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40 years!
Last updated:
August 18, 2020
Years published: 1987, 1990, 1998, 2005, 2008, 2016, 2020
NORD gratefully acknowledges Mousumi Bose, PhD, Assistant Professor, Montclair State University; Scientific Advisory Board Member, 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.
Summary
Zellweger spectrum disorders (ZSD) are a group of rare, genetic, multisystem disorders that were once thought to be separate entities. These disorders are now classified as different expressions (variants) of one disease process due to their shared biochemical basis. Collectively, they form a spectrum or continuum of disease. The most severe form of these disorders was previously referred to as Zellweger syndrome, the intermediate form was referred to as neonatal adrenoleukodystrophy, and the milder forms were referred to as infantile Refsum disease or Heimler syndrome, depending on the clinical presentation. ZSD can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. ZSD often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. ZSD are inherited in an autosomal recessive pattern.
Introduction
ZSD are also known as peroxisome biogenesis disorders (PBDs) – a group of disorders characterized by the failure of the body to produce peroxisomes that function properly. Peroxisomes are very small, membrane-bound structures within the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. PBDs are subdivided into ZSD and rhizomelic chondrodysplasia punctata.
Zellweger syndrome was described in the medical literature in 1964 by Dr. Hans Zellweger. Neonatal adrenoleukodystrophy, infantile Refsum disease and Heimler syndrome were described later. As the molecular and biochemical understanding of these disorders improved, it became apparent that they represented variants of one disorder and some researchers started using the term “Zellweger spectrum disorder” to describe these disorders.
The symptoms of ZSD vary greatly from one individual to another. The specific number and severity of symptoms present in an individual are highly variable and affected individuals will not have all of the symptoms discussed below. The most severe forms are usually noticeable shortly after birth. Severely affected infants often have distinct craniofacial features, neurological deficits, progressive dysfunction of the liver and kidneys and usually develop life-threatening complications during the first year of life.
Children with milder forms of ZSD 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 speak. Some children with these milder forms of ZSD do not have any craniofacial abnormalities or only very mild ones.
In extremely rare cases, affected individuals have gone undetected until older childhood or 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 ZSD 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 may 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 ZSD, 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 ZSD 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 ZSD can cause loss of vision to varying degrees. In addition to vision loss, infants with ZSD 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 ZSD 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 ZSD 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 ZSD. Respiratory support may entail the use of a nasal cannula for oxygen to more aggressive forms of support as the disease progresses.
In some male infants with ZSD, 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).
Intermediate/milder forms of ZSD may present in the newborn period or be detected by newborn screening, but generally come to attention later because of developmental delays and sensory impairment. The clinical course for ZSD is variable. Despite low tone, some may learn to walk, speak and achieve some developmental milestones. Some develop adrenal insufficiency, osteopenia, or seizures over time. Teeth eruption is often delayed, and individuals often have tooth enamel abnormalities in their secondary teeth. Disease progression is often attributed to a leukodystrophy, or progressive degeneration of myelin in the central nervous system, which often results in loss of skills and untimely death.
Even milder forms of ZSD present with primarily sensory impairment and little to no developmental delay.
ZSD develop due to changes (mutations) of one of 13 different genes involved in the creation and proper function of peroxisomes (peroxisome biogenesis). These 13 genes contain instructions for creating (encoding) proteins known as peroxins that are essential for the proper development of peroxisomes. Approximately 61% of individuals with a ZSD have a mutation in the peroxisome biogenesis factor 1 (PEX1) gene. The other genes that cause ZSD are PEX2, PEX3, PEX5, PEX6, PEX10, PEX11, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26.
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.
ZSD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Determining the true incidence of ZSD in the general population can be difficult. ZSD are usually diagnosed at birth, although some cases can be diagnosed later in life. ZSD affect individuals of all ethnic groups. In the United States, the estimated incidence of these disorders is somewhere in between 1 in 50,000 and 1 in 75,000 live births.
A ZSD diagnosis is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. ZSD can be diagnosed by showing peroxisome abnormalities that can be monitored in body fluids. The primary step in ZSD 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 ZSD. 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 ZSD, in contrast to biochemical tests, will also identify carriers for ZSD, 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. Newborn screening for X-linked adrenoleukodystrophy should increase early diagnosis of ZSD and determination of accurate incidence estimates of the disease. In 2016, 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. Legislation for X-linked adrenoleukodystrophy newborn screening has been passed and initiated in 21 states; continued legislative efforts are expected to expand through movements initiated by patient families and advocacy organizations to lobby their state legislatures.
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.
Treatment
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 ZSD).
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 ZSD 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 ZSD 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 ZSD. 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 ZSD and pathologic fractures have occurred in patients. Therefore, evaluation for bone disease should be considered. Additionally, many children with ZSD have enamel abnormalities of permanent teeth and should receive appropriate dental care.
Early intervention is important in treating children with ZSD. Services that may be beneficial may include special education, physical and orthopedic therapy, special services for children with deaf-blindness, and other medical, social, and/or vocational services. Other treatment is symptomatic and supportive.
Genetic counseling is recommended for families of affected individuals.
A variety of therapies have been investigated to treat individuals with ZSD including specific dietary modifications or regimens such as a diet low in phytanic acid. Specific dietary modifications have had limited effect on individuals with ZSD.
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 ZSD. More research is necessary to determine the long-term safety and effectiveness of this potential therapy for individuals with ZSD.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
McGuinness MC, Smith KD. Peroxisomal Biogenesis Disorders. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:486-487.
JOURNAL ARTICLES
Moser AB, Jones RO, Hubbard WC, Tortorelli S, Orsini JJ, Caggana M, Vogel B, Raymond GV. Newborn screening for X-linked adrenoleukodystrophy. Int J Neonatal Screen. 2016;2:15. doi: 10.3390/ijns2040015.
Rush ET, Goodwin JL, Braverman NE, Rizzo WB. Low bone mineral density is a common feature of Zellweger spectrum disorders. Mol Genet Metab. 2016;117:33–7. doi: 10.1016/j.ymgme.2015.11.009.
Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol. Genet. Metab. 2015. In press. https://dx.doi.org/10.1016/j.ymgme.2015.12.009
Berendse, K., Engelen, M., Linthorst, G. E., van Trotsenburg, A. S., & Poll-The, B. T. High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders. Orphanet J Rare Dis. 2014; 9: 133. doi: 10.1186/s13023-014-0133-5
Ebberink MS, Koster J, Visser G, Spronsen F, Stolte-Dijkstra I, Smit GP, Fock JM, Kemp S, Wanders RJ, Waterham HR. A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene. J Med Genet. 2012;49(5):307–313. doi: 10.1136/jmedgenet-2012-100778.
Rosewich H, Ohlenbusch A, Gartner J. Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations. J Med Genet. 2005;42:e58.
Crane DI, Maxwell MA, Paton BC. PEX1 mutations in the Zellweger spectrum of the peroxisome biogenesis disorders. Hum Mutat. 2005;26:167-175.
Gootjes J, Schmohl F, Waterham HR, Wanders RJA. Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder. Eur J Hum Genet. 2004;12:115-120.
Wanders RJA, Waterham HR. Peroxisomal biogenesis I: biochemistry and genetics of peroxisome biogenesis disorders. Clin Genet. 2004;67:107-133.
Walter C, Gootjes J, Mooijer PA, et al. Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. Am J Hum Genet. 2001;69:35-48.
McGuinness MC, Wei H, Smith KD. Therapeutic developments in peroxisome biogenesis disorders. Exp Opin Invest Drugs. 2000;9:1985-1992.
Wei HW, Kemp S, McGuinness MC, et al. Pharmacological induction of peroxisomes in peroxisomes biogenesis disorders. Ann Neurol. 2000;47:286-296.
Moser HW. Genotype-phenotype correlations in disorders of peroxisome biogenesis. Mol Genet Metab. 1999;68:316-327.
INTERNET
Steinberg SJ, Raymond GV, Braverman NE, et al. Zellweger Spectrum Disorder. 2003 Dec 12 [Updated 2017 Dec 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1448/ Accessed August 18, 2020.
Abdel-Hamid H. Peroxisomal Disorders. Medscape.Updated: Jul 29, 2020. Available at: https://emedicine.medscape.com/article/1177387-overview Accessed August 18, 2020.
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