Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and hyperpipecolic acidemia are all part of Zellweger spectrum disorders. This group of diseases affects the biogenesis of the cellular organelle called “peroxisoma” to varying degrees and can lead to premature death.

In this article we will describe the causes and main symptoms of Zellweger syndrome , the most severe variant of peroxisome biogenesis disorders. In the rest of the disorders of this group the signs are similar but have a lower intensity.

What is Zellweger syndrome?

Zellweger syndrome is a disease that affects functions such as muscle tone or visual and auditory perception, as well as bone and organ tissues such as the heart and liver. Its origin has been related to the presence of mutations in certain genes that are transmitted by autosomal recessive inheritance.

Children diagnosed with Zellweger syndrome tend to die before the end of the first year of life . Many of them die before the age of 6 months as a result of alterations in the liver or in the respiratory and gastrointestinal systems. However, people with mild variants may live into adulthood.

At present, there is no known treatment that resolves the profound alterations that cause Zellweger syndrome, so the management of this disease is of a symptomatic nature.

Zellweger spectrum disorders

Zellweger syndrome is now known to be part of a group of diseases that have the same genetic cause: disorders of peroxisome biogenesis (organelles that play a role in the functioning of enzymes), also known as “Zellweger spectrum disorders”.

Classic Zellweger syndrome is the most severe variant of peroxisome biogenesis disorders, while cases of intermediate severity are called “neonatal adrenoleukodystrophy” and milder ones “infantile Refsum disease”. Hyperpipecolic acidemia is also a low intensity form of this disorder.

Previously it was believed that these alterations were independent of each other. Zellweger syndrome was first described in 1964; the identification of the remaining spectrum disorders occurred in the following decades.

Main symptoms and signs

In Zellweger syndrome, the alteration in the biogenesis of the peroxisome causes neurological deficits that cause a wide variety of symptoms in different body systems and functions. In this sense, the signs of the disorder are related to the development of the brain, and particularly to neuronal migration and positioning.

Among the most common and characteristic signs and symptoms of Zellweger syndrome are the following:

  • Decreased muscle tone (hypotonia)
  • Seizures
  • Loss of sensory hearing abilities
  • Alterations of the ocular system and vision (nystagmus, cataracts, glaucoma)
  • Difficulties in eating
  • Affecting normal physical development
  • Presence of characteristic facial features (flat face, high forehead, wide nose…)
  • Presence of other morphological alterations (microcephaly or macrocephaly, neck folds…)
  • Abnormalities in bone structure, especially chondrodysplasia punctata (calcification of cartilage)
  • Increased risk of developing heart, liver and kidney disorders
  • Respiratory disorders such as apnea
  • Appearance of cysts in the liver and kidneys
  • Enlargement of the liver (hepatomegaly)
  • Detection of abnormalities in the encephalographic (EEG) record
  • General alteration of the functioning of the nervous system
  • Hypomyelination of central nervous system axonal fibres

Causes of this disease

Zellweger syndrome has been associated with the presence of mutations in at least 12 genes; although there may be alterations in more than one of these, it is sufficient for one altered gene to cause the symptoms described in the previous section to appear. In approximately 70% of cases the mutation is located in the PEX1 gene .

The disease is transmitted through an autosomal recessive inheritance mechanism. This means that a person must inherit one mutated copy of the gene from each parent to have the typical symptoms of Zellweger syndrome. When both parents carry the mutant gene, there is a 25% risk of developing the disease.

These genes are related to the synthesis and functioning of the peroxisome , structures that are common in the cells of organs such as the liver and that are essential for the metabolism of fatty acids, for the elimination of waste and for the development of the brain in general. Mutations alter the gene expression of the peroxisome.

Treatment and handling

To date, there is still no known effective treatment for Zellweger syndrome, despite improved understanding of the genetic, molecular and biochemical alterations associated with the disease. This is why the therapies applied in these cases are basically symptomatic and are adapted to the signs of each specific case.

Problems in eating properly are a sign of particular relevance because of the risk of malnutrition. In these cases it may be necessary to apply a feeding tube to minimize interference with the child’s development.

The treatment of Zellweger syndrome is carried out by multidisciplinary teams that may include professionals from paediatrics, neurology , orthopaedics, ophthalmology, audiology and surgery, among other branches of medical science.