NORD gratefully acknowledges Mousumi Bose, PhD, Medical/Scientific Liaison, Mid-Atlantic Regional Coordinator, The Global Foundation for Peroxisomal Disorders and Steven J. Steinberg, PhD, FACMG, Assistant Professor, Department of Neurology and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, for the preparation of this report.
The symptoms of Zellweger spectrum disorders vary greatly from one individual to another. The specific number and severity of symptoms present in an individual are highly variable and affected infants will not have all of the symptoms discussed below. The most severe form, Zellweger syndrome, is usually noticeable shortly after birth. Infants with Zellweger syndrome often have severe neurological deficits, progressive dysfunction of the liver and kidneys and usually develop life-threatening complications during the first year of life.
Children with neonatal adrenoleukodystrophy and infantile Refsum disease may not develop symptoms until later during infancy. Some of these children reach adolescence or adulthood although most have some degree of intellectual disability, hearing loss and vision problems. Some have profound loss of muscle tone (hypotonia or floppiness), but some learn to walk and to speak. Some children with these milder forms of Zellweger spectrum disorders do not have any craniofacial abnormalities or only very mild ones.
In extremely rare cases, affected individuals have gone undetected until adulthood. These individuals have had only mild symptoms such as adult-onset hearing loss or vision problems and/or mild developmental delays.
Many symptoms of Zellweger spectrum disorders are present at birth (congenital). Affected infants often exhibit prenatal growth failure in spite of a normal period of gestation and may also have a profound lack of muscle tone (hypotonia or floppiness). Affected infants may be limp, show little movement (lethargic) and poorly respond to environmental stimuli. Infants may be unable to suck and/or swallow leading to feeding difficulties and failure to gain weight and grow as expected (failure to thrive).
Infants also develop a variety of neurological complications including frequent seizures, poor or absent reflexes, intellectual disability, and delays in reaching developmental milestones such as sitting, crawling or walking (developmental delays). Affected infants have various brain abnormalities including defects caused by the abnormal migration of brain cells (neurons). Neurons are created in the center of the developing brain and must travel to other areas of the brain to function properly. In individuals with Zellweger spectrum disorders the neurons fail to migrate properly resulting in a variety of brain abnormalities (neuronal migration defects). Some affected infants also develop progressive degeneration of the nerve fibers (white matter) of the brain (leukodystrophy).
Infants may have distinctive facial features including a flattened appearance to the face, a high forehead, abnormally large “soft spots” (fontanelles) on the skull, broad bridge of the nose, a small nose with upturned nostrils (anteverted nares), an abnormally small jaw (micrognathia), a highly arched roof of the mouth (palate), a small chin, extra (redundant) folds of skin on the neck, and minor malformation of the outer part of the ears. The bony ridges of the eye socket may be abnormally shallow and the back of the head may be abnormally flat (flat occiput).
A variety of eye abnormalities may occur including eyes that are spaced widely apart (hypertelorism), clouding of the lenses of the eyes (cataracts) or the clear (transparent) outer layer of the eye (corneal opacities), degeneration of the nerve that carries visual images from the eye to the brain (optic atrophy), and rapid, involuntary eye movements (nystagmus). Many infants with Zellweger spectrum disorders develop degeneration of the retina, which is the thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to the brain through the optic nerve. Glaucoma, a condition characterized by increased pressure within the eye causing a distinctive pattern of visual impairment, may also occur. The various eye abnormalities associated with Zellweger spectrum disorders can cause loss of vision to varying degrees. In addition to vision loss, infants with Zellweger spectrum disorders also experience hearing loss with onset during the first few months of life.
Some infants may have an abnormally large spleen (splenomegaly) and/or liver (hepatomegaly). The liver may also be scarred (fibrotic) and inflamed (cirrhosis), with progressive loss of function resulting in a variety of symptoms such as yellowing of the skin and whites of the eyes (jaundice). Additional findings include small cysts on the kidneys and gastrointestinal bleeding due to deficiency of a coagulation factor in the blood. Some children may develop episodes of exaggerated or uncontrolled bleeding (hemorrhaging) including bleeding within the skull (intracranial bleeding). Eventually, liver failure may occur.
Minor skeletal abnormalities may also be present in Zellweger spectrum disorders including clubfoot, fingers that are fixed or stuck in a bent position and cannot extend or straighten fully (camptodactyly), and chondrodysplasia punctata, a condition characterized by the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs.
Certain heart defects may also occur in infants with Zellweger spectrum disorders including septal defects and patent ductus arteriosus. Septal defects are “holes” in the heart, specifically holes in the thin partition (septum) that separates the chambers of the heart. Small septal defects may close on their own; larger defects may cause various symptoms including breathing irregularities and high blood pressure. Patent ductus arteriosus is a condition in which the two large arteries of the body (aorta and pulmonary artery) remain connected by a small blood vessel (ductus arteriosus) that is supposed to close after birth.
Due to the lack of muscle tone, laryngomalacia (floppy airway) and other respiratory problems may occur in infants with Zellweger spectrum disorders. Respiratory support may entail the use of a nasal cannula for oxygen to more aggressive forms of support as the disease progresses.
In some males infants with Zellweger spectrum disorders, additional symptoms may occur including the abnormal placement of the urinary opening on the underside of the penis (hypospadias) and failure of the testes to descend into the scrotum (cryptorchidism).
Zellweger spectrum disorders develop due to changes (mutations) of one of 13 different genes involved in the creation and proper function of peroxisomes (peroxisome biogenesis). These mutations are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that are involved in numerous chemical processes required for the proper function of the body. Peroxisomes are found in nearly every cell type of the body, but are larger and more numerous in the kidney and liver. Some cells contain less than one hundred peroxisomes; others may contain more than a thousand. Some processes for which peroxisomes are vital include the proper breakdown (metabolism) of fatty acids and the production of certain lipids important to the nervous system (plasmalogens) or digestion (bile acids). Peroxisomes are essential parts of the body’s waste disposal system and help ensure the proper development and function of the brain and central nervous system. Defective peroxisomes can cause numerous problems in the body. For example, since affected individuals lack sufficient levels of the enzymes normally produced by peroxisomes, very long chain fatty acids (VLCFA) accumulate in the cells of the affected organ.
Mutation of any one of 13 different genes involved in the proper creation or function of peroxisomes can result in the development of one of the Zellweger spectrum disorders. These thirteen genes contain instructions for creating (encoding) proteins known as peroxins that are essential for the proper development of peroxisomes. Approximately 68 percent of individuals with a Zellweger spectrum disorder have a mutation in the peroxisome biogenesis factor 1 (PEX1) gene located on the long arm of chromosome 7 (7q21-22).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 7q21-q22″ refers to band 21-22 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The other genes that cause Zellweger spectrum disorders are PEX2, PEX3, PEX5, PEX6, PEX10, PEX11, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26.
Zellweger spectrum disorders are usually apparent at birth. They affect individuals of all ethnic groups. In the United States, the combined incidence of these disorders is at least 1 in 50,000 live births. Because some cases go undiagnosed, determining these disorders true frequency in the general population is difficult.
A Zellweger spectrum disorders diagnosis is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Zellweger spectrum disorders can be diagnosed by showing peroxisome abnormalities that can be monitored in body fluids. The primary step in Zellweger spectrum disorders diagnosis involves the detection of elevated very long chain fatty acids. Additional tests on blood and urine samples to detect other substances associated with peroxisome metabolism may be performed. Biochemical testing of skin fibroblasts is useful to confirm the abnormalities seen in the blood and urine and clarify questionable results in body fluids.
Genetic testing is available for Zellweger spectrum disorders; next generation sequencing methods (sequencing millions of small fragments of DNA at the same time) are being used more frequently as a confirmatory test, and may be required for peroxisome disorders that are difficult to determine by traditional biochemical methods. Additionally, genetic determination of mutations in Zellweger spectrum disorders, in contrast to biochemical tests, will also identify carriers for Zellweger spectrum disorders, which will allow reliable genetic counseling of families and may also assist with eligibility for future clinical trials.
Methods have been developed to detect elevated levels of very long chain fatty acids in newborn screening for X-linked adrenoleukodystrophy, a related peroxisomal disorder. Legislation for X-linked adrenoleukodystrophy newborn screening has passed in many states and screening has begun in New York; continued legislative efforts are expected to expand through movements initiated by patient families and advocacy organizations to lobby their state legislatures. Recently, the Department of Health and Human Services Advisory Committee for Heritable Disorders for Newborns and Children voted to propose the addition of X-linked adrenoleukodystrophy screening in the Recommend Uniform Screening Panel. Newborn screening for X-linked adrenoleukodystrophy should increase early diagnosis of Zellweger spectrum disorders and determination of accurate incidence estimates of the disease.
Certain tests (biochemical or genetic) can be performed prenatally in the first or second trimester using chorionic villus sampling or amniocentesis. Ultrasonography, a test that uses reflected sound waves to create a picture of internal organs, may be used to detect cysts on the kidneys or an enlarged liver. Preimplantation genetic diagnosis with in vitro fertilization can also be performed when the gene mutations are known.
In 2015, Cholbam (cholic acid) was approved as the first treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for patients with peroxisomal disorders (including Zellweger spectrum disorders). Cholbam is marketed by Retrophin, Inc.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, endocrinologists, surgeons, specialists who assess and treat hearing problems (audiologists), specialists who assess and treat vision problems (ophthalmologists), specialists who assess and treat skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Children with Zellweger spectrum disorders may require a feeding (gastrostomy) tube to ensure proper intake of calories. A gastrostomy tube is inserted directly into the stomach. Additional therapies that may be used to treat Zellweger spectrum disorders include hearing aids, cochlear implants, fat-soluble vitamin supplementation (particularly vitamin K to treat bleeding complications due to clotting defects), surgery to treat cataracts, and glasses to improve vision.
Anti-epileptic drugs may be used to treat seizures, but seizures may persist and be difficult to control despite such therapy.
Adrenal insufficiency occurs frequently in more intermediate forms of Zellweger spectrum disorders. It is recommended that yearly adrenal monitoring with adrenocorticotropic hormone (ACTH) and morning cortisol be performed. Treatment with adrenal replacement (Cortef) using standard dosing should be implemented if abnormal. Even if adrenal measurements appear normal, families and clinicians should be aware of the possibility of adrenal insufficiency and consider stress dosing in periods of sudden severe illness, fever, and major surgical procedures.
Progressive decreased bone mineral density has been associated with Zellweger spectrum disorders and pathologic fractures have occurred in patients. Therefore, evaluation for bone disease should be considered. Additionally, many children with Zellweger spectrum disorders have enamel abnormalities of permanent teeth and should receive appropriate dental care.
Early intervention is important in treating children with Zellweger spectrum disorders. Services that may be beneficial may include special education, physical and orthopedic therapy, special services for children with hearing, and other medical, social, and/or vocational services.
Genetic counseling may be of benefit and is often required in prenatal testing for families of affected individuals. Other treatment is symptomatic and supportive.
A variety of therapies have been investigated to treat individuals with Zellweger spectrum disorders including specific dietary modifications or regimens such as a diet low in phytanic acid. Specific dietary modifications have had limited effect on individuals with Zellweger spectrum disorders.
Primary bile acid therapy has been used to improve liver function and sodium-4-phenylbutyrate and other pharmacologic agents have been studied.
Some researchers have studied the use of docosahexaenoic acid (DHA), a compound important in the proper function of the brain and retina. DHA is low in individuals with Zellweger spectrum disorders. More research is necessary to determine the long-term safety and effectiveness of this potential therapy for individuals with Zellweger spectrum disorders.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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