About zellweger syndrome

What is zellweger syndrome?

Zellweger spectrum disorders 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. Collectively, they form a spectrum or continuum of disease. Zellweger syndrome is the most severe form; neonatal adrenoleukodystrophy is the intermediate form; and infantile Refsum disease is the mildest form. Zellweger spectrum disorders 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. Zellweger spectrum disorders often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. Zellweger spectrum disorders are inherited as autosomal recessive traits.

Zellweger spectrum disorders 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 the three Zellweger spectrum disorders and rhizomelic chondrodysplasia punctata.

What are the symptoms for zellweger syndrome?

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.

What are the causes for zellweger syndrome?

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.

What are the treatments for zellweger syndrome?

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.

What are the risk factors for zellweger syndrome?

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.

Is there a cure/medications for zellweger syndrome?

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.

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