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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.
How is Zellweger Syndrome Diagnosed?
The distinctive shape of the head and face of a child born with Zellweger Syndrome, 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.
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.
Some Symptoms of Zellweger Syndrome are:
- High forehead
- Large fontanelle (baby’s “soft spot”)
- Low-broad nasal bridge (the bridge across the nose)
- External ear deformities
- Redundant skin folds of the neck
- 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
- Severe hypotonia: decreased skeletal muscle tone, also called “floppiness”
- Poor sucking
- Epileptic seizures
- Impaired hearing
- 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 Zellweger Syndrome treated?
There is no cure for Zellweger syndrome, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. The prognosis for individuals with Zellweger syndrome is poor. Death usually occurs by 6 months of age, and may be caused by respiratory distress, gastrointestinal bleeding, or liver failure.
