Zellweger Spectrum Disorders: Disease Mechanism & Causes

Zellweger spectrum disorders are a group of rare genetic conditions. The genetic disorders under this umbrella have a similar disease process and are considered as variants of the same type.

These are:

• Zellweger Syndrome (ZS) – Most severe form
• Neonatal Adrenoleukodystrophy (NALD) – Medium severity form
• Infantile Refsum Disease (IRD) – Least severe form

In Zellweger syndrome, many systems and organs are affected, can have severe manifestations and can result in serious life threatening complications, while the other two forms have comparatively less severe effects. It may, at times be difficult to differentiate between these three forms.

Zellweger spectrum disorders are featured under the category of peroxisome biogenesis disorders (PBDs). These PBDs are a group of inherited disorders, in which the body fails to produce certain cell structures called peroxisomes, which are responsible for important bodily processes. These peroxisomes aid in breaking down toxic substances and fatty acids. They produce lipids necessary for body functions, digestion and nervous system. They also play an important role in waste disposal and proper brain development and functioning.

As the body lacks proper functioning of peroxisomes, the organs and functions that are dependent on peroxisomes are affected. The clinical features and associated complications are a result of abnormal functioning of peroxisomes.

Zellweger spectrum disorders are an inherited disorder and are caused due to genetic mutations or changes in one of the genes (called PEX genes) responsible for the production and functioning of peroxisomes. These genetic mutations affect the normal functioning of peroxisomes. As a result, the body suffers the consequences of deficiency or improper functioning of peroxisomes, which results into multi-systemic involvement.

In Zellweger syndrome, the organs are malformed during embryonic development of the fetus in utero and the clinical features become evident during the first few hours or days of the neonate’s life.

• Appearance – The neonates with Zellweger Syndrome have a typical appearance called dysmorphic craniofacial features characterized by large anterior fontanel, flattened face and occiput, high forehead, broad nasal bridge, upslanting palpebral fissures, epicanthal folds, widely set eyes, under developed eyebrow ridges. Sometimes large or small head, skin folds on neck, protruding tongues may also be seen.
• Other findings may include nystagmus, cataract, glaucoma, retinal degeneration, optic nerve atrophy, seizures, impaired hearing and mental retardation.
• Hypotonia – The neonates with Zellweger Syndrome can have a reduced muscle tone to the extent that they are unable to move. They have poor sucking abilities and feeding difficulties.
• Systemic Findings – Some neonates may present with an enlarged liver, liver cysts or abnormal functioning of liver, jaundice, gastrointestinal bleeding, renal cysts and other severe problems with the functioning of kidneys and heart. Skeletal abnormalities like widely spaced skull bones and bone spots may be identified on imaging studies. Central nervous system and its function is affected with psychomotor delay; seizures may also be commonly noted.

The typical appearance at birth and the clinical features generally raises suspicion. Further, laboratory tests are ordered for screening and confirmation of Zellweger syndrome.

• Blood And Urine Tests- To detect the presence of increased levels of very long fatty acids as they are not broken down properly. Similar other tests related to improper functioning of peroxisomes and Zellweger syndrome may be ordered.
• Genetic Testing– To detect the genetic mutation or defect related to Zellweger syndrome.
• Imaging Studies- To identify structural abnormalities in bones and other organs. An x-ray of bones to determine skeletal abnormalities, ultrasound of abdomen and pelvis to detect liver enlargement or kidney cysts may be performed.

While there is no proper cure for Zellweger syndrome, symptomatic treatment may be given. Seizures are controlled by giving anti-epileptic drugs. Coagulopathy of liver is appropriately managed with supplement of vitamin K. For poor feeding and failure to thrive, a gastrostomy tube may be required to maintain sufficient calorie intake. Certain food like cow’s milk is restricted as it contains phytanic acids. Other bile acids essential for liver functioning and DHA may be supplemented.

The prognosis is poor and usually do not survive beyond first year of their life. Most infants succumb to systemic complications of this disorder that include respiratory distress, infection, intractable epilepsy, gastrointestinal hemorrhage or liver failure. Parents and families can get some help from support groups.

In these forms, there are variable features and clinical picture may not be visible at birth but by early childhood or late infancy. Some clinical features noted may include low muscle tone or hypotonia, vision or hearing problems, delayed milestones, intellectual impairment to some extent and sometimes involvement of liver.

Most of these features may be present in severely affected children, but the progression of disease is usually slow. Occasionally, in some cases of the mildest form of this disorder, children may show delayed development but not have vision and hearing problems until adulthood.