Zellweger spectrum disorder is a condition that affects many parts of the body. Cases of Zellweger spectrum disorder are often categorizes as severe, intermediate, or mild.

Individuals with severe Zellweger spectrum disorder usually have signs and symptoms at birth, which worsen over time. These infants experience weak muscle tone (hypotonia), feeding problems, hearing and vision loss, and seizures. These problems are caused by reduced myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is called white matter. Reduced myelin (demyelination) leads to loss of white matter (leukodystrophy).

Children with severe Zellweger spectrum disorder also develop life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys, and their liver or spleen may be enlarged. They may have skeletal abnormalities, including a large space between the bones of the skull (fontanelles) and characteristic bone spots known as chondrodysplasia punctata that can be seen on x-ray. Affected individuals can have eye abnormalities, including clouding of the lenses of the eyes (cataracts) or involuntary, side-to-side movements of the eyes (nystagmus). Severe Zellweger spectrum disorder involves distinctive facial features, including a flattened face, broad nasal bridge, high forehead, and widely spaced eyes (hypertelorism). Children with severe Zellweger spectrum disorder typically do not survive beyond the first year of life.

People with intermediate or mild Zellweger spectrum disorder have more variable features that progress more slowly than those with the severe form. Affected children usually do not develop signs and symptoms of the disease until late infancy or early childhood. Children with these intermediate and mild forms often have hypotonia, vision problems, hearing loss, liver dysfunction, developmental delay, and some degree of intellectual disability. Most people with the intermediate form survive into childhood, and those with the mild form may reach adulthood. In rare cases, individuals at the mildest end of the condition spectrum have developmental delay in childhood and hearing loss or vision problems beginning in adulthood and do not develop the other features of this disorder.

The severe, intermediate, and mild forms of Zellweger spectrum disorder were once thought to be distinct disorders. The severe form was known as Zellweger syndrome, the intermediate form was neonatal adrenoleukodystrophy (NALD), and the mild form was infantile Refsum disease. These conditions were renamed as a single condition when they were found to be part of the same condition spectrum.

Infantile Refsum disease (IRD) is the mildest of a group of disorders known as peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS). PBD-ZSS is a group of inherited genetic disorders that damage the white matter of the brain and affect motor movements. Peroxisome biogenesis disorders, in turn, are part of a larger group of disorders called leukodystrophies.

IRD can cause low muscle tone (hypotonia), retinitis pigmentosa (a visual impairment that can lead to blindness), developmental delay, sensorineural hearing loss, and liver dysfunction. IRD usually presents at birth or in infancy. Most individuals with IRD can achieve motor milestones, though they may be delayed, and most individuals can communicate with a few words or signs. Leukodystrophy with loss of acquired skills can occur at any age and may stabilize or progress. Peroxisome biogenesis disorders are caused by genetic changes in one of the PEX genes and are inherited in an autosomal recessive manner.

Adult Refsum disease and infantile refsum disease are separate disorders caused by different genetic defects.

Variants (also called mutations) in at least 12 genes have been found to cause Zellweger spectrum disorder. These genes provide instructions for making a group of proteins known as peroxins, which are essential for the formation and normal functioning of cell structures called peroxisomes. Peroxisomes are sac-like compartments that contain enzymes needed to break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production of fats (lipids) used in digestion and in the nervous system. Peroxins assist in the formation (biogenesis) of peroxisomes by producing the membrane that separates the peroxisome from the rest of the cell and by importing enzymes into the peroxisome.

Variants in the genes that cause Zellweger spectrum disorder prevent peroxisomes from forming normally. Diseases that disrupt the formation of peroxisomes, including Zellweger spectrum disorder, are called peroxisome biogenesis disorders. If the production of peroxisomes is altered, these structures cannot perform their usual functions. The signs and symptoms of severe Zellweger spectrum disorder are due to the absence of functional peroxisomes within cells. Intermediate and mild Zellweger spectrum disorder are caused by variants that allow some peroxisomes to form.

Variants in the PEX1 gene are the most common cause of Zellweger spectrum disorder and are found in nearly 70 percent of affected individuals. The other genes associated with Zellweger spectrum disorder each account for a smaller percentage of cases of this condition.

Normal Function

The PEX1 gene provides instructions for making a protein called peroxisomal biogenesis factor 1 (Pex1p), which is part of a group of proteins called peroxins. Peroxins are essential for the formation and normal functioning of cell structures called peroxisomes. Peroxisomes are sac-like compartments that contain enzymes needed to break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production of fats (lipids) used in digestion and in the nervous system. Peroxins assist in the formation (biogenesis) of peroxisomes by producing the membrane that separates the peroxisome from the rest of the cell and by importing enzymes into the peroxisome. Pex1p enables other peroxins to bring enzymes into the peroxisome.

Health Conditions Related to Genetic Changes

Zellweger spectrum disorder

At least 114 mutations in the PEX1 gene have been identified in people with Zellweger spectrum disorder, which is a group of conditions that have overlapping signs and symptoms and affect many parts of the body. The conditions' features, which vary in severity, can include weak muscle tone (hypotonia), developmental delay, and vision and hearing problems. Mutations in the PEX1 gene are the most common cause of Zellweger spectrum disorder and are found in nearly 70 percent of affected individuals.

There are two common PEX1 gene mutations found in people with Zellweger spectrum disorder. One mutation replaces the protein building block (amino acid) glycine with the amino acid aspartic acid at position 843 in Pex1p (written as Gly843Asp or G843D). This mutation leads to reduced levels of the protein. Individuals who have the G843D mutation tend to have signs and symptoms that are at the less-severe end of the condition spectrum. The other common mutation, which is known as the 1700fs mutation, leads to the production of an abnormally short, nonfunctional Pex1p. People who have the 1700fs mutation often have signs and symptoms that are at the severe end of the condition spectrum.

Mutations in the PEX1 gene that cause Zellweger spectrum disorder reduce or eliminate the activity of the Pex1p protein. Without enough functional Pex1p, enzymes are not properly imported into peroxisomes. As a result, cells contain empty peroxisomes that cannot carry out their usual functions. The severe end of the condition spectrum is caused by the absence of functional peroxisomes within cells. The less severe end of the condition spectrum results from mutations that allow some peroxisomes to form.

Other Names for This Gene

• peroxin1
• peroxisome biogenesis disorder protein 1
• PEX1_HUMAN
• Pex1p
• ZWS1

Genomic Location

ZSD is a genetic condition. Babies inherit it from their biological (birth) parents.

• ZSD is an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene to their baby. Only babies with two matching nonworking genes—for example, one nonworking PEX1 from the mom and one nonworking PEX1 from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking PEX1 from the mom and one nonworking PEX2 from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the gene, they have a 1 in 4 chance of having a child with ZSD.
  • Carriers for ZSD often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with ZSD.
  • Parents who already have a child with ZSD still have a 1 in 4 chance of having another child with ZSD. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs and symptoms of ZSD can occur right away at birth or a little later in infancy.

Signs of the condition in severe ZSD may include the following:

• Floppy arms and legs (hypotonia)
• Feeding problems
• Hearing loss
• Vision loss
• Seizures
• Facial features that are different from their parents

Signs of the condition in intermediate or mild ZSD may include the following:

• Developmental delay
• Growing slowly or gaining weight slowly (failure to thrive)
• Hearing loss
• Vision problems
• Liver problems
• Problems with coordination and balance (ataxia)

Newborn screening for ZSD requires collecting a small amount of blood from your baby’s heel. Screening measures the level of a type of fat called “very long chain fatty acids” in your baby’s blood. Babies with high levels of these substances might have ZSD. Newborn screening cannot tell what type of ZSD a baby has.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for ZSD is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood tests
• Urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems right away if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. Babies with other conditions that have high levels of very long chain fatty acids may also be detected through this screening. An example of another condition that may be detected is X-linked adrenoleukodystrophy.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. While there are no treatment options available that can stop the progression of ZSD, there are treatments for symptoms of ZSD.

Treatments may include the following:

• Vitamin supplements
• Medications
• Correction of hearing and vision problems
• Surgery

Zellweger spectrum disorder is estimated to occur in 1 in 50,000 individuals.