Zellweger Syndrome Spectrum

Zellweger spectrum disorder is a rare genetic condition that affects how the body's cells function. Inside our cells are tiny structures called peroxisomes, which act like recycling centers to break down certain fats and chemicals. In people with this disorder, these peroxisomes don't form properly or don't work as they should. This causes harmful substances to build up in the body, which can damage the brain, liver, kidneys, and other organs. The condition can range from very severe to mild. Babies with the severe form often have weak muscles, feeding difficulties, seizures, and distinct facial features. Unfortunately, the severe form is life-threatening early in life. Children with milder forms may develop symptoms later, such as developmental delays, liver problems, and hearing loss. Vision is also significantly affected by this disorder. Most patients develop a condition called retinal dystrophy, where the light-sensitive tissue at the back of the eye slowly breaks down. This can lead to vision loss and eventually blindness. Some children may also develop cataracts or glaucoma. While there is currently no cure for Zellweger spectrum disorder, treatments focus on managing symptoms, such as using hearing aids, glasses, and medications to improve the patient's quality of life.

Condition category: Syndromic IRD

Prevalence: 1 in 50,000 to 1 in 133,000

Inheritance patterns: Autosomal Recessive

Age of onset: Birth to early childhood

Clinical overview: Zellweger spectrum disorder (ZSD) is a rare, inherited condition characterized by the absence or significant reduction of functional peroxisomes in cells. It represents a phenotypic continuum that ranges from severe to mild. Historically, this continuum was divided into three distinct phenotypes: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). However, because these phenotypes overlap, the terms "severe," "intermediate," and "milder" ZSD are now preferred. The disorder affects almost every organ system. Severe ZSD typically presents in the neonatal period with profound hypotonia, characteristic craniofacial abnormalities (high forehead, large fontanelles, broad nasal bridge), seizures, inability to feed, renal cysts, hepatic dysfunction, and chondrodysplasia punctata. Infants with severe ZSD are significantly impaired and usually die during the first year of life. Individuals with intermediate or milder forms of ZSD may present later in childhood or even adulthood. They often manifest retinal dystrophy, sensorineural hearing loss, developmental delay, and liver dysfunction. Retinal degeneration leading to vision loss is a common feature across the spectrum. Some patients may develop adrenal insufficiency, leukodystrophy, cerebellar ataxia, and peripheral neuropathy. The severity and progression of symptoms vary widely depending on the specific genetic mutation and the residual function of peroxisomes.

Patient and family guide: Zellweger spectrum disorder is a rare genetic condition that affects how the body's cells function. Inside our cells are tiny structures called peroxisomes, which act like recycling centers to break down certain fats and chemicals. In people with this disorder, these peroxisomes don't form properly or don't work as they should. This causes harmful substances to build up in the body, which can damage the brain, liver, kidneys, and other organs. The condition can range from very severe to mild. Babies with the severe form often have weak muscles, feeding difficulties, seizures, and distinct facial features. Unfortunately, the severe form is life-threatening early in life. Children with milder forms may develop symptoms later, such as developmental delays, liver problems, and hearing loss. Vision is also significantly affected by this disorder. Most patients develop a condition called retinal dystrophy, where the light-sensitive tissue at the back of the eye slowly breaks down. This can lead to vision loss and eventually blindness. Some children may also develop cataracts or glaucoma. While there is currently no cure for Zellweger spectrum disorder, treatments focus on managing symptoms, such as using hearing aids, glasses, and medications to improve the patient's quality of life.

Symptoms and clinical features: Symptoms of Zellweger spectrum disorder vary widely depending on the severity of the condition. In severe cases, newborns present with profound hypotonia (floppiness), poor feeding, and a weak cry. They often have distinct facial features, including a high forehead, broad nasal bridge, and large fontanelles. Neonatal seizures and liver dysfunction (jaundice) are common. In intermediate and milder forms, symptoms may appear later in infancy or childhood. These include developmental delays, sensorineural hearing loss, and vision problems such as retinal dystrophy, cataracts, and glaucoma. Children may experience liver dysfunction, bleeding episodes due to vitamin K deficiency, and adrenal insufficiency. As the disease progresses, patients may lose previously acquired developmental milestones due to the breakdown of myelin in the brain (leukodystrophy). Older individuals may develop cerebellar ataxia and peripheral neuropathy.

Molecular pathology: Zellweger spectrum disorder is caused by mutations in various PEX genes required for peroxisome biogenesis. These genes encode proteins called peroxins, which are essential for the proper assembly of functional peroxisomes. The most common mutations involve the PEX1 or PEX6 genes, which encode ATPases needed to import proteins into peroxisomes from the cytosol. Peroxisomes are single membrane-bounded organelles containing over 50 enzymes involved in lipid metabolism. They are crucial for the beta-oxidation of very-long-chain fatty acids (VLCFA), alpha-oxidation of branched-chain fatty acids, biosynthesis of bile acids and steroid hormones, and the formation of plasmalogens, which are important constituents of cell membranes and myelin. They also degrade cytotoxic hydrogen peroxide. The defect in peroxisome formation leads to lower or undetectable levels of key internal enzymes. This results in the accumulation of VLCFA and branched-chain fatty acids in plasma and tissues, and reduced levels of plasmalogens. The accumulation of VLCFA and reduced degradation of hydrogen peroxide cause neuronal membrane injury and demyelination. Reduced steroid biosynthesis and VLCFA accumulation in adrenal cells lead to adrenal insufficiency. Major abnormalities occur in the brain (demyelination, polymicrogyria), liver (fibrosis), and kidneys (cortical cysts).

Genetics: Zellweger spectrum disorder is inherited in an autosomal recessive manner. It is caused by biallelic pathogenic variants in one of at least 13 different PEX genes, which encode peroxins necessary for peroxisome assembly. The most common mutations occur in the PEX1 or PEX6 genes, accounting for approximately 65% of patients. A general relationship exists among the genotype, cellular phenotype, and clinical phenotype. Loss-of-function variants (e.g., large deletions, nonsense, frameshift variants) abolish activity and are associated with the most severe phenotypes. Missense variants that retain some residual function typically have a less severe effect on peroxisome assembly, leading to milder phenotypes. Genetic counseling is crucial for affected families. Because it is an autosomal recessive condition, parents of an affected child are obligate heterozygotes (carriers) and have a 25% chance of having another affected child with each pregnancy. Prenatal diagnosis is possible through biochemical testing of cultured amniocytes or chorionic villus sampling, or by molecular genetic testing if the pathogenic variants in the family are known.

Diagnostic evaluation: Diagnosis is established by identifying clinical features and demonstrating elevated very-long-chain fatty acids (VLCFA) in blood or plasma. Biochemical testing also looks for elevated levels of phytanic or pristanic acid, pipecolic acid, bile acid intermediates, and reduced levels of plasmalogen in red blood cells. If biochemical tests are normal but clinical suspicion is high, confirmation in cultured skin fibroblasts at 40°C is required. Genetic testing for mutations in the PEX genes confirms the diagnosis.

Differential diagnosis: Down syndrome, Prader-Willi syndrome, Spinal muscular atrophy, Hypoxic-ischemic encephalopathy, Acyl-CoA oxidase type 1 deficiency, D-bifunctional protein deficiency, Usher syndrome, Cockayne syndrome, Alport syndrome, Waardenburg syndrome, Classical Refsum disease, Lowe syndrome, Galactosemia, Rhizomelic chondrodysplasia punctata, X-linked adrenoleukodystrophy

Natural history: The natural history of Zellweger spectrum disorder varies depending on the severity of the phenotype. In the severe form (classic Zellweger syndrome), infants present in the neonatal period with profound hypotonia, seizures, and inability to feed. They typically make no developmental progress and usually die within the first year of life due to progressive apnea or respiratory compromise from infection. In intermediate and milder forms (previously known as neonatal adrenoleukodystrophy and infantile Refsum disease), children may present later with developmental delay, vision and hearing loss, and liver dysfunction. They may experience regression of previously attained neurological milestones secondary to demyelination (leukodystrophy). Older children may develop adrenal insufficiency and osteopenia. Survival in these milder forms is longer, with some individuals reaching adolescence or adulthood, but they usually develop progressive neurological symptoms, including spasticity and peripheral neuropathy.

Management and treatment research: ### Current management and standard of care There is currently no cure for Zellweger spectrum disorder (ZSD), a group of inherited peroxisome biogenesis disorders. Care focuses on treating symptoms, supporting development and nutrition, and monitoring for complications involving the liver, nervous system, hearing, vision, and adrenal glands. Management is typically coordinated by a multidisciplinary team that may include metabolic specialists, neurologists, hepatologists, endocrinologists, audiologists, ophthalmologists, dietitians, and physical, occupational, and speech therapists. Management may include: - **Seizure care:** Antiseizure medicines may be used for seizures. - **Nutrition and feeding support:** Feeding difficulties and poor growth may require individualized nutrition plans, supplementation of fat-soluble vitamins (A, D, E, and K), and, for some people, tube feeding through a gastrostomy tube. - **Liver and bleeding monitoring:** ZSD can affect liver function and blood clotting. Vitamin K and other supportive treatments may be used when needed. - **Adrenal care:** Some people develop adrenal insufficiency, meaning the adrenal glands do not produce enough hormones. Corticosteroid hormone replacement may be needed. - **Hearing support:** Hearing aids or cochlear implants may help some people with sensorineural hearing loss. - **Vision and retinal care:** Regular ophthalmic examinations can monitor retinal disease, cataracts, refractive errors, and other eye concerns. Glasses, cataract treatment when appropriate, low-vision services, and educational accommodations may help support visual function and independence. - **Developmental and mobility services:** Early-intervention programs, individualized educational support, assistive devices, and physical, occupational, and speech therapy can address developmental, communication, and mobility needs. ### Approved therapies **Cholic acid** is FDA-approved as an adjunctive treatment for peroxisomal disorders, including ZSD. Cholic acid is a primary bile acid that may reduce the buildup of potentially harmful abnormal bile acids and support bile acid-related liver function in some individuals. Treatment and monitoring should be directed by clinicians experienced in metabolic and liver disease. **Docosahexaenoic acid (DHA)** is an omega-3 fatty acid that may be low in ZSD and has been studied as a dietary supplement. Controlled studies have not shown clear improvement in neurologic or visual outcomes. DHA is not an approved disease-modifying treatment for ZSD. ### Investigational therapies There are no active disease-modifying treatment programs listed in the current ZSD clinical pipeline. Laboratory and animal research continues to explore ways to improve peroxisome function or address the underlying genetic cause, but these approaches are not currently available as treatments for people with ZSD. ### Clinical trial participation The currently recruiting ZSD studies are natural-history studies. These studies do not test a new treatment; instead, they follow participants over time to better understand disease progression and identify measures that may be useful in future treatment trials. - **NCT06190626:** Longitudinal Prospective Natural History Study of Retinopathy in Zellweger Spectrum Disorder — recruiting - **NCT01668186:** Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD) — recruiting Participation may include eye examinations, retinal imaging, medical assessments, laboratory testing, and collection of health information over time. Families can discuss whether a study may be appropriate with their metabolic specialist or ophthalmology team.

Outlook: The prognosis for Zellweger spectrum disorder is generally poor and depends on the severity of the phenotype. Infants with the severe form (classic Zellweger syndrome) have a very poor prognosis, typically making no developmental progress and dying within the first year of life. Patients with intermediate or milder forms have a slightly longer survival, sometimes reaching adolescence or adulthood. However, they usually experience progressive neurological decline, vision and hearing loss, and liver dysfunction, which significantly impacts their quality of life. The disease is ultimately fatal, and care is focused on symptom management and palliative support.

Epidemiology: Zellweger spectrum disorder occurs worldwide with varying prevalence. In the United States, the incidence is estimated at 1 in 50,000 live births. However, recent data from newborn screening in New York state suggests a confirmed incidence of 1 in 133,000 births. The incidence is higher in the Quebec region (1 in 12,000) and significantly lower in Japan (1 in 500,000), mainly due to the absence of common European PEX1 variants.

Selected references: 1. Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321. 2. Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Zellweger Spectrum Disorder. 2003 Dec 12 [Updated 2020 Oct 29]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. 3. Trompier D, et al. Zellweger spectrum disorder, also known as cerebrohepatorenal syndrome. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. 4. Argyriou C, D'Agostino MD, Braverman N. Peroxisome biogenesis disorders. Transl Sci Rare Dis. 2016;1(2):111-144.