The human perspective

Diseases that Result from Abnormal Peroxisomal Function

Gerald Karp <<CELL AND MOLECULAR BIOLOGY>> 4th Edition

Some facts about peroxisomes

Peroxisomes (microbodies) are simple, membranebound vesicle with a diameter of 0.1 to 1.0 um. Peroxisomes are multifunctional organelles, containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens.

These organelles were named peroxisomes because they are the site of synthesis and degradation of hydrogen peroxide (H2O2), a highly reactive and toxic oxidizing agent.

Plasmalogen: an unusual class of phopholipids in which one of the fatty acids is linked to glycerol by an ether linkage rather than an ester linkage Abundant in the Myelin sheaths that insulate axons in the brain

peroxisomal diseases
Genes mutation proteins involved in the uptaking Machinery for transport

Empty peroxisomes
Enzymes fail to be imported ZS

Zellweger syndrome

A single peroxisomal enzyme absence

VLCFAs accumulate in the brain

Defect in a membrane protein that transports VLCFAs

ALD

adrenoleukodystrophy

ZS: Zellweger syndrome VLCFAs: Very-long-chain fatty acids

ALD : adrenoleukodystrophy

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Adrenoleukodystrophy (ALD) is a rare, inherited metabolic disorder that afflicts the young boy Lorenzo Odone, whose story is told in the 1993 film "Lorenzo's oil." In this disease, the fatty covering (myelin sheath) on nerve fibers in the brain is lost, and the adrenal gland degenerates, leading to progressive neurological disability and death. People with ALD accumulate high levels of saturated, very long chain fatty acids in their brain and adrenal cortex because the fatty acids are not broken down by an enzyme in the normal manner. So, when the ALD gene was discovered in 1993, it was a surprise that the corresponding protein was in fact a member of a family of transporter proteins, not an enzyme. It is still a mystery as to how the transporter affects the function the fatty acid enzyme and, for that matter, how high levels of very long chain fatty acids cause the loss of myelin on nerve fibers. More recently, all the transporters related to ALD protein have been found in the yeast Saccharomyces cerevisiae, and a mouse model for the human disease has been developed. These and other molecular biology approaches should further our understanding of ALD and hasten our progress toward effective therapies

What is Zellweger Syndrome? Zellweger syndrome is a rare, congenital (present at birth) disorder characterized by the reduction or absence of peroxisomes (cell structures that rid the body of toxic substances) in the cells of the liver, kidneys, and brain. Zellweger syndrome is one of a group of genetic disorders called peroxisomal diseases that affect brain development and the growth of the myelin sheath, the fatty covering-which acts as an insulator-on nerve fibers in the brain. The most common features of Zellweger syndrome include an enlarged liver, high levels of iron and copper in the blood, and vision disturbances. Some affected infants may show prenatal growth failure. Symptoms at birth may include lack of muscle tone and an inability to move. Other symptoms may include unusual facial characteristics, mental retardation, seizures, and an inability to suck and/or swallow. Jaundice and gastrointestinal bleeding may also occur. Is there any treatment? 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. What is the prognosis? The prognosis for individuals with Zellweger syndrome is poor. Death usually occurs within 6 months after onset, and may be caused by respiratory distress, gastrointestinal bleeding, or liver failure. What research is being done? The NINDS supports research on genetic disorders including leukodystrophies such as Zellweger syndrome. The goals of this research are to increase scientific understanding of these disorders, and to find ways to prevent, treat, and cure them.