and how is it inherited?

Refsum Disease arises from inherited genetic mutations present from birth. These mutations are passed down from one or both biological parents.

Infantile Refsum Disease can result from mutations in several genes, with the most common being PEX1 (accounting for 60% of cases), followed by PEX6 (15%), PEX12 (7.6%), and PEX26 (4.2%).

Similarly, Adult Refsum Disease is linked to inherited gene mutations. Approximately 90% of individuals with Adult Refsum Disease have a mutation in the PHYH gene, while others may have a mutation in the PEX7 gene.

Incidence and Demographics of Refsum Disease

How common is Refsum Disease, and what are its demographic patterns?

Refsum Disease is an extremely rare disorder, with most documented cases found in the United Kingdom and Norway, where awareness is comparatively higher. The estimated prevalence in the UK is about 1 in 1,000,000. There is no known racial predisposition for this disease. Refsum Disease affects both males and females equally. Classic Refsum Disease (CRD) tends to appear later in life compared to Infantile Refsum Disease (IRD). While CRD can be identified as early as 2-7 years of age, diagnosis often occurs in early adulthood. In contrast, IRD typically becomes apparent in early infancy.

Understanding Classic/Adult and Infantile Refsum Disease Pathophysiology

How do the pathophysiologies of Classic/Adult Refsum Disease (CRD) and Infantile Refsum Disease (IRD) differ, and what are their implications?

In Classic/Adult Refsum Disease:

  1. CRD and Phytanic Acid: CRD involves the accumulation of phytanic acid, a branched-chain fatty acid found in the human diet. Mutations in patients lead to impaired degradation of phytanic acid due to reduced activity of phytanoyl-CoA hydroxylase.
  2. Impact of Phytanic Acid: This acid builds up in adipose tissue, myelin sheaths, kidneys, and liver, causing cellular and tissue damage by interfering with covalent bonds, leading to various symptoms.

In Infantile Refsum Disease:

  1. Pathophysiological Differences: Unlike CRD, IRD involves multiple enzyme deficiencies, leading to the accumulation of several substances, including VLCFA, di- and tri-hydroxycholestanoic acid, pipecolic acid, and phytanic acid, with reduced plasmalogen levels.
  2. Normalization of Phytanic Acid: Phytanic acid levels in IRD may normalize with age.
  3. Cell Membrane Disruption: Elevated phytanic acid levels and other intermediates may disrupt retinal cell membranes, contributing to dystrophy.
  4. Similar Symptoms to CRD: Due to deficient beta-oxidation of VLCFA and alpha-oxidation of phytanic acid, along with reduced plasmalogen synthesis, IRD shares several symptoms with CRD.

In both types, high phytanic acid levels interfering with vitamin A esterification in the retinal pigment epithelium contribute to progressive visual impairment, aiding in early diagnosis.

Evaluating Symptoms for Accurate Diagnosis of Refsum Disease

How critical is it to analyze the progression of symptoms in differentiating Refsum Disease from other peroxisomal biogenesis disorders and between Classic Refsum Disease (CRD) and Infantile Refsum Disease (IRD)?

The abundance and overlap of symptoms in Refsum Disease necessitate careful assessment of symptom chronology to differentiate it from other peroxisomal biogenesis disorders and to distinguish between CRD and IRD. The combination of clinical observations with a series of biochemical tests and genetic analysis forms the foundation for an accurate diagnosis.

Clinical Presentation and Progression in Classic/Adult Refsum Disease

What are the key symptoms and progression patterns of Classic/Adult Refsum Disease?

Classic/Adult Refsum Disease typically becomes apparent in late childhood or adolescence, though it may emerge later:

  1. Vision Issues: Initial symptoms often involve night vision deterioration due to retinitis pigmentosa, detectable in early stages through electroretinography. Common issues include reduced visual fields, miosis, and cataracts.
  2. Anosmia: Loss of smell, and potentially taste.
  3. Progressive Symptoms: Over a decade or so, patients may develop sensorineural deafness, peripheral polyneuropathy, elevated cerebrospinal fluid (CSF) protein levels, proteinuria, and ataxia.
  4. Neurological Features: Characterized by mixed asymmetric polyneuropathy affecting both motor and sensory nerves, leading to muscle atrophy and weakness in the lower limbs and potentially spreading to the trunk.
  5. Hearing Impairment: Sensorineural hearing loss is common and can be evaluated through a brainstem auditory evoked response test.
  6. Motor Coordination: Cerebellar ataxia manifests later, impacting gait stability.
  7. Other Symptoms:

   – Skin abnormalities like ichthyosis.

   – Kidney dysfunction and cardiac arrhythmias correlated with phytanic acid levels.

   – Shortening of metacarpals or metatarsals in about 30% of patients.

   – Psychiatric disturbances in a minority of cases.

Characterization of Infantile Refsum Disease

What are the typical presentations and associated symptoms of Infantile Refsum Disease?

Infantile Refsum Disease can manifest with various symptoms, often starting as early as six months of age:

  1. Early Symptoms: The disease may first appear as severe developmental delays in infancy.
  2. Vision Problems: Visual impairments are commonly due to tapeto-retinal degeneration.
  3. Neurological Symptoms:

   – Muscle weakness (Hypotonia)

   – Lack of muscle coordination (Cerebellar ataxia) affecting movement and gait

   – Nerve damage (Peripheral neuropathy)

   – Profound cognitive impairment

   – Hearing loss (Sensorineural deafness)

   – Loss of smell (Anosmia)

   – Neurological decline, slower than in conditions like Zellweger’s syndrome or neonatal adrenoleukodystrophy, often allowing patients to walk despite ataxia. Many survive into adolescence.

  1. Facial Features: Distinct craniofacial abnormalities (Craniofacial dysmorphism).
  2. Additional Less Common Symptoms:

   – Enlarged liver with cirrhosis (Hepatomegaly)

   – Occasional bleeding episodes

   – Digestive issues like vomiting, diarrhea, and malabsorption

  1. Severity and Prognosis: The disease can be life-threatening.
  2. Variability in Severity: Some individuals exhibit a milder form of the disease, enabling survival into adulthood, often linked to the G843D mutation.

Understanding Autosomal Recessive Inheritance

How does autosomal recessive inheritance work, particularly in the context of passing on genetic conditions?

In an autosomal recessive inheritance pattern:

– Both gene copies in each cell must have mutations for the condition to manifest. Parents usually carry one mutated gene each but generally do not exhibit symptoms.

– If both parents carry the same mutated gene, there’s a random chance of passing either the mutated or the normal gene to their offspring.

– Each child has a 25% probability (1 in 4 chance) of receiving mutated genes from both parents, leading to the condition.

– Conversely, there’s a 75% likelihood (3 in 4 chance) that the child won’t be affected by the condition. This probability is consistent across all pregnancies and applies equally to sons and daughters.

– There’s also a 50% chance (2 in 4) the child will inherit only one mutated gene, becoming a healthy carrier like the parents.

– Finally, there’s a 25% probability (1 in 4) the child will inherit two normal gene copies, thus neither having the condition nor being a carrier.

Diagnostic Approach for Refsum Disease

What methods are utilized to diagnose Classic/Adult and Infantile Refsum Disease, considering clinical, biochemical, and genetic aspects?

Diagnosing Refsum Disease involves a comprehensive approach that includes clinical evaluation, biochemical tests, and molecular genetic testing. Early diagnosis is crucial, particularly for Classic/Adult Refsum Disease (CRD), which responds well to dietary management and plasmapheresis.

For Classic/Adult Refsum Disease:

  1. Clinical Assessment:

   – Ocular Examination: Complete eye check-up, with attention to visual field changes and arteriolar narrowing.

   – Anosmia Testing: Using specialized identification tests like the University of Pennsylvania’s.

   – Neurological Evaluation: Assessing for intellectual deficits and plasmalogen synthesis.

   – Audiology Tests: Including pure tone audiometry and brainstem auditory evoked response testing.

   – Radiological Assessment: Examining hands, feet, and knees for bone abnormalities.

   – Cardiac Evaluation: Conducting electrocardiogram and cardiac ultrasound for arrhythmias and cardiomyopathy.

  1. Genetic Profiling:

   – Consultation with a clinical geneticist or counselor.

  1. Biochemistry:

   – Measuring plasma phytanic acid levels, typically above 200 µmol/L.

   – Evaluating CSF for albuminocytologic dissociation.

   – Testing for phytanoyl-CoA hydroxylase enzyme activity in liver tissue.

  1. Histopathology:

   – Peripheral nerve biopsy to observe hypertrophic changes and paracrystalline inclusions.

For Infantile Refsum Disease:

  1. Biochemistry:

   – Assessment of metabolic profile for elevated VLCFA, di- and tri-hydroxycholestanoic acid, pipecolic acid, and phytanic acid levels, with reduced plasmalogens in tissues and erythrocytes.

  1. Histopathology:

   – Liver biopsy to confirm the absence of peroxisomes and retinal layer degeneration.

Management Strategies for Classic/Adult and Infantile Refsum Disease

How is Classic/Adult and Infantile Refsum Disease managed through diet and other therapeutic interventions?

For Classic/Adult Refsum Disease:

Dietary Approach:

  1. Restrict phytol-containing foods like meats from ruminants (lamb, beef), certain fish, animal fat-based baked goods, and dairy products like butter and cheese.
  2. Aim to keep daily dietary phytanic acid intake below 10 mg, avoiding rapid weight loss or fasting which can trigger severe clinical relapse due to rapid phytanic acid release from hepatic lipid and body fat stores.
  3. Maintain a high-calorie diet to prevent metabolism of stored lipids and phytate, reducing their release into the bloodstream.
  4. Use parenteral nutrition post-surgery with phytanic acid-free solutions, such as those based on soybean and egg yolk.
  5. Monitor phytanic acid levels closely during pregnancy, especially in the third trimester due to increased catabolism.
  6. Avoid medications like ibuprofen and amiodarone that can interfere with phytanic acid metabolism or increase thyroxine levels.
  7. Prefer fish-based oils for calorie intake.

Plasmapheresis (Therapeutic Plasma Exchange – TPE):

  1. TPE is effective in reducing phytanic acid concentration, especially when rapid reduction is needed, and can be performed serially over weeks.
  2. TPE should be considered clinically, particularly for patients with rapidly worsening symptoms.
  3. Plasma phytanic acid concentrations can be reduced by 50% to 70% through TPE.

For Infantile Refsum Disease:

Dietary Management:

  1. Strict dietary restriction of phytanic acid sources and occasional use of TPE in critical situations.
  2. TPE is beneficial as phytanic acid is present in plasma triglycerides in VLDL and LDL fractions.

Symptomatic Treatment:

  1. Use urea for hydration and keratin removal in hyperkeratosis.
  2. Apply ammonium lactate for its keratolytic action, aiding in comedones release.
  3. Employ keratolytic and emollients for skin manifestations, with mineral oil aiding in minor skin irritations and excess keratin removal.

Conditions Similar to Refsum Disease and Their Differentiation

What are some conditions that resemble Refsum Disease, and how can they be distinguished from it?

Several conditions share similarities with Refsum Disease, yet they can be differentiated based on clinical presentations, biochemical tests, and genetic profiling. These include:

  1. Zellweger Syndrome: This is another peroxisomal biogenesis defect caused by mutations in the PEX gene. Zellweger syndrome differs from Refsum disease in its clinical manifestations.
  2. Neonatal Adrenoleukodystrophy: An autosomal recessive disorder also resulting from PEX gene mutations. Characterized by severe psychomotor delay and early mortality, usually within the first seven months. Surviving patients exhibit significant mental disability, sensorineural deafness, and blindness.
  3. Rhizomelic Chondrodysplasia: Caused by variants in the PEX7 gene. While Refsum disease and rhizomelic chondrodysplasia type 1 are clinically distinguishable, some moderate cases of rhizomelic chondrodysplasia may present with Refsum disease-like symptoms.
  4. Alpha-Methyl Acyl-CoA Racemase Deficiency: Distinguished through peroxisome metabolite screenings, fibroblast studies, and genetic testing.
  5. Retinitis Pigmentosa: Often an early symptom in Refsum disease. It’s advisable to test for plasma phytanic acid in patients presenting with retinitis pigmentosa, especially if accompanied by other indicative symptoms of Refsum disease.
  6. Alstrom Syndrome: Characterized by similar clinical features to Refsum disease but can be differentiated through biochemical and genetic profiles. This syndrome is caused by bi-allelic variants in the ALMS1 gene.
  7. Bardet-Bidel Syndrome: Presents with retinal cell dystrophy and retinitis pigmentosa like Refsum disease but also includes obesity, limb deformities, diabetes mellitus, and hypogonadism. The severity of retinitis pigmentosa is typically greater than that in Refsum disease.
  8. Kearns-Sayre Syndrome: Identified by pigmentary retinopathy and progressive ophthalmoplegia occurring before the second decade of life. It also features anomalies like cardiac conduction block, elevated CSF protein concentration, or cerebellar ataxia. This syndrome is generally sporadic, resulting from mitochondrial DNA deletion.
  9. Friedrich Ataxia: Marked by progressive ataxia beginning as early as 10 years of age. Symptoms include dysarthria, muscle weakness, and sensory loss, often accompanied by scoliosis, bladder dysfunction, and hearing loss. It results from bi-allelic pathogenic variants in the FXN gene.

Outlook for Individuals with Infantile and Classic Refsum Disease

What is the expected lifespan and quality of life for individuals with Infantile Refsum Disease (IRD) and Classic Refsum Disease (CRD), and how does treatment compliance affect the prognosis?

The life expectancy for individuals with Infantile Refsum Disease typically ranges from 5 to 13 years, with the possibility of surviving into adulthood. For those with Classic Refsum Disease, life expectancy extends into the 4th or 5th decade. The prognosis tends to be poor for patients who are untreated or not compliant with their treatment regimen. Progressive degeneration of myelinated nerve fibers and cardiac electro-conduction pathways can result in central and peripheral neuropathic symptoms, cardiac arrhythmias, and impaired vision and hearing. Cardiac arrhythmias are a common cause of death in these patients.

A period free from relapses and a favorable prognosis are achievable through strict dietary control complemented by therapeutic plasma exchange (TPE). Early diagnosis and prompt treatment have shown that reducing phytanic acid levels leads to improvements in ichthyosis and potentially resolves some neurological symptoms, such as cardiac arrhythmias, paraesthesia, muscle tone loss, and ataxia. While hearing and vision loss may not be reversible, their progression can be slowed down. Even with complications, patients who adhere to their treatment can expect a comfortable quality of life.

Potential Health Issues in Untreated or Poorly Managed Refsum Disease

What are the possible health complications associated with elevated levels of phytanic acid in Refsum disease?

If Refsum disease is not adequately treated or if there is poor adherence to treatment, elevated levels of phytanic acid, along with increased levels of very long-chain fatty acids (VLCFA), di- & tri-hydroxycholestanoic acid, and pipecolic acid, can lead to an accumulation in myelin sheaths, adipose tissue, liver, and kidneys. This can result in various complications, including:

– Cardiomyopathy

– Arrhythmia

– Progressive vision loss

– Cataract formation

– Neuropathy in the lower limbs

– Ataxia (lack of muscle coordination)

– Aciduria (acid in the urine)

– Diabetes Mellitus

– High blood pressure (Hypertension)

– Muscular atrophy

– Renal atrophy

– Progressive hearing loss

– Atheroma (plaque in arteries)

Calcium- driven apoptotic damage is believed to play a role in cardiac and neuropathic disorders, contributing to arrhythmias, peripheral neuropathies, loss of hearing and vision, and ataxia.

Minimizing the Risk and Managing Refsum Disease

What steps can be taken to manage the risk of Refsum disease, and what should I discuss with my healthcare provider if I suspect I have the condition?

Since Refsum disease is a hereditary disorder, it cannot be prevented. However, if you are affected by Refsum disease or believe you might be a carrier, genetic testing is a valuable tool. This testing can identify the specific gene mutation responsible for Refsum disease. A genetic counselor can assist in interpreting the results and advise on the likelihood of transmitting the condition to your offspring.

Key questions to consider asking your healthcare provider if you have or suspect you have Refsum disease include:

– What are the initial indicators of Refsum disease?

– Which diagnostic tests are used for Refsum disease?

– What treatment options are available for Refsum disease?

– Is it advisable for me to undergo genetic testing for Refsum disease?

– What is the probability of passing Refsum disease to my children?

Handling Pregnancy in Women with Refsum Disease

What are the critical considerations for managing pregnancy in women diagnosed with Refsum Disease?

In managing pregnancies for women with Refsum Disease, it is crucial to monitor and control plasma phytanic acid levels, especially due to pregnancy’s potential to trigger catabolic processes. Notably, there have been observations of a rapid reduction in visual fields during the third trimester of pregnancy, potentially linked to elevated plasma phytanic acid concentrations resulting from increased catabolism during this period.

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