The Zellweger Spectrum

Zellweger Syndrome, Neonatal Adrenoleukodystrophy (NALD), and Infantile Refsum’s Disease (IRD)

The disorders of the Zellweger spectrum result from defects in the assembly of a cellular structure called the peroxisome, and are therefore also sometimes called the peroxisome biogenesis disorders, or PBDs. There are three disorders considered to be part of the Zellweger spectrum: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). While these disorders all share a similar cause, they reflect varying degrees of severity of disease.

What causes the Zellweger spectrum of diseases?

As we mentioned, disorders of the Zellweger spectrum are caused by defects in the assembly of the peroxisome. There are at least 12 genes required for proper assembly of the peroxisome. Defects in any of these 12 genes result in disorders of the Zellweger Spectrum.

This peroxisome is one of four special compartments within all human cells. These individual compartments are separated from the rest of the cell by a membrane (a “wall” made up of fats and proteins). The peroxisome performs a number of important jobs within the cell that are needed to break down certain types of fats, to produce hormones, and to help the nervous system work properly. In order for it to properly do its job, the peroxisome must be correctly assembled.  If it is not, then it results in one of the diseases of the Zellweger spectrum.

What are the clinical symptoms of the Zellweger spectrum of diseases?

The disorders of the Zellweger spectrum are congenital (present at birth). Patients with Zellweger syndrome have consistent clinical characteristics, listed below along with a clarification of the clinical terms as necessary. The exact number and combination of clinical characteristics is highly variable. In general, many of the major systems are affected, including the eye (many vision difficulties), the liver (enlarged), the kidney, the cartilage, the heart (malformation of the cardiovascular system), and the muscles.

Symptoms of the Zellweger spectrum of disease include:

  • High forehead
  • Flat occiput: The occiput is the bone forming the back of the skull, and encloses the hole where the spinal cord reaches the brain
  • Large fontanelle (baby’s “soft spot)
  • Shallow orbital ridge (bony ridge beneath the eyebrow)
  • Low-broad nasal bridge (the bridge across the nose)
  • Epicanthus a fold of skin that comes in across the inner angle of the eye, common in children with birth defects such as Down syndrome
  • High arched palate (roof of the mouth)
  • External ear deformities
  • Micrognathia: small chin
  • Redundant skin folds of the neck
  • Brushfield spots: speckled iris, though this can also occur in children without birth defects.
  • Cataract/cloudy cornea: a cataract is a clouding over the lens of the eye which impairs norma lvision
  • Glaucoma: an eye condition in which the fluid pressure inside the eyes is high, may damage the eye, leading to vision loss
  • abnormal retinal pigmentation
  • optic disk pallor
  • Severe hypotonia: decreased skeletal muscle tone, also called “floppiness”
  • Abnormal Moro response: The Moro response is a normal reflex for an infant when he or she is startled or feels like they are falling. The infant will have a “startled” look and the arms will fling out sideways with the palms up and the thumbs flexed.:
  • Hyporeflexia: slow reflexes
  • Poor sucking
  • Gavage feeding (feeding by a tube)
  • Epileptic seizures
  • Psychomotor retardation
  • Impaired hearing
  • Nystagmus: rapid rhythmimc repetitious involuntary eye movements
  • Hepatomegaly: enlarged liver

What are the differences between ZS, NALD, and IRD?

The difference between these disorders is one of severity. Patients with ZS rarely survive the first year, patients with NALD can live into childhood, while patients with IRD can survive even longer; sometimes into adulthood.

At a genetic level, the severity of the disease depends on the severity of the defect in the protein. Patients with IRD have a lesser defect, resulting in peroxisomes retaining some function. However, patients with ZS have a severe defect, resulting in essentially nonfunctional peroxisomes. This phenomenon produces the range of severity of the disorders.

  

How is the Zellweger Spectrum Diagnosed?

The distinctive shape of the head and face of a child born with one of the diseases of the Zellweger spectrum, in conjunction with other clinical signs and symptoms, will be used to suggest a diagnosis. In addition, Zellweger syndrome causes the build-up of very-long-chain fatty acids (VLCFA). Therefore, a blood test for elevated levels of these VLCFA will be used to confirm the diagnosis.

Much work has been done to identify the genetic basis of the peroxisomal biogenesis disorders; as a result, genetic counseling can be of benefit to families of patients with this disorder. These diseases are inherited in an autosomal recessive manner (see our fact sheet on genetic inheritance for more information about what this means). Briefly, this means that both you and your partner must be carriers of the disease in order to have an affected child. If someone in your family has one of these diseases, you and your partner may be able to be screened for the disease in order to determine the likelihood of this occurring, which can allow you to make an informed decision about having children.

How are the diseases of the Zellweger Spectrum treated?

Treatment of Zellweger syndrome is primarily symptomatic and supportive. Infections should be guarded against carefully to delay complications, and Vitamin K may be needed to avoid abnormal bleeding.

Experimental therapies with docosahexaenoic acid (DHA) are being studied. DHA is an essential fatty acid, which is deficient in patients with Zellweger syndrome. Improvement has been reported in some patients. Another approach being tested is the administration of bile acids, such as cholic acid or chenodeoxycholic acid, which may be of help in respect to liver function. 

Are there other names for diseases of the Zellweger Spectrum?

The other name for this general group of diseases is the peroxisome biogenesis disorders, or PBDs