Zellweger Spectrum Disorder

What’s in a name…
You may often hear Zellweger Spectrum Disorder (ZSD) referred to by several other names. ZSD belongs to a group of diseases called Peroxisomal Disorders; metabolic conditions that can be split into two major categories; Peroxisomal Biogenesis Disorder (PBD) and Single Enzyme Defects.

The Zellweger spectrum belongs to the Peroxisome Biogenesis Disorders group. It is most commonly referred to as a spectrum condition with a varying degree of disease severity. However, before the condition was linked to the peroxisome it was considered to consist of three separate conditions. Zellweger Syndrome (ZS) the most severe form, Neonatal Adrenoleukodystrophy (NALD) mid spectrum and Infantile Refsum Disease (IRD) at the milder end of the spectrum. Although less common, you may occasionally hear ZSD referred to as one of the above disorders.

Additionally, Heimler Syndrome has recently been identified as a part of ZSD, on the milder end of the spectrum.

So what is Zellweger Spectrum Disorder?
Peroxisomal Disorder on the Zellweger Spectrum (also sometimes referred to as Generalized Peroxisomal Disorder) is categorised by the absence of peroxisomes. Peroxisomes are cell structures that break down toxic substances and synthesize lipids (fatty acids, oils, and waxes) that are necessary for cell function. Peroxisomes are required for normal brain development and function and the formation of myelin, the substance that coats nerve fibres.

ZSD affects an estimated 1/50,000 live births. Children usually don’t live long into adulthood, however the spectrum is wide and life expectancy ranges from days old to patients who live into their 30s. Most children have some degree of facial characteristics such as a broad nasal bridge, low set ears, a large fontanelle (soft spot) and a high forehead (which in our humble opinion makes for incredibly beautiful children!) they also usually have shortened limbs to some degree and small hands and feet.

Affected children generally show symptoms from birth such as jaundice, hypotonia, failure to thrive and liver dysfunction. Many children fail to pass their newborn hearing screening. As the disease progresses children commonly deal with global disabilities, vision impairment, adrenal insufficiency and seizures. Children may also suffer other common symptoms such as renal stones, low bone density and blood clotting issues that can lead to haemorrhage and intracranial bleeding.

Diagnosis and Genetics
The diagnosis of Zellweger Spectrum Disorder can be determined by biochemical abnormalities detected in blood or cultured skin fibroblasts. The level of very long chain fatty acids (VLCAs) is usually an informative initial screen. Mutations can be found in 13 different PEX genes, but are most commonly found on PEX1. As ZSD is an autosomal recessive condition, each parent has 1 affected gene and 1 non affected gene, therefore the chances of their children being affected is 1 in 4, or 25%. Once their mutation has been identified, further children can be diagnosed by genetic testing either in utero or after birth. It is also possible to determine whether healthy siblings and other members of the family are carriers once each parent’s mutations are identified.

It should be noted that it is still possible to diagnose in utero by biochemical testing if genetic mutations haven’t been identified, but this requires culturing of chorionic villi cells and therefore will take longer than genetic testing.

Treatments
Currently there are no effective treatments for ZSD, only management of symptoms such as cortisol supplementation for adrenal insufficiency, anti-seizure medications, vitamin K for blood clotting disorders and pamidronate infusions for children who suffer with low bone density.
Children have also benefited from supplementation of DHA (docosahexaenoic acid) an essential fatty acid that children with ZSD are often deficient in, and some children seem to benefit from a diet restricted in phytanic acid, although some specialists don’t believe this is largely effective.

Reminder: This information is not to take the place of your child’s primary care physician and medical team.
Articles on Peroxisomal Biogenesis Disorder – Zellweger Spectrum Disorder

Acharya: Medical-dental findings and management of a child with Infantile Refsum Disease

Berendse: High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders

Berendse: Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood

Mast: A Drosophila Model for the Zellweger Spectrum of Peroxisome Biogenesis Disorders

Poll-The: Peroxisome Biogenesis Disorders with Prolonged Survival

Raas-Rothschild: PEX-6 Defective PBD infant vs Ushers

Shimozawa: Molecular and Clinical Findings and Diagnostic Flowchart of Peroxisomal Disorders

Steinberg: “Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum

Tran: Infantile Refsum Disease with Enamel Defects

Zhang: “ecovery of PEX1-Gly843Asp Peroxisome Dysfunction

Information and Resources for other Peroxisomal Disorders

Acyl-CoA Oxidase Deficiency
D-Bifunctional Protein Deficiency
X-Linked Adrenoleukodystrophy (X-ALD)