Zellweger spectrum disorders (NORD)

Definitions & Key takeaways

Zellweger spectrum disorders, or ZSDs, are rare autosomal recessive disorders caused by mutations in the PEX genes. Symptoms and disease progression vary greatly where severe forms are evident at birth, and mild and intermediate forms may go undetected until childhood. Symptoms often include cranial abnormalities, visual and hearing impairments, developmental delays, hypotonia, seizures, and bleeding problems.

ZSD affects the functioning of peroxisomes, causing buildup of very long-chain fatty acids and degeneration of nerves, affecting multiple organ systems. Diagnosis involves a thorough clinical examination, as well as biochemical and genetic testing. Effective treatment for ZSD requires early diagnosis and involves oral bile acid replacement therapy with cholic acid.

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Zellweger spectrum disorders, also called ZSDs, are a group of rare genetic diseases that impair the development of peroxisomes, which are structures found in almost every cell of the body.
Peroxisomes house enzymes that are responsible for a number of biochemical pathways, including the metabolism of fatty acids and the synthesis of lipids essential for nervous system development.
A low level of peroxisomes in the body causes visual, auditory, and neurological deterioration as well as liver and kidney dysfunction.
For this reason, ZSDs are also known as peroxisome biogenesis disorders, or PBDs. ZSDs are named after Dr.
Hans Zellweger, who first described the disease in 1964. ZSDs were originally characterized as individual diseases of varying severity, however it was later determined that all of these diseases are part of the same disease spectrum.
ZSDs affect many parts of the body. In severe cases, symptoms can present shortly after birth, whereas less severe forms may have symptoms that do not appear until late infancy or childhood.
Infants with severe ZSD often, but don’t always have cranial abnormalities such as flattening of the face, high forehead, widely spaced eyes, broad nose bridge, and an abnormally small jaw.
The roof of the mouth may be unusually high and narrow, and the fontanelles may feel abnormally large. Infants with ZSD may experience deteriorating visual, auditory, and neurological symptoms.
Visual impairments may include cataracts, glaucoma, and nystagmus. Progressive vision loss may manifest as difficulty following objects with the eyes and eyes pointing in different directions.
Hearing loss may present as a lack of a startle response to loud noises and not turning towards sounds. Neurological symptoms may include seizures and delays in developmental milestones like sitting, crawling, or walking.
Other symptoms include a lack of muscle tone, called hypotonia, and affected children may appear limp and lethargic. Infants may have difficulty sucking or swallowing, causing problems in feeding and gaining weight.
Infants with ZSD may also develop liver and kidney-related disorders, causing liver dysfunction, enlarged liver, bleeding problems, and kidney cysts.
Individuals with intermediate or milder forms of ZSD often have a slower disease progression and may exhibit milder symptoms.
Some symptoms that may become noticeable in childhood include adrenal insufficiency, skeletal and dental abnormalities, and continued developmental delay as individuals approach school age.
ZSDs are genetic disorders caused by mutations in any of 13 of the 14 PEX genes, which encode for peroxins, proteins involved in peroxisome assembly.
Most children with ZSD have mutations in the PEX1 gene, though mutations can also occur in PEX2, PEX3, PEX5, PEX6, PEX10, PEX11, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26.
These mutations impair the function of peroxisomes, leading to the buildup of very-long-chain fatty acids and degeneration of nerves that cause multi-system complications.
ZSDs are inherited in an autosomal recessive pattern, so a child must inherit an abnormal gene from both parents, who are carriers, in order to be affected.
Traditionally, diagnosis begins with an assessment of the individual’s clinical signs and symptoms followed by biochemical and genetic testing.
However, recently adopted newborn screening for X-linked adrenoleukodystrophy, a related peroxisomal disorder, may be able to detect ZSD prior to clinical observation of symptoms.
Biochemical testing typically shows high levels of very-long-chain fatty acids. Genetic testing is often used to confirm ZSD.
Early diagnosis is important in treating ZSD. Treatment may involve oral bile acid replacement therapy with cholic acid as the first-line therapy.
Annual adrenal monitoring is recommended, with adrenal replacement therapy as needed. Subsequent treatment is supportive and varies based on symptoms.
Affected individuals may benefit from special education, physical and orthopedic therapy, speech therapy, and other medical, social, or vocational services.
Genetic counseling is recommended to help families understand the genetics and natural history of ZSD and to provide psychosocial support.
##Summary As a quick recap, Zellweger Spectrum Disorders, or ZSDs, are rare autosomal recessive disorders caused by mutations in the PEX genes.
Symptoms and disease progression vary greatly where severe forms are evident at birth, and mild and intermediate forms may go undetected until childhood.
Symptoms often include cranial abnormalities, visual and hearing impairments, developmental delays, hypotonia, seizures, and bleeding problems.
ZSD affects the functioning of peroxisomes, causing buildup of very-long-chain fatty acids and degeneration of nerves, affecting multiple organ systems.
Diagnosis involves a thorough clinical examination, as well as biochemical and genetic testing. Effective treatment for ZSD requires early diagnosis and involves oral bile acid replacement therapy with cholic acid.
Other treatment is supportive and based on symptoms. multiple organ systems diagnosis involves a thorough clinical examination as well as biochemical and genetic testing effective treatment for GSD requires early diagnosis and involves oral bile acid replacement therapy with Kool-Aid Acid other treatment is supportive and based on symptoms.