Peroxisomal Disorders

Definition

Peroxisomal disorders are a group of congenital (existing from birth) diseases characterized by the absence of normal peroxisomes in the cells of the body. Peroxisomes are special parts (organelles) within a cell that contain enzymes responsible for critical cellular processes, including oxidation of fatty acids, biosynthesis of membrane phospholipids (plasmalogens), cholesterol, and bile acids, conversion of amino acids into glucose, reduction of hydrogen peroxide by catalase, and prevention of excess synthesis of oxalate (which can form crystals with calcium, resulting in kidney stones ). Peroxisomal disorders are subdivided into two major categories. The first are disorders resulting from a failure to form intact, normal peroxisomes, resulting in multiple metabolic abnormalities, which are referred to as peroxisome biogenesis disorders (PBD) or as generalized peroxisomal disorders. The second category includes those disorders resulting from the deficiency of a single peroxisomal enzyme. There are about 25 peroxisomal disorders known, although the number of diseases that are considered to be separate, distinct peroxisomal disorders varies among researchers and health care practitioners.

Description

A cell can contain several hundred peroxisomes, which are round or oval bodies with diameters of about 0.5 micron, that contain proteins that function as enzymes in metabolic processes. By definition, a peroxisome must contain catalase, which is an enzyme that breaks down hydrogen peroxide.

Approximately 50 different biochemical reactions occur entirely or partially within a peroxisome. Some of the processes are anabolic, or constructive, resulting in the synthesis of essential biochemical compounds, including bile acids, cholesterol, plasmalogens, and docosahexanoic acid (DHA), which is a long chain fatty acid that is a component of complex lipids, including the membranes of the central nervous system. Other reactions are catabolic, or destructive, and lead to the destruction of some fatty acids, including very long chain fatty acids (VLCFAs, fatty acids with more than 22 carbon atoms in their chains), phytanic acid, pipecolic acid, and the prostoglandins. The peroxisome is involved in breaking down VLCFAs to lengths that the body can use or get rid of.

When VLCFAs accumulate due to abnormal functioning of the peroxisomes, they are disruptive to the structure and stability of certain cells, especially those associated with the central nervous system and the myelin sheath, which is the fatty covering of nerve fibers. The peroxisomal disorders that include effects on the growth of the myelin sheath are considered to be part of a group of genetic disorders referred to as leukodystrophies. While metachromatic leukodystrophy (MLD) usually has its onset in infants or juveniles, there have been reports of its onset in young adults.

There are many other metabolic deficiencies that can occur in those who have peroxisomal disorders, which result in other types of detrimental effects, and together result in the abnormalities associated with the peroxisomal disorders. Unfortunately, it is not known how these abnormalities, and combinations of abnormalities, cause the disabilities seen in those afflicted with the disease.

Peroxisomal disorders form a heterogeneous disease group, with different degrees of severity. Included in the group referred to as PBD are:

• Zellweger syndrome (ZS), which is usually fatal within the first year of life,
• neonatal adrenoleukodystrophy (NALD), which is usually fatal within the first 10 years,
• infantile Refsum disease (IRD), which is not as devastating as ZS and NALD, as the children with this disorder with time and patience can develop some degree of motor, cognitive, and communication skills, although death generally occurs during the second decade of life.
• rhizomelic chondrodysplasia punctata (RCDP), which in its most severe form is fatal within the first year or two of life. However, survival into the teens has been known to occur. It is characterized by shortening of the proximal limbs (i.e., the legs from knee to foot, and the arms from elbow to hand).
• Zellweger-like syndrome, which is fatal in infancy, and is known to be a defect of three particular enzymes.

The differences among these disorders are continuous, with overlap between abnormalities. The range of disease abnormalities may be a result of a corresponding range of peroxisome failure; that is, in severe cases of ZS, the failure is nearly complete, while in IRD, there is some degree of peroxisome activity.

In peroxisomal single-enzyme disorders, the peroxisome is intact and functioning, but there is a defect in only one enzymatic process, with only one corresponding biochemical abnormality. However, these disorders can be as severe as those in which peroxisomal activity is nearly or completely absent.

X-linked adrenoleukodystrophy (X-ALD) is the most common of the peroxisomal disorders, affecting about one in 20,000 males. It is estimated that there are about 1,400 people in the United States with the disorder. In X-ALD there is a deficiency in the enzyme that breaks down VLCFAs, which then accumulate in the myelin and adrenal glands. Onset of X-ALD-related neurological symptoms occurs at about five-12 years of age, with death occurring within one to 10 years after onset of symptoms. In addition to physical abnormalities seen in other types of peroxisomal disorders, common symptoms of X-ALD also include behavioral changes such as abnormal withdrawal or aggression, poor memory, dementia, and poor academic performance. Other symptoms are muscle weakness and difficulties with hearing, speech, and vision. As the disease progresses, muscle tone deteriorates, swallowing becomes difficult and the patient becomes comatose. Unless treated with a diet that includes Lorenzo's oil, the disease will result in paralysis, hearing loss, blindness, vegetative state, and death. There are also milder forms of X-ALD: an adult onset ALD that typically begins between the ages of 21 and 35, and a form that is occasionally seen in women who are carriers of the disorder. In addition to X-ALD, there are at least 10 other single-enzyme peroxisomal disorders, each with its own specific abnormalities.

Causes and symptoms

Most peroxisomal disorders are inherited autosomal recessive diseases, with X-ALD as an exception. They occur in all countries, among all races and ethnic groups. They are extremely rare, with frequencies reported at one in 30,000 to one in 150,000, although these numbers are only estimates.

In general, developmental delay, mental retardation, and vision and hearing impairment are common in those who have these disorders. Acquisition of speech appears to be especially difficult, and because of the reduced communication abilities, autism is common in those who live longer. Peroxisomal disorder patients have decreased muscle tone (hypotonia), which in the most severe cases is generalized, while in less severe cases, is usually restricted to the neck and trunk muscles. Sometimes this lack of control is only noticeable by a curved back in the sitting position. Head control and independent sitting is delayed, with most patients unable to walk independently.

Failure to thrive is a common characteristic of patients with peroxisomal disorder, along with an enlarged liver, abnormalities in liver enzyme function, and loss of fats in stools (steatorrhea).

Peroxisomal disorders are also associated with facial abnormalities, including high forehead, frontal bossing (swelling), small face, low set ears, and slanted eyes. These characteristics may not be prominent in some children, and are especially difficult to identify in an infant.

Diagnosis

Since hearing and vision deficiencies may be difficult to identify in infants, peroxisomal disorders are usually detected by observations of failure to thrive, hypotonia, mental retardation, widely open fontanel, abnormalities in liver enzymes, and an enlarged liver. If peroxisomal disorders are suspected, blood plasma assays for VLCFAs, phytanic acid, and pipecolic acid are conducted. Additional tests include plasmalogen biosynthesis potential.

Treatment

For many of the peroxisomal disorders, there is no standard course of treatment, with supportive treatment strategies focusing on alleviation of complications and symptoms. In general, most treatments that are attempted are dietary, whereby attempts are made to artificially correct biochemical abnormalities associated with the disorders. Therapies include supplementation of the diet with antioxidant vitamins, or limitation of intake of fatty acids, especially VLCFAs.

Another area of dietary therapy that is being investigated is the supplementation of the diet with pure DHA, given as early in life as possible, in conjunction with a normal well-balanced diet. Some results have indicated that if given soon enough during development, DHA therapy may prevent some of the devastating consequences of peroxisomal disorders, including brain damage and the loss of vision.

Other treatment strategies include addition of important missing chemicals. For example, in disorders where there is faulty adrenal function, replacement adrenal hormone therapy is used.

Any dietary changes should be monitored biochemically to determine if the supplements are having their desired effects and are not causing additional adverse effects.

Bone marrow transplants may be used to treat X-ALD, and can be effective if done early in the course of the childhood form of the disease.

Physical and psychological therapies are important for all types of peroxisomal disorders.

Alternative treatment

Patients with peroxisomal disorders, and particularly X-ALD, have been treated with a mixture of glycerol trioleate-glycerol trieucate (4:1 by volume), prepared from olive and rapeseed oils, and referred to as Lorenzo's oil (developed by parents of a son, Lorenzo, who had X-ALD, whose story was documented in the 1992 movie, Lorenzo's Oil ), to decrease the levels of VLCFA. Other diets that have been tried include dietary supplementation with plasmalogen precursors to increase plasmalogen levels and with cholic acid to normalize bile acids. However, there has been only limited success demonstrated with the use of these treatments. More research is needed to determine the long-term safety and effectiveness of these treatment strategies.

Prognosis

Peroxisomal disorders range from life-threatening to cases in which people may function with some degree of mental and motor retardation. As of 2001, there was not yet a cure. Enzyme replacement therapies, including enzyme infusion, transplantation, and gene therapy, may hold promise for future advances in the treatment of these disorders. Research is being conducted to increase scientific understanding of these disorders and to find ways to prevent, treat, and cure them.

Prevention

Unfortunately not enough is yet known about these diseases to develop comprehensive strategies for prevention. Genetic counseling is recommended for known or suspected carriers. As genes are identified that result in the disorders, genetic testing is being developed to identify carriers, who then can manage their reproduction to avoid the possibility of children being born with these deficiencies. As the genetic bases for the disorders are defined, prenatal diagnosis and identification of carriers will be facilitated. For example, for X-ALD, diagnosis can be made from cultured skin fibroblasts or amniotic fluid cells. This allows prenatal diagnosis and carrier identification in 90% of those affected. More recently it has been shown that biochemical diagnosis can be performed through chorionic villi biopsy, a procedure performed very early in the first trimester of pregnancy.

Animal models of ZS and X-ADL have been developed and are providing researchers with methods to define pathogenic mechanisms and to evaluate new therapies.

KEY TERMS

Autosomal recessive inheritance— Two copies of an altered gene located on one of the autosomes must be present for an individual to be affected with the trait or condition determined by that gene:

• an affected individual (homozygote) has two parents who are unaffected but each parent carries the altered gene (heterozygote).
• the risk of two heterozygotes, or carriers, having an affected child is 25%, one in four, for each child that they have; similarly, there is a three in four chance that each child will not be affected.
• males and females are at equal risk for being affected.
• two affected individuals usually produce children, all of whom are affected as well.

Autosome— A chromosome not involved in sex determination.

Fontanel— One of the membranous intervals between the uncompleted angles of the parietal and neighboring bones of a fetal or young skull; so called because it exhibits a rhythmical pulsation.

Metabolic— Relating to the chemical changes in living cells.

Organelle— Specialized structure within a cell, which is separated from the rest of the cell by a membrane composed of lipids and proteins, where chemical and metabolic functions take place.

Resources

PERIODICALS

Gallo, S., et al. "Late Onset MLD With Normal Nerve Conduction Associated With Two Novel Missense Mutations in the ASA Gene." Journal of Neurology, Neurosurgery, and Psychiatry April 2004: 655-658.

Martinez, Manuela. "The Fundamental and Practice of Docosahexanoic Acid Therapy in Peroxisomal Disorders." Current Opinion in Clinical Nutrition and Metabolic Care 3 (2000): 101-108.

Martinez, M., E. Vazquez, M. T. Garcia Silva, J. Manzanares, J. M. Bertran, F. Castello, and I. Mougan. "Therapeutic Effects of Docosahexanoic Acid in Patients with Generalized Peroxisomal Disorders." American Journal of Clinical Nutrition 71 (2000): 376s-385s.

Moser, Hugo W. "Molecular Genetics of Peroxisomal Disorders." Frontiers in Bioscience 5 (March 1, 2001): 298-306.

Raymond, G. V. "Peroxisomal Disorders." Current Opinion in Pediatrics 11 (December 1999): 572-576.

ORGANIZATIONS

National Institute of Neurological Disorders and Stroke, NIH Neurological Institute. P.O. Box 5801 Bethesda, MD 20824. (800) 352-9424. 〈http://www.ninds.nih.gov/index.htm〉.

National Organization for Rare Disorders. P.O. Box 8923, New Fairfield, CT 06812-8923.

OTHER

The Peroxisome Website. 〈http://www.peroxisome.org〉.

Peroxisomal disorders

Definition

Peroxisomal disorders are a group of congenital diseases characterized by the absence of normal peroxisomes in the cells of the body.

Description

Peroxisomes are organelles within a cell that contain enzymes responsible for critical cellular processes. A cell can contain several hundred peroxisomes, round or oval bodies with diameters of about 0.5 micron that contain proteins that function as enzymes in metabolic processes. By definition, a peroxisome must contain catalase, which is an enzyme that breaks down hydrogen peroxide.

Peroxisomal disorders are subdivided into two major categories: those disorders resulting from a failure to form intact, normal peroxisomes, resulting in multiple metabolical abnormalities, which are referred to as peroxisome biogenesis disorders (PBD) or generalized peroxisomal disorders; and those disorders resulting from the deficiency of a single peroxisomal enzyme. There are about 25 known peroxisomal disorders, although the number of diseases that are considered to be separate, distinct peroxisomal disorders varies among researchers and healthcare practitioners.

Approximately 50 different biochemical reactions occur entirely or partially within a peroxisome. Some of the processes are anabolic (constructive), resulting in the synthesis of essential biochemical compounds, including bile acids, cholesterol, plasmalogens, and docosahexanoic acid (DHA), which is a long chain fatty acid that is a component of complex lipids, including the membranes of the central nervous system. Other reactions are catabolic (destructive) and lead to the destruction of some fatty acids, including very long chain fatty acids (VLCFAs, fatty acids with more than 22 carbon atoms in their chains), phytanic acid, pipecolic acid, and the prostoglandins. The peroxisome is involved in breaking down VLCFAs to lengths that the body can use or get rid of.

When VLCFAs accumulate due to abnormal functioning of the peroxisomes, they are disruptive to the structure and stability of certain cells, especially those associated with the central nervous system and the myelin sheath, which is the fatty covering of nerve fibers. The peroxisomal disorders that include effects on the growth of the myelin sheath are considered to be part of a group of genetic disorders referred to as leukodystrophies.

Peroxisomal disorders form a heterogeneous disease group, with different degrees of severity. The differences among these disorders are continuous, with overlap between abnormalities. Examples of peroxisomal disorders are:

• X-linked adrenoleukodystrophy (X-ALD), a sex-linked disorder characterized by progressive symptoms that begin as behavioral changes, muscle weakness, and speech difficulties.
• Zellweger syndrome (ZS), which is usually fatal within the first year of life.
• Neonatal adrenoleukodystrophy (NALD), which is usually fatal within the first ten years.
• Infantile Refsum disease (IRD), which is not as devastating as ZS and NALD, as the children with this disorder with time and patience can develop some degree of motor, cognitive, and communication skills , although death generally occurs during the second decade of life.
• Rhizomelic chondrodysplasia punctata (RCDP), which in its most severe form is fatal within the first year or two of life; however, survival into the teens has been known to occur. It is characterized by shortening of the proximal limbs (i.e., the legs from knee to foot and the arms from elbow to hand).
• Zellweger-like syndrome, which is fatal in infancy and known to be a defect of three particular enzymes.

Transmission

Most peroxisomal disorders are inherited autosomal recessive diseases. This means that both parents need to be carriers of the defective gene in order for a child to develop the disease. If both parents are carriers but do not show signs of disease, each child has a 25 percent chance of having the disease. If one parent has the disease and the other is a carrier, each child has a 50 percent chance of having the disease. As a sex-linked genetic disorder, the daughters of males affected with X-ALD become carriers and the sons are not affected. The children of female carriers have a 50 percent chance of having the genetic mutation, which means that sons who inherit the mutation have the disease, and daughters who inherit the mutation are carriers.

Demographics

Peroxisomal disorders occur in all countries, among all races and ethnic groups. They are extremely rare, with frequencies reported at one in 30,000 to one in 150,000, although these numbers are only estimates. X-ALD is the most common of the peroxisomal disorders, affecting about one in 20,000 males. It is estimated that there are about 1,400 people in the United States with the disorder. ZS is estimated to affect one in 50,000 to 100,000 live births.

Causes and symptoms

The range of disease abnormalities may be a result of a corresponding range of peroxisome failure. For example, in severe cases of ZS, the failure is nearly complete, while in IRD, there is some degree of peroxisome activity. In peroxisomal single-enzyme disorders, the peroxisome is intact and functioning, but there is a defect in only one enzymatic process, with only one corresponding biochemical abnormality. These disorders, however, can be as severe as those in which peroxisomal activity is nearly or completely absent.

In general, developmental delay , mental retardation , and vision and hearing impairment are common in those who have these disorders. Acquisition of speech appears to be especially difficult, and because of the reduced communication abilities, autism is common in those who live longer. Peroxisomal disorder patients have decreased muscle tone (hypotonia ), which in the most severe cases is generalized, while in less severe cases, is usually restricted to the neck and trunk muscles. Sometimes this lack of control is only noticeable by a curved back in the sitting position. Head control and independent sitting is delayed, with most patients unable to walk independently.

Failure to thrive is a common characteristic of patients with peroxisomal disorder, along with an enlarged liver, abnormalities in liver enzyme function, and loss of fats in stools (steatorrhea). Peroxisomal disorders are also associated with facial abnormalities, including high forehead, frontal bossing (swelling), small face, low set ears, and slanted eyes. These characteristics may not be prominent in some children and are especially difficult to identify in an infant.

In X-ALD there is a deficiency in the enzyme that breaks down VLCFAs, which then accumulate in myelin and the adrenal glands. Onset of X-ALD-related neurological symptoms occurs at about five to 12 years of age, with death occurring within one to ten years after onset of symptoms. In addition to physical abnormalities seen in other types of peroxisomal disorders, common symptoms of X-ALD also include behavioral changes such as abnormal withdrawal or aggression, poor memory, dementia, and poor academic performance. Other symptoms are muscle weakness and difficulties with hearing, speech, and vision. As the disease progresses, muscle tone deteriorates, swallowing becomes difficult, and the patient becomes comatose. Unless treated with a diet that includes a mixture of oils called Lorenzo's oil, the disease will result in paralysis, hearing loss, blindness, vegetative state, and death. There are also milder forms of X-ALD, an adult onset ALD that typically begins between the ages of 21 and 35, and a form that is occasionally seen in women who are carriers of the disorder. In addition to X-ALD, there are at least ten other single-enzyme peroxisomal disorders, each with its own specific abnormalities.

When to call the doctor

A healthcare provider should be contacted if a child develops symptoms suggestive of peroxisomal disorder or if a child already diagnosed with a peroxisomal disorder shows signs of worsening disease.

Diagnosis

Since hearing and vision deficiencies may be difficult to identify in infants, peroxisomal disorders are usually detected by observations of failure to thrive, hypotonia, mental retardation, widely open fontanel, abnormalities in liver enzymes, and an enlarged liver. If peroxisomal disorders are suspected, blood plasma assays for VLCFAs, phytanic acid, and pipecolic acid are conducted. Additional tests include plasmalogen biosynthesis potential.

It is possible to diagnose peroxisomal disorders in utero. For example, for X-ALD, diagnosis can be made from cultured skin fibroblasts or amniotic fluid cells. This allows prenatal diagnosis and carrier identification in 90 percent of those affected. As of the early 2000s it has been shown that biochemical diagnosis can be performed through chorionic villus testing, a procedure performed very early in the first trimester of pregnancy.

Treatment

For many of the peroxisomal disorders, there is no standard course of treatment, with supportive treatment strategies focusing on alleviation of complications and symptoms. Bone marrow transplants may be effective for children with X-ALD if administered early in the course of the childhood form of the disease. Physical and psychological therapies are important for all types of peroxisomal disorders.

Alternative treatment

Patients with peroxisomal disorders, and particularly X-ALD, have been treated with a mixture of glycerol trioleate-glycerol trieucate (4:1 by volume), prepared from olive and rapeseed oils, and referred to as Lorenzo's oil (developed by the parents of a son, Lorenzo, who had X-ALD, whose story was documented in the 1992 movie, Lorenzo's Oil ), to decrease the levels of VLCFA. Other diets that have been tried with varying success include dietary supplementation with plasmalogen precursors to increase plasmalogen levels and with cholic acid to normalize bile acids.

Nutritional concerns

In general, most treatments that are attempted for peroxisomal disorders are dietary, whereby attempts are made to artificially correct biochemical abnormalities associated with the disorders. Therapies include supplementation of the diet with antioxidant vitamins or limitation of intake of fatty acids, especially VLCFAs.

Another area of dietary therapy that is being investigated is the supplementation of the diet with pure DHA, given as early in life as possible, in conjunction with a normal well-balanced diet. Some results have indicated that if given soon enough during development, DHA therapy may prevent some of the devastating consequences of peroxisomal disorders, including the loss of vision and brain damage.

Other treatment strategies include addition of important missing chemicals. For example, in disorders where there is faulty adrenal function, replacement adrenal hormone therapy is used.

Any dietary changes should be monitored biochemically to determine if the supplements are having their desired effects and are not causing additional adverse effects.

Prognosis

Peroxisomal disorders range from life-threatening to cases in which people may function with some degree of mental and motor delays. As of 2004, there was not yet a cure for peroxisomal disorders. Enzyme replacement therapies, including enzyme infusion, transplantation, and gene therapy, may hold promise for future advances in the treatment of these disorders. As of the early 2000s research is conducted in order to increase scientific understanding of these disorders and find ways to prevent, treat, and cure them.

Prevention

It is not possible to prevent the transmission of an abnormal peroxisomal gene from parent to child or spontaneous mutations that may arise.

Parental concerns

Numerous professional and parent-led organizations exist to support parents as they first learn of a peroxisomal disorder diagnosis and as they provide care for their child. Genetic counseling is recommended for known or suspected carriers. As genes are identified that result in the disorders, genetic testing is being developed to identify carriers, who then can manage their reproduction to avoid the possibility of children being born with these deficiencies.

KEY TERMS

Adrenal glands —A pair of endocrine glands (glands that secrete hormones directly into the bloodstream) that are located on top of the kidneys. The outer tissue of the glands (cortex) produces several steroid hormones, while the inner tissue (medulla) produces the hormones epinephrine (adrenaline) and norepinephrine.

Autosomal recessive mutation —A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Autosome —A chromosome not involved in sex determination.

Enzyme —A protein that catalyzes a biochemical reaction without changing its own structure or function.

Fontanelle —One of several "soft spots" on the skull where the developing bones of the skull have yet to fuse.

Organelle —A specialized structure within a cell, which is separated from the rest of the cell by a membrane composed of lipids and proteins, where chemical and metabolic functions take place.

Resources

BOOKS

Moser, Hugo W. "Disorders of Very Long Chain Fatty Acids: Peroxisomal Disorders." In Nelson Textbook of Pediatrics, 17th ed. Edited by Richard E Behrman et al. Philadelphia: Saunders, 2004.

PERIODICALS

Martinez, Manuela. "The Fundamental and Practice of Docosahexanoic Acid Therapy in Peroxisomal Disorders." Current Opinion in Clinical Nutrition and Metabolic Care 3 (2000): 101–8.

Martinez, M., et al. "Therapeutic Effects of Docosahexanoic Acid in Patients with Generalized Peroxisomal Disorders." American Journal of Clinical Nutrition 71 (2000): 376–85.

Moser, Hugo W. "Molecular Genetics of Peroxisomal Disorders." Frontiers in Bioscience 5 (March 1, 2001): 298–306.

Senior, Kathryn. "Lorenzo's Oil May Help to Prevent ALD Symptoms." The Lancet Neurology 1, no. 8 (December 2002): 468.

ORGANIZATIONS

The Myelin Project. 2136 Gallows Rd., Suite E, Dunn Loring, VA 22027. Web site: <www.myelin.org>.

United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. Web site: <www.ulf.org>.

WEB SITES

Chedrawi, Aziza, and Gary Clark. "Peroxisomal Disorders." eMedicine, April 28, 2002. Available online at <www.emedicine.com/neuro/topic309.htm> (accessed January 16, 2005).

Judith Sims Stephanie Dionne Sherk