Zellweger spectrum disorders (ZSDs) are also named peroxisomal biogenesis disorders. These diseases have an influence on peroxisomes which are cell parts playing an essential role in multiple body functions.

The other Zellweger spectrum disorders are:

• Heimler syndrome which leads to hearing loss as well as tooth problems in late infancy and early childhood.
• Infantile Refsum disease which causes issues with muscle movements together with delays of child's development.
• Neonatal adrenoleukodystrophy leading to hearing and vision deterioration together with problems linked to brain, muscle and spine.

Zellweger syndrome (ZS) is a genetic disorder found in newborns. It is an autosomal recessive disorder meaning that the child can only inherit the disorder if both parents pass on a copy of the mutated gene. ZS is the most severe of the four diseases which contribute to the Zellweger spectrum and are often categorised as severe, intermediate or mild. It leads to serious issues linked to nerves and metabolism (switching food products into energy) just after the baby is born. Moreover, ZS affects vital organs including brain, liver and kidneys. It also has a devastating effect on the important functions throughout the body. Zellweger syndrome is also referred to as cerebrohepatorenal syndrome. The condition is typically fatal.

Zellweger syndrome (ZS) is extremely rare. Together with other diseases contributing to the Zellweger spectrum, they affect approximately 1 in 50,000 to 1 in 75,000 newborns.

Causes

A mutation in any of the 12 PEX genes is the cause of ZS. Majority of ZS cases occur because of mutation in the PEX1 gene. These genes are responsible for control of peroxisomes, which are required for normal cell functioning. Peroxisomes supervise destruction of toxins and fats. Therefore, there is an over-accumulation of long-chain fatty acids and phytanic acid together with defects of bile acids and plasmalogens which are specialised lipids located within cell membranes and myelin sheaths of nerve fibres. Moreover, they play a crucial role in the development of multiple structures such as bones, eyes, brain, heart, kidneys, liver and nerves.

Phytanic acid (3,7,11,15-tetramethyl hexadecanoic acid)

Phytanic acid is a branched chain fatty acid which can be obtained by consumption of dairy products, ruminant animal fats and certain fish. It is estimated that Western diets deliver approximately 50-100mg of phytanic acid per day. According to an Oxford study, individuals who ate meat had a 6.7-fold greater geometric mean plasma phytanic acid concentration contrary to vegans. As opposed to majority of fatty acids, phytanic acid is unable to be metabolized by β-oxidation. On the other hand, it undergoes α-oxidation within peroxisome where it is being changed into pristanic acid by elimination of one carbon. Pristanic acid can undergo multiple rounds of β-oxidation in order to create medium chain fatty acids which can be converted into carbon dioxide and water respectively.

Adult Refsum disease (an autosomal recessive neurological disorder caused by mutations within PHYH gene) show diminishing of α-oxidation activity which leads to accumulation of major stores of phytanic acid within blood and tissues. This commonly causes anosmia, hearing loss, retinitis pigmentosa, peripheral polyneuropathy as well as cerebellar ataxia.

With regards to ruminant animals the gut fermentation of plants causes phytol release which is a constituent of chlorophyll. Phytol is then converted into phytanic acid and deposited in fats.

Symptoms

ZS symptoms usually manifest soon after birth. Facial abnormalities related to ZS involve broad nose bridge, flattened face, high forehead, epicanthal folds (skin folds located at inner corners of the eyes), underdeveloped eyebrow ridge and wide-set eyes.

Additional features include problematic feeding, enlarged liver and/or spleen, hearing and vision issues, gastrointestinal bleeding, jaundice (yellow tint to the skin related to liver disfunction), seizures and underdevelopment of muscles and movement difficulty.

Diagnosis

Facial features of ZS are usually recognised straight after birth. The following tests can be done in order to confirm the diagnosis:

• Blood and urine tests - elevated levels of certain substances within blood or urine such as fat molecules.
• Imaging tests - An ultrasound is used to determine the side and liver function together with kidneys and other organs. Moreover, brain MRI is also performed during the diagnostic process.
• Genetic tests - Blood test can indicate existence of the mutated PEX genes.

Diagnosis prior birth

An unborn child is at risk of developing ZS if both parents carry mutated PEX genes. In such scenario blood tests together with imaging tests can be performed while baby is still in the womb.

Complications

It is prevalent that infants with Zellweger syndrome present hearing problems, visual or eating difficulties. In addition, those with severely underdeveloped muscles might be unable to initiate movement. Moreover, breathing problems, liver failure or digesting tract bleeding can occur.

Treatment

Unfortunately, there is no cure available for Zellweger syndrome. Since the metabolic as well as neurological anomalies causing the symptoms of ZS are present during foetal development, treatments intended for correction of such abnormalities after birth are limited.

Certain therapies could target and reduce severity of symptoms, yet there are no treatments that address the cause of ZS. A strict diet minimizing intake of beef, lamb, certain seafood and dairy products while maintaining carbohydrate intake is recommended in order to reduce phytanic acid from entering the blood from fat or liver stores. An adequate supportive therapy and training is important in order to improve the quality of life of these individuals.

Future research and hope

Future suggestions for research include a 24-hour monitoring system of phytanic acid and development of foods that does not increase phytanic acid in the blood. Theoretically this could be achieved if animals do not consume chlorophyll containing organisms but more research needs to be carried out.

Renald Blundell is a biochemist and biotechnologist with a special interest in Natural and Alternative Medicine. He is a professor at the Faculty of Medicine and Surgery,

University of Malta

Andrea Weronika Gieleta is a registered nurse and is currently a medical student at the

University of Malta