Zellweger Syndrome

Overview

Zellweger syndrome is a rare congenital disorder that falls under a group of conditions known as peroxisome biogenesis disorders (PBDs), specifically the Zellweger spectrum disorders. It is characterized by a severe impairment in the formation and function of peroxisomes - cellular structures responsible for breaking down toxic substances and producing certain essential lipids. First described by Hans Zellweger in the 1960s, the syndrome presents in infancy and is considered the most severe form of PBDs.

Causes

Zellweger syndrome is caused by mutations in one of several PEX genes, which are essential for the formation of peroxisomes. These mutations lead to defective or absent peroxisomes, disrupting many metabolic processes. The disorder is inherited in an autosomal recessive manner, meaning both parents must carry one defective copy of the gene for their child to be affected. Mutations in PEX1 are the most commonly implicated, though others like PEX2, PEX6, and PEX10 can also be involved.

Symptoms

Signs and symptoms of Zellweger syndrome usually become evident at birth or shortly afterward. Common features include:

• Hypotonia (low muscle tone)

• Feeding difficulties and failure to thrive

• Seizures

• Hearing and vision impairment

• Distinctive facial features (high forehead, broad nasal bridge, large anterior fontanelle)

• Liver dysfunction (hepatomegaly, jaundice)

• Developmental delays

• Skeletal abnormalities

Neurological abnormalities are severe and progressive, often leading to an inability to achieve developmental milestones such as sitting, walking, or speaking.

Diagnosis

Diagnosis of Zellweger syndrome involves a combination of clinical evaluation, laboratory testing, and genetic analysis. Diagnostic steps include:

• Plasma biochemical tests showing elevated very long-chain fatty acids (VLCFAs), bile acid intermediates, and phytanic acid

• Neuroimaging (MRI) revealing cortical dysplasia or other brain malformations

• Liver function tests indicating hepatic dysfunction

• Hearing and vision evaluations

• Confirmatory genetic testing to identify mutations in PEX genes

Early diagnosis is crucial for supportive care and family planning, including carrier testing for parents and prenatal diagnosis in future pregnancies.

Treatment

There is no cure for Zellweger syndrome. Treatment is supportive and aims to manage symptoms and improve quality of life. Interventions may include:

• Feeding support via nasogastric or gastrostomy tube

• Antiepileptic medications for seizure control

• Physical and occupational therapy to manage hypotonia and improve function

• Hearing aids and visual support if applicable

• Liver support with close monitoring of liver enzymes and function

Due to the progressive nature of the disease, a multidisciplinary team approach involving neurologists, hepatologists, nutritionists, and therapists is essential.

Prognosis

The prognosis for Zellweger syndrome is poor. Most affected infants do not survive beyond the first year of life, primarily due to severe neurological impairment and liver failure. In very rare cases, children may live longer, but they typically experience profound intellectual and physical disabilities. Despite ongoing research, no disease-modifying therapies are currently available, making early diagnosis and palliative care critical for affected families.