Zellweger Syndrome: Causes, Symptoms, Diagnosis, and Treatment

Introduction

Zellweger syndrome is a very rare congenital peroxisome biogenesis disorder that is characterized by defective neuronal migration in the brain, morphologically abnormal craniofacial features, profound hypotonia with progressive loss of muscle tone, and seizures typically occurring in neonates, along with liver dysfunction in some cases. It is the most serious form of the family of Zellweger spectrum disorders.

Zellweger syndrome is named after a Swiss -American pediatrician Hans Zellweger who described the disorder in the year 1964. It affects the nerves and metabolism in newborn children severely. The brain, liver, and kidneys are also affected by the syndrome. It poses serious harm to important functions throughout the body of the newborn.

What Are the Alternative Names for Zellweger Syndrome?

• Cerebrohepatorenal syndrome.

• Peroxisome biogenesis disorders.

• Zellweger syndrome spectrum.

• Zellweger spectrum.

• Zellweger syndrome spectrum.

• Neonatal adrenoleukodystrophy.

What Is Zellweger Spectrum Disorder (ZSD)?

It is also called peroxisomal biogenesis disorder. The group of these disorders affects the cell organelle peroxisomes. Peroxisomes are membrane-closed small cellular organelles that contain enzymes that are essential for carrying out many metabolic reactions in the body.

The Zellweger spectrum disorders include:

• Heimler Syndrome: It is responsible for hearing loss and tooth problems in early childhood.

• Infantile Refsum Disorder: It causes a problem in muscle movement and delayed development in a baby.

• Neonatal Adrenoleukodystrophy: It causes vision and hearing loss, along with problems in the development and functioning of the infant’s brain, muscles, and spine.

• Zellweger Syndrome: It is the most serious form of the spectrum of diseases and is associated with impaired neuronal migration, poor brain development, hypomyelination (body is unable to produce myelin in normal quantities), hepatomegaly (enlarged liver), and renal cysts.

Who Is Affected by Zellweger Syndrome?

Zellweger syndrome is an autosomal recessive disorder. This suggests that the disorder will be passed on to the children if both parents carry the mutated gene individually. If the mutated gene is present in both parents, there is a 50 % chance of their children being carriers. A carrier genetically inherits defective genes without actually developing the disease. Therefore, the children have a 25 % chance of encountering the disorder.

How Common Is Zellweger Syndrome?

Zellweger syndrome is a rare hereditary disorder. It usually affects one in 75,000 newly born infants worldwide. The highest incidence of Zellweger syndrome was reported to be around 1/12000 in the Saguenay-Lac region of Quebec.

What Causes Zellweger Syndrome?

Zellweger syndrome is caused due to a genetic mutation in one of the PEX (peroxisomal biogenesis factor) genes. These genes provide signals to synthesize a group of proteins called peroxins, which are necessary for the biogenesis and proper functioning of the cell organelle called peroxisomes. Most cases of the syndrome occur due to a genetic mutation in the PEX1 gene. These mutations, in turn, reduce or inactivate the maternal and paternal copies of one of the PEX genes that control peroxisomes. Peroxisomes are responsible for breaking down toxins and fats. They are also found to contribute to the development of these organs:

• Nerves.

• Brain.

• Eyes.

• Kidneys.

• Heart.

• Liver.

• Bones.

As a result of impaired functioning of the peroxisomes, the patient can accumulate a very long branched chain of fatty acids and toxins. The accumulation of these long-chain fatty acids can, in turn, affect the normal functioning of multiple organ systems.

What Are the Symptoms of Zellweger Syndrome?

Individuals with Zellweger syndrome usually present with clinical features since birth, but these features start deteriorating with time. The symptoms include:

1. The infants experience profound hypotonia and seizures. These problems occur due to hypomyelination, which is a reduction in the myelin sheath. Myelin is the protective sheath that insulates nerves and aids in the transmission of impulses effectively.

2. The white matter of the brain and spinal cord consists of myelin. Reduced myelin (demyelination) often leads to leukodystrophy, which is the loss of white matter.

3. Neonatal seizures.

4. Underdeveloped muscles and profound hypotonia or poor muscle movement.

5. Broad nasal bridge.

6. Flattened occiput (flattened shape and structure of the occipital bone).

7. Flattened facies (abnormally distinctive facial appearance).

8. Hypoplastic supraorbital ridges (underdeveloped ridges of the supraorbital margin).

9. Large anterior fontanel (enlarged soft spots on an infant’s head).

10. High forehead (forehead having larger height than normal).

11. Upslanting palpebral fissures (Upward slanting of the fissure between the eyelids).

12. Hypertelorism (increased distance between two eyes).

13. Macrocephaly or microcephaly (large or small head circumference, respectively).

14. High-arched palate (palate is usually high and narrow).

15. Micrognathia (small jaw).

16. Chondrodysplasia punctata (an abnormality observed on X-rays as spots near the ends of bones and cartilage).

17. Renal cysts (cyst formation in kidneys).

18. Hepatomegaly (enlarged liver).

19. Jaundice (yellowish discoloration of sclera, skin).

20. Cataracts (cloudy lens in the eyes).

21. Glaucoma (elevated blood pressure in the eyeballs).

22. Nystagmus (eyes rapidly moving involuntarily).

23. Optic nerve degeneration (damage to the optic nerve causing gradual loss of eyesight).

24. Hearing loss (hearing impairment).

25. Gastrointestinal tract bleeding (bleeding in the digestive tract).

26. Feeding problems (the infant is not able to feed properly).

How Is Zellweger Syndrome Diagnosed?

The syndrome diagnosis is usually based on a thorough clinical examination done by a healthcare provider. Elaborated patient history and identification of the characteristic features of the disorder are some of the important points to keep in mind while evaluating the patient. The following diagnostic tests are done to confirm the diagnosis:

• Blood and Urine Tests: Elevated levels of long-chain fatty acids can be detected in the blood or urine of these patients.

• Imaging Tests: Ultrasound should be done to check the body organs such as the liver, kidneys, etc. Magnetic resonance imaging (MRI) can also be done to check the functioning of the brain.

• Skin Fibroblasts: They are obtained from the affected patients and can be cultured to demonstrate elevated long-chain branched fatty acids and plasmalogen biosynthesis.

• Genetic Tests: These testsare conducted to test the presence of one of the mutated PEX genes.

• Next-Generation Sequencing Methods: They are used to initiate the sequencing of small DNA and are being used more commonly as confirmatory tests. They may be required to determine peroxisomal disorders that are otherwise difficult to diagnose by conventional biochemical techniques.

Can Zellweger Syndrome Be Diagnosed Before Child’s Birth?

A fetus is at high risk for developing the syndrome if both parents are disease carriers of the mutated PEX genes responsible for causing the syndrome. A healthcare provider should conduct various blood, biochemical, and imaging tests for Zellweger syndrome for the unborn baby in the womb.

What Are the Complications of Zellweger Syndrome?

Infants suffering from this syndrome may suffer from hearing and vision impairment. Underdeveloped muscles may not allow the infant to be able to move properly. Babies can often develop respiratory problems, liver dysfunction, or gastrointestinal bleeding.

What Is the Treatment of Zellweger Syndrome?

There is no known specific treatment for Zellweger syndrome. Some therapies are employed to ease symptoms, but there is no specific cure for the disease. Treatment may require a well-coordinated team of specialists that includes pediatricians, neurologists, endocrinologists, surgeons, audiologists, ophthalmologists, orthopedic surgeons, and other healthcare professionals to systematically plan the child’s treatment. Children affected with the syndrome may require a feeding tube to ensure proper intake of nutrients.

• Additional Therapies:

Hearing aids, cochlear implants, vitamin supplementation, and cataract surgery are some of the additional therapies that can be done. Anti-epileptic drugs may be used to minimize the attack of seizures. Adrenal monitoring with adrenocorticotropic hormone (ACTH) and morning cortisol is recommended for patients with adrenal insufficiency.

How to Prevent the Syndrome?

The disease cannot be prevented. Genetic counseling can be done for people with a family history of Zellweger syndrome. Genetic counseling will enable the patient to evaluate the risk of passing the disorder to children or grandchildren.

What Is the Prognosis for Infants Affected With Zellweger Syndrome?

Infants suffering from Zellweger syndrome usually do not survive beyond 12 months of life.

Conclusion

Zellweger syndrome is a very serious disorder with high morbidity in almost all patients and mortality in some. Although treatment is only symptomatic, it is very important to initiate proper supportive therapy for these patients to improve their quality of life. Advanced genetic testing should be done to identify carriers for this disease. This will enable reliable genetic counseling for families and may also pave the way for conducting future clinical trials.