Zellweger Syndrome

Overview

Zellweger syndrome (ZS) is the most severe form within a spectrum of genetic conditions collectively known as the Zellweger spectrum disorders. Symptoms of ZS often appear at birth and include poor muscle tone (hypotonia), feeding difficulties, seizures, hearing and vision loss, distinctive facial features, and skeletal abnormalities. The condition also causes life-threatening issues in major organs like the liver, heart, and kidneys.

ZS arises from genetic mutations in one of at least 12 genes, with mutations in the PEX1 gene being the most common. It is inherited in an autosomal recessive manner, meaning both parents must carry a mutated gene to pass it on.

What is Zellweger Syndrome?

ZS, also known as cerebrohepatorenal syndrome, affects peroxisomes—cell structures crucial for various metabolic functions. Without properly functioning peroxisomes, the body struggles with nerve development, metabolism, and detoxification processes, influencing the brain, liver, and kidneys. As a result, ZS is typically fatal in infancy. Zellweger spectrum disorders, sometimes called peroxisomal biogenesis disorders, represent a continuum of severity, with Zellweger syndrome being the most severe form.

Types of Zellweger Syndrome

Other than the Zellweger syndrome (severe), Zellweger spectrum disorder is a genetic condition that varies in severity, historically classified into two more forms: Neonatal Adrenoleukodystrophy (NALD; intermediate), and Infantile Refsum Disease (mild).

Neonatal Adrenoleukodystrophy (NALD) (Intermediate Form)

This form is a type of leukodystrophy that damages the myelin sheath or the insulating layer around nerve cells in the brain's white matter. NALD also impacts the adrenal glands and testes, leading to hormone imbalances and neurological complications. Children with NALD may have progressive issues with movement, muscle control, and other developmental challenges.

Infantile Refsum Disease (Mild Form)

This is the least severe form, though still highly disabling. Affected children often face feeding challenges, seizures, and gradual loss of vision and hearing. They also experience neurological symptoms like balance problems and sensory deficits.

Although some individuals may live into adulthood, respiratory complications can significantly shorten life expectancy. Adult Refsum disease, a related but distinct condition, causes a progressive decline in vision, weakness, and coordination.

Symptoms of Zellweger Syndrome

Symptoms of Zellweger syndrome (ZS) usually become apparent shortly after birth and affect multiple organs and systems. Some characteristic facial features associated with ZS include underdeveloped eyebrow ridges, epicanthal folds (skin folds at the inner corners of the eyes), widely spaced eyes, a flattened facial profile, a broad nasal bridge, and a high forehead
Additional symptoms and complications of ZS often include enlarged liver and/or spleen (hepatosplenomegaly), difficulty with feeding and poor weight gain, gastrointestinal bleeding, seizures, hearing and vision impairments, jaundice (yellowing of the skin and eyes due to liver dysfunction), and low muscle tone, underdeveloped muscles, and movement difficulties.

Zellweger Syndrome Causes

Zellweger spectrum disorder is caused by mutations in at least 12 different genes, which encode proteins known as peroxins. These proteins are essential for creating and maintaining peroxisomes or sac-like structures within cells that house enzymes you need to break down substances such as fatty acids and toxic compounds. Peroxisomes are also involved in producing lipids essential for digestion and nervous system function. Peroxins aid in peroxisome biogenesis by building the membrane that encloses peroxisomes and ensuring enzymes are properly transported into them.

In Zellweger spectrum disorder, gene mutations prevent peroxisomes from forming or functioning correctly, leading to a group of conditions called peroxisome biogenesis disorders. When peroxisome production is severely impaired, as in Zellweger syndrome, the body lacks functional peroxisomes, causing widespread symptoms. Milder forms of the disorder occur when some peroxisomes can still form.

Mutations in the PEX1 gene are the most common cause of Zellweger spectrum disorder, accounting for nearly 70% of cases. Other associated genes contribute to the disorder in smaller percentages.

Zellweger Syndrome Diagnosis and Tests

Healthcare providers typically recognise Zellweger syndrome (ZS) through characteristic facial features observed at birth. To confirm the diagnosis, doctors use several tests:

Imaging Tests: Ultrasound scans assess the size and function of the liver, kidneys, and other organs. Doctors perform a brain MRI to evaluate neurological effects.

Genetic Testing: A blood test can identify mutations in the PEX genes, confirming the presence of ZS.

Blood and Urine Tests: Elevated levels of specific substances, such as certain fats, in the blood or urine can indicate ZS.

Treatment Options for Zellweger syndrome

Zellweger spectrum disorder is a rapidly progressive condition with a high mortality rate, and there is currently no cure. Doctors focus the treatment on supportive care to enhance the quality of life and manage symptoms. Key treatment options include:

Lorenzo’s Oil: A mixture of glyceryl trioleate and glyceryl trifurcate, Lorenzo’s oil was initially developed for X-linked adrenoleukodystrophy. While it reduces very long-chain fatty acids (VLCFAs) in the blood, it has not shown significant effects on disease progression in Zellweger spectrum disorder.

Cholic Acid: A 24-carbon bile acid used to aid in the absorption of fat-soluble vitamins. Due to impaired liver function and lipoprotein synthesis in Zellweger spectrum disorder, patients often lack vitamins A, D, E, and K. FDA approves of Cholic acid for use in similar liver-related disorders, though evidence of its efficacy in Zellweger syndrome is limited.

Docosahexaenoic Acid (DHA): DHA is a long-chain unsaturated fatty acid vital for myelination and the development of the brain and eyes. Individuals with Zellweger spectrum disorder often have low plasma levels of DHA, but clinical trials have shown that supplementation does not improve neurological or visual symptoms.

Supportive care measures are crucial for symptom management and may include:

• Hearing aids or cochlear implants to manage hearing loss
• Vitamin K supplementation for managing coagulopathy
• Vitamin supplements to address deficiencies in fat-soluble vitamins (A, D, E, and K)
• Cortisone therapy for adrenal insufficiency
• Standard drugs for seizure control
• Referral to an ophthalmologist, cataract removal if necessary, and corrective glasses for vision impairments
• Gastrostomy to ensure adequate nutrition if feeding is challenging

Preventive Measures for Zellweger Syndrome

There is currently no particular way to prevent ZS. Individuals with a family history of ZS may want to consider genetic counselling. There are genetic counsellors who can assist in evaluating the risk of passing the disease to children or grandchildren.