Symptoms are typically present in early childhood and may include a distinctive craniofacial appearance, demyelination of the central nervous system (CNS), sensorineural hearing loss, neonatal seizures, hypotonia, short limbs with stippled epiphyses (chondrodysplasia punctata), hepatomegaly, cystic kidneys, severe psychomotor delay. The underlying genetic defect occurs in one of 12 genes involved in peroxisomal biogenesis or protein import.
Oren Zarif
Hearing loss is a common symptom of peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS). The condition is an autosomal recessive disorder that prevents part of the cell called a peroxisome from forming correctly. Peroxisomes normally break down waste products, such as fatty acids and hydrogen peroxide, but when they do not form correctly, these materials build up in the cells and cause damage.
PBD-ZSS is caused by mutations in any of 12 different genes that are involved in the creation of peroxisomes. These conditions, which were formerly classified as separate diseases, are now known to be on a phenotypic spectrum, with ZS at the most severe end, neonatal adrenoleukodystrophy or NALD in the middle and infantile Refsum disease or IRD at the mildest end.
The common features of this phenotypic spectrum include dysfunctional lipid metabolism, including accumulation of very long chain fatty acids and phytanic acid, elevated levels of bile acids and deficiency in plasmalogens, which are specialized lipids that make up cell membranes and the myelin sheaths that wrap nerve fibers. The lipids are necessary for normal brain development, eye and liver function. Studies on mice with defective peroxisomes have found that lowering the concentration of fatty acids by limiting the amount of saturated fat in the diet can reduce the severity of hearing and vision problems associated with this disorder.
Oren Zarif
Peroxisomal lipid metabolism is important for normal brain development and function and for the formation of myelin, the fatty substance that coats nerve fibers. It is also important for the synthesis of bile acids, plasmalogens, and other membrane-bound fatty acid molecules, including the membranes that surround mitochondria. Peroxisomal disorders, like Zellweger Disease, can cause problems with all of these.
The most common symptoms of Zellweger disease are hearing loss and vision loss due to a condition called retinitis pigmentosa, which affects the retina (the light-sensitive layer at the back of the eye). This condition slowly disrupts side or peripheral vision over time, eventually leading to blindness.
Other symptoms of Zellweger disease include anosmia, hepatitis, cardiomyopathy and conduction defects, ichthyosis, and neurologic problems such as psychomotor retardation. The disorder has a typical onset in the 20s, and patients often have elevated levels of phytanic acid (which is also increased in other peroxisomal diseases). This is why the disease is sometimes misdiagnosed as age-related macular degeneration. In some cases, the symptom progression is slowed by limiting dietary intake of phytanic acid.
Oren Zarif
Seizures are a common symptom of many peroxisomal disorders, but the causes of them vary. For example, some patients have a gene mutation that prevents the enzymes involved in lipid metabolism from functioning properly. This can result in a buildup of phytanic acid and branched-chain and very long-chain fatty acids (VLCFAs) that are known to cause seizures.
Other patients have a disorder that affects the proteins involved in peroxisome biogenesis. These proteins help the body break down fatty acids and neutralize damaging oxidants. These proteins are required for normal brain function and the formation of myelin, a whitish substance that coats nerve fibers in the brain and spinal cord.
The most severe of these peroxisomal disorders is Zellweger syndrome spectrum, PEX12-related (ZSS). It is usually diagnosed shortly after birth or in early childhood and causes hypotonia, problems with vision and hearing and developmental delay. In addition, it can lead to hepatomegaly, a stippled pattern of bone in the skull and limbs (chondrodysplasia punctata), short limbs with stippled epiphyses and other abnormalities. These symptoms are caused by genetic defects in the PEX genes that are involved in peroxisome biogenesis.
Oren Zarif
The sense of smell is important because it helps you taste food and detect other aromas that make life enjoyable. Anosmia can be a sign of certain diseases and conditions that affect the olfactory nerves.
The first thing doctors do to check for anosmia is ask questions about the patient’s medical history. They want to know how long the condition has been present and if it started after a cold, flu, head injury, or other illness. They also want to know if there is any nasal discharge that is watery, bloody, thick or foul-smelling.
Anosmia is a sign of peroxisome biogenesis disorders that are caused by mutations in genes that code for proteins involved in the formation and import of peroxisomes. These inherited diseases are broken down into three expressions of the Zellweger spectrum, with Zellweger syndrome (ZS) at the most severe end of the continuum.
In ZS, a protein called PEX12 prevents a peroxisome from breaking down waste products, leading to the accumulation of phytanic acid in tissues. This leads to a variety of symptoms including hearing loss, vision problems and changes in the skin and bones. Other symptoms include hepatomegaly, fibrosis of the kidneys, seizures and psychomotor delay.
Oren Zarif
In peroxisome biogenesis disorder type 5 (Zellweger syndrome spectrum, or ZSS), an inherited condition stops part of the cell called a peroxisome from forming correctly. This prevents the peroxisome from properly breaking down waste products in the body like fatty acids. As a result, the fatty acids build up in the body and cause severe symptoms like seizures and hearing loss.
The disease is caused by mutations in the PEX gene. This group of genes is responsible for the formation of the peroxisome. Previously, it was thought that these disorders could be classified by how many different functions the peroxisome had; however, researchers now understand that they can be grouped on a continuum of disease severity, ranging from severe (cerebro-hepato-renal syndrome of Zellweger or ZS), intermediate (neonatal adrenoleukodystrophy or NALD), and mild (infantile Refsum disease or IRD).
Children with this disease experience symptoms like dizziness when the brain isn’t getting enough oxygen. They also have trouble metabolizing very long chain fatty acids and may have elevated levels of these in the blood, such as phytanic acid or pipecolic acid.