Adrenoleukodystrophy, Zellweger Syndrome, Refsum's Disease explained

Cell Biology

A elaboration on the structure and function of peroxisomes, highlighting how their unique organization supports their essential roles in metabolism, detoxification, and cellular homeostasis.

Peroxisomes are small, single-membrane–bound organelles found in eukaryotic cells that play essential roles in cellular metabolism and protection. They are best known for carrying out oxidation reactions, including the breakdown of fatty acids through beta-oxidation and the detoxification of harmful substances, particularly hydrogen peroxide, which is rapidly converted into water and oxygen by the enzyme catalase. Peroxisomal functions vary by cell type and organism, contributing to lipid synthesis and bile acid production in animals, photorespiration and fat-to-sugar conversion in plants, and close metabolic coordination with mitochondria and the endoplasmic reticulum. Lacking their own DNA and ribosomes, peroxisomes import all necessary proteins from the cytoplasm and replicate through growth and division or formation from the ER, allowing their number and size to adjust quickly to the metabolic needs of the cell.

One of the biggest functions of peroxisomes is their role in --fatty acid metabolism--, specifically:

--Very Long Chain Fatty Acids (VLCFAs)--

--Branched Chain Fatty Acids (BCFAs)--

These fatty acids are brought into the peroxisomes through special transporters called --ABCD1 transporters--. These transporters are essential for getting the fatty acids into the peroxisome.

Once inside, --VLCFAs-- undergo --beta-oxidation--, a 4-step process remembered by the mnemonic --OHOT--:

--O--xidation

- --H--ydration

--O--xidation (again)

--T—hiolysis

The result of this process is the production of:

--Acetyl-CoA--

--Acyl-CoAs--

The acyl-CoAs can go back into the cycle for further breakdown.

During this process, --hydrogen peroxide (H₂O₂)-- is generated as a byproduct. So the --first function-- of peroxisomes is --beta-oxidation of VLCFAs--.

The --second function-- is the --alpha-oxidation-- of --branched chain fatty acids--. This process converts branched-chain fatty acids into VLCFAs, which can then be beta-oxidized. This step is unique to peroxisomes and helps remove methyl branches from fatty acids.

Another interesting role of peroxisomes is in --ethanol metabolism--, which is the --third function--. Ethanol can be broken down in peroxisomes into --acetaldehyde--, using --hydrogen peroxide--, resulting in the formation of --water and oxygen--.

--Zellweger Syndrome--

--Autosomal recessive--

- Caused by mutations in the --PEX gene--, which encodes --peroxins-- (proteins required for peroxisome formation).

--No functional peroxisomes-- are formed → loss of all peroxisomal functions.

 Leads to accumulation of:

  - VLCFAs

  - BCFAs

  - Ethanol

  - Hydrogen peroxide

  - Decreased synthesis of:

  - Cholesterol

  - Plasmalogens

  - Symptoms:

--Neurohepatorenal syndrome--

  - CNS: --Neurodegeneration--, --hypotonia (floppy baby)--, --seizures--

  - Liver: --Jaundice-- due to --bilirubin buildup--

  - Kidneys: --Polycystic kidney disease--

--Refsum’s Disease--

 - Also --autosomal recessive--

- Due to deficiency in --alpha-oxidation--

- Leads to accumulation of --branched chain fatty acids--, especially --phytanic acid--

- Affects:

   - --CNS-- (especially --cerebellum--) → --ataxia--

  - --Peripheral nerves-- → --neuropathy--

  - --Retina-- → --retinitis pigmentosa-- (night blindness, vision loss)

  - --Skin-- → --ichthyosis-- (dry, scaly skin)

  - --Epiphyseal plates-- → --epiphyseal dysplasia--, especially --shortening of the 4th toe--

 --Adrenoleukodystrophy (ALD)--

- --X-linked recessive-- → more common in --males--

- Due to mutation in the --ABCD1 gene--

- ABCD1 protein normally transports VLCFAs into the peroxisome

- Without it, VLCFAs accumulate

- Affects:

  - --CNS-- → --progressive neurodegeneration--, --dementia--

  - --Adrenal cortex-- → decreased --aldosterone-- and --cortisol-- → leads to --adrenal crisis--, especially dangerous in children

--Peroxisomal functions--

- The 7 major metabolic roles they play

- Key --peroxisomal disorders--: --Zellweger syndrome--, --Refsum's disease--, and --Adrenoleukodystrophy--

Medications to avoid or use with caution in individuals with Adrenoleukodystrophy (ALD), Zellweger Syndrome, and Refsum’s Disease. Because these are rare metabolic disorders, medication safety often depends on how the drug is metabolized and whether it worsens toxic metabolite buildup or interacts with compromised organs (like liver, kidneys, or adrenal glands).

1. Adrenoleukodystrophy (ALD)

Key issue: Accumulation of very long chain fatty acids (VLCFAs) due to defective ABCD1 transporter. Also, adrenal insufficiency is common.

Medications to Avoid or Use with Caution:

 

Glucocorticoid interference

    Avoid abrupt withdrawal of corticosteroids if the patient is already on them (due to adrenal insufficiency).

    Stress-dose steroids may be needed during illness or surgery.

Medications that suppress adrenal function (use with caution):

   - Ketoconazole

   - Etomidate (used for anesthesia)

These can worsen cortisol deficiency and the risk of adrenal crisis.

Drugs that affect CNS myelin or increase oxidative stress:
    Amiodarone – may impair fatty acid metabolism
    Valproic acid – hepatotoxicity risk, caution if liver is affected

Immunosuppressants or cytotoxic drugs:
    Should be used cautiously in patients undergoing hematopoietic stem cell transplantation (HSCT), a   treatment for cerebral ALD.

2. Zellweger Syndrome

Key issue: Complete or near-complete absence of peroxisomes, leading to buildup of VLCFAs, phytanic acid, and other toxic substances. Multisystem organ involvement: liver, brain, kidneys.

Medications to Avoid or Use with Caution:

Hepatotoxic medications:
    Valproic acid
    Acetaminophen (high doses)
    Methotrexate
    Isoniazid

Zellweger patients often have liver dysfunction, so hepatotoxic medications should be avoided or strictly monitored.

Nephrotoxic drugs (due to possible kidney cysts and dysfunction):
    NSAIDs (e.g., ibuprofen, naproxen)
    Aminoglycoside antibiotics (e.g., gentamicin)
    Contrast agents for imaging

CNS depressants:
    Benzodiazepines or sedatives may worsen hypotonia or respiratory depression.

Lipid-rich drug carriers or formulations:
    Some IV lipid emulsions or fat-soluble drug preparations may increase VLCFA burden. Caution is advised.

3. Refsum’s Disease
        Key issue: Defective alpha-oxidation of phytanic acid → accumulation in nerves, skin, and eyes.

Medications to Avoid or Use with Caution:

Drugs that increase lipolysis or mobilize fat stores:
    Glucagon
    Beta-agonists (e.g., albuterol)
    Corticosteroids (high doses, long term)
These can increase release of stored phytanic acid into the blood.

Fasting or rapid weight-loss regimens should be avoided, but that’s more of a metabolic management issue than a medication.

Fat-soluble vitamin overload:
    Avoid excessive vitamin A or E supplements, as lipid storage disorders can worsen toxicity.

Lipid-based formulations:
    IV lipid emulsions, certain capsules with long-chain triglyceride oils, or fat-based drug carriers may contain phytanic acid or related fatty acids.

Hepatotoxic drugs:
        As in Zellweger, some Refsum patients may have mild liver involvement, so caution is needed with:
        Valproic acid
        High-dose acetaminophen

Summary Table

Disorder	Medication Concerns	Medications to Avoid or Caution
ALD	Adrenal insufficiency, VLCFA buildup	Ketoconazole, etomidate, valproic acid, amiodarone
Zellweger	Liver and kidney dysfunction, VLCFA buildup	Valproic acid, NSAIDs, aminoglycosides, benzodiazepines, lipid-based drug carriers
Refsum’s Disease	Phytanic acid accumulation, lipid metabolism	Corticosteroids (high dose), glucagon, beta-agonists, lipid emulsions, fat-soluble vitamin excess

Foods to avoid for Adrenoleukodystrophy (ALD), Zellweger Syndrome, and Refsum’s Disease,

Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy (ALD) presents with a wide range of symptoms that commonly involve the nervous system, including poor coordination, seizures, vision and hearing loss, learning difficulties, and behavioral changes such as hyperactivity and emotional instability, particularly in children. As the disease progresses, individuals may develop leg stiffness, muscle weakness, and paralysis. Adrenal dysfunction is also common, leading to symptoms such as fatigue, low blood pressure, and vomiting. ALD can affect both boys and adult carriers, with adult-onset forms often characterized primarily by progressive stiffness and mobility problems.

Problem: The body cannot properly break down very long chain fatty acids (VLCFAs), leading to their accumulation, especially in the brain and adrenal glands.

Category	Foods to Avoid or Strictly Limit
High-fat animal products	Beef, lamb, pork, fatty cuts of meat, bacon and sausage
Full-fat dairy products	Whole milk, cheese, butter, cream
Certain vegetable oils	Peanut oil, canola oil
Processed and fried foods	Fast food, commercial baked goods

Additional Information:
Many patients are treated with Lorenzo’s Oil, which helps reduce VLCFA levels. This treatment is most effective when paired with a low-VLCFA diet.

Zellweger Syndrome

Zellweger syndrome, a severe condition within the Zellweger Spectrum Disorder (ZSD), typically presents at birth or during early infancy and is characterized by profound hypotonia, severe feeding difficulties, seizures, hearing and vision loss, distinctive facial features, and enlargement of the liver and spleen. These symptoms lead to significant developmental delays and often result in early death. Milder forms within the ZSD spectrum may appear later in life and are associated with less severe symptoms, such as hearing or vision impairment and learning disabilities.

Problem: This condition involves a near-complete loss of functional peroxisomes, leading to the accumulation of several harmful substances like VLCFAs, branched-chain fatty acids, phytanic acid, and hydrogen peroxide. Since peroxisomes play multiple metabolic roles, dietary changes are supportive but not curative.

Category	Foods to Avoid
High-fat animal products	Fatty meats, Processed meats
Dairy products (often restricted)	Whole milk, Butter, Cheese
Foods high in phytanic acid	Beef, Lamb, Certain types of fish (especially fatty ones)

Additional Information:
Due to the complex metabolic dysfunction in Zellweger syndrome, patients may require specialized nutritional formulas, often low in fat or using medium-chain triglycerides (MCTs), which bypass peroxisomal metabolism.

Refsum’s Disease

Refsum's Disease symptoms involve progressive vision loss (retinitis pigmentosa), loss of smell (anosmia), hearing loss, poor balance (ataxia), peripheral neuropathy (nerve damage), dry scaly skin (ichthyosis), and skeletal issues like short fingers/toes, plus serious heart problems (arrhythmias, cardiomyopathy), all stemming from phytanic acid buildup. These symptoms, often starting in childhood or adolescence, worsen over time but can improve with a strict, low-phytanic acid diet.

Problem: The body cannot perform alpha-oxidation, a process required to break down phytanic acid. As a result, phytanic acid accumulates in tissues, especially the nervous system and skin.

Foods to Strictly Avoid:

Category	Examples
Dairy products	Milk, Butter, Cheese, Ice cream
Ruminant animal fats	Beef, Lamb, Goat
Fatty fish	Cod, Haddock, Tuna, Salmon

Additional Restrictions:

Fasting and rapid weight loss should be avoided, as these can cause the release of stored phytanic acid from fat tissue into the bloodstream.

Additional Information:

This condition is highly responsive to diet. Proper restriction of phytanic acid intake can significantly reduce symptoms and slow disease progression.

Summary Table

Disorder	Main Metabolic Problem	Foods to Avoid
ALD	Accumulation of VLCFAs	Animal fats, full-fat dairy, certain oils
Zellweger	Loss of all peroxisomal function	Fatty meats, dairy, ruminant fats, fatty fish
Refsum’s Disease	Accumulation of phytanic acid	Dairy, beef, lamb, fatty fish

When a person has low cortisol due to adrenal insufficiency (whether from Addison’s disease, adrenal crisis, or secondary causes like ALD or chronic steroid use), diet becomes an important part of supporting adrenal function and managing symptoms.

Here's a breakdown of how low cortisol changes dietary needs and why:

1. Increased Salt (Sodium) Needs

Why: Cortisol helps regulate blood pressure and supports the action of aldosterone, which retains sodium and excretes potassium. In adrenal insufficiency, especially primary types (like in ALD or Addison’s), aldosterone may also be low, leading to salt loss, low blood pressure, and dehydration.

Dietary Adjustment:

            Liberalize salt intake, especially if you're feeling weak, dizzy, or have low BP.

Use salted broths, soups, or electrolyte drinks.

Some patients are prescribed fludrocortisone (a synthetic aldosterone) but still may need extra dietary sodium.

2. Stable, Frequent Meals (Prevent Hypoglycemia)

Why: Cortisol helps maintain normal blood sugar, especially during fasting or stress. With low cortisol, blood sugar can drop too low — especially in children, or during illness or physical stress.

Dietary Adjustment:

Eat small, frequent meals throughout the day.

Avoid fasting or long gaps between meals.

Include complex carbs (like oats, brown rice, sweet potato) and protein in meals and snacks to stabilize blood sugar.

Carry emergency glucose tablets or a quick sugar source if needed.

3. Adequate Protein Intake

Why: Cortisol plays a role in protein metabolism, and low levels can lead to muscle weakness or fatigue.

Dietary Adjustment:

Include lean protein sources regularly: eggs, fish, poultry, legumes, tofu, and Greek yogurt.

Spread protein intake throughout the day, not just one meal.

4. Avoid High Potassium in Some Cases

Why: Low aldosterone (often seen with cortisol deficiency) can lead to hyperkalemia (high potassium).

Dietary Adjustment (if potassium is elevated):

Limit very high-potassium foods:

Bananas, oranges, potatoes, spinach, avocados

Use low-potassium alternatives if recommended by your doctor

Monitor blood levels before restricting potassium—not all adrenal insufficiency patients have high potassium

5. Stay Hydrated

Why: Cortisol and aldosterone help retain water and electrolytes. Without them, the body can dehydrate quickly, especially in hot weather or during illness.

Dietary Adjustment:

Drink plenty of fluids, especially electrolyte-balanced fluids (like Pedialyte, WHO solutions, or electrolyte tablets in water)

Increase fluid intake during fever, vomiting, diarrhea, or exercise

6. Monitor Stress-Related Needs

Why: During physical stress (illness, injury, surgery), people with adrenal insufficiency need more cortisol than usual. If they can’t produce it, they may go into adrenal crisis, which is life-threatening.

Dietary Adjustment:

During illness, you may need:

            Increased salt
            Increased fluids
            Easily digestible carbs to prevent hypoglycemia

Follow “sick day rules” given by your doctor, which may include doubling steroid doses and increasing oral intake

7. Avoid Stimulants or “Adrenal Fatigue” Supplements

Why: These products often contain herbs or stimulants (like licorice, ginseng, caffeine) that can interfere with blood pressure, potassium, or interact with steroid medications.

Dietary Adjustment:

Avoid unregulated “adrenal support” supplements unless approved by a doctor
Rely on medically guided hydrocortisone/fludrocortisone replacement and supportive diet

Summary: How Diet Changes with Low Cortisol

Issue	Dietary Need
Salt wasting	Increase sodium intake
Hypoglycemia risk	Eat frequent, balanced meals with carbs and protein
Muscle weakness	Ensure adequate protein
Risk of dehydration	Drink fluids, use electrolytes
Hyperkalemia (if present)	Limit high-potassium foods (only if needed)
Stress or illness	Increase salt, fluids, and calories temporarily
Avoid risky supplements	Stick to medically approved treatment and diet

Guide to the key diagnostic tests used for identifying and confirming:

Adrenoleukodystrophy (ALD)

Zellweger Spectrum Disorders (ZSD)

Refsum’s Disease

These tests help detect biochemical abnormalities, genetic mutations, and clinical features specific to each disorder.

1. Adrenoleukodystrophy (ALD)

Main problem: Impaired peroxisomal import of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene → VLCFA buildup in tissues.

 

Test	Purpose
Plasma VLCFA Profile	Measures levels of VLCFAs like C24:0, C26:0, and their ratios to C22:0.
ABCD1 Genetic Testing	Confirms mutation in the ABCD1 gene (X-linked).
ACTH stimulation test / Morning cortisol	Screens for adrenal insufficiency, often seen in ALD.
Brain MRI	Detects white matter changes (demyelination), especially in cerebral ALD.
Very long-chain acyl-CoA oxidase or peroxisomal enzyme assays	May be used in specialized labs to assess peroxisomal function.
Newborn screening (where available)	Many states/countries now screen for ALD in newborns via VLCFA levels on dried blood spots.

2. Zellweger Syndrome / Zellweger Spectrum Disorders (ZSD)

Main problem: Absent or dysfunctional peroxisomes due to mutations in PEX genes → accumulation of toxic fatty acids, bile acid intermediates, and hydrogen peroxide.

 

Test	Purpose
Plasma VLCFA Profile	Elevated C24:0, C26:0, and abnormal C24/C22, C26/C22 ratios.
Plasma Phytanic and Pristanic Acid	Often elevated.
Plasmalogen levels (in erythrocytes or plasma)	Often decreased; reflects impaired lipid synthesis.
Urinary bile acid intermediates (via mass spectrometry)	Abnormally elevated due to defective bile acid metabolism.
PEX Gene Panel / Whole Exome Sequencing	Confirms diagnosis by identifying mutations in PEX1, PEX6, or other PEX genes.
Brain MRI	May show structural abnormalities (e.g. neuronal migration defects, white matter disease).
Liver function tests	May show elevated liver enzymes and signs of hepatomegaly.

 3. Refsum’s Disease (Adult Refsum Disease)

Main problem: Deficiency of phytanoyl-CoA hydroxylase → defective alpha-oxidation of phytanic acid → toxic buildup.

Key Tests:

Test	Purpose
Plasma Phytanic Acid	Elevated — the key diagnostic marker. May be >200 µmol/L in untreated individuals.
Plasma Pristanic Acid	Often normal or slightly elevated (helps in differential diagnosis).
Genetic Testing	Mutation in PHYH gene (most common) or PEX7 (less common).
Nerve conduction studies (EMG/NCS)	To evaluate peripheral neuropathy.
Electroretinogram (ERG)	May show changes consistent with retinitis pigmentosa.
MRI Brain / Spine	May show cerebellar atrophy or white matter changes in some cases.

Summary Table

Disorder	Biochemical Tests	Genetic Tests	Imaging / Other
ALD	Plasma VLCFA, cortisol/ACTH	ABCD1 gene	Brain MRI, adrenal testing
Zellweger	VLCFA, phytanic/pristanic acid, bile acids, plasmalogens	PEX gene panel	MRI, liver enzymes, hearing/vision tests
Refsum's	Plasma phytanic acid	PHYH or PEX7	EMG, ERG, MRI (if needed)

References:

Lecture: https://www.youtube.com/watch?v=sQDrhn_I1-8

- Key --peroxisomal disorders--: --Zellweger syndrome--, --Refsum's disease--, and --Adrenoleukodystrophy--

- Peroxisomal functions

- The 7 major metabolic roles they play

Adrenoleukodystrophy (ALD)
https://www.hopkinsmedicine.org/health/conditions-and-diseases/adrenoleukodystrophy

Zellweger Syndrome https://my.clevelandclinic.org/health/diseases/6116-zellweger-syndrome

Refsum disease https://medlineplus.gov/genetics/condition/refsum-disease/

Peroxisomes: https://www.ncbi.nlm.nih.gov/books/NBK26858/

Peroxisomes: https://www.ncbi.nlm.nih.gov/books/NBK9930/