Peroxisome Biogenesis Disorder (Zellweger Spectrum Disorders)

Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders (PBD) caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Although they were once thought to be 3 separate diseases; from least to most severe; Infantile Refsum Disease, Neonatal Adrenoleukodystrophy and Zellweger Syndrome. It is now understood that these disorders form a spectrum or continuum of disease that can range from mild to moderate to severe and the more formal classifications are less often used.  Patients are often now often classified to the severity of Zellweger Spectrum Disorder (mild, moderate or severe).

These disorders occur due to a defect or deficiency in a specific part of the cell called the peroxisome. Peroxisomes are important parts of your cells that are responsible for breaking down fats and other chemicals responsible for metabolic processes.  The defective genes are known as PEX genes and can be detected through genetic testing.

At this time, there are no known cures for the disease which impacts multiple organs. Available treatments are largely supportive for individual organs.

Symptoms- ZSD

Because peroxisomes are involved in multiple biochemical functions, ZSDs can cause an

array of effects throughout the body. ZSD’s present and progress with a wide variation in severity, age at when symptoms appear, and organs that are affected

• Hypotonia
• Failure to thrive
• Hepatic dysfunction (jaundice)
• Feeding problems
• Hearing and vision loss
• Seizures
• Craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel)
• Coagulopathy
• Sensorineural hearing loss
• Ocular abnormalities
• Enamel abnormalities
• Peripheral neuropathy
• Cerebellar ataxia
• Leukodystrophy
• Skeletal abnormalities
• Development delay
• Adrenal insufficiency
• Hepatomegaly (enlarged liver)
• Chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body)

Liver injury is almost universal in people with ZSD. It is important to know that the liver will most likely become affected at some point in your child’s or loved one’s life.

Causes – ZSD

Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, or PEX26 genes. In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these PEX genes.

As a result of impaired peroxisome function, an individual’s tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems.

Prevention – ZSD

Since ZSD’s are caused by genetic defect, there is no known prevention. It is important to understand some of the problems that can develop cannot be reversed, such as abnormal brain development and neurological symptoms, but medical issues that arise and affect other organs can often be managed with therapeutic intervention.

Diagnosis – ZSD

Additional studies demonstrating defects in multiple peroxisome enzyme pathways are necessary to diagnose PBD-ZSD, such as measurement of the methyl-branched fatty acids phytanic and pristanic acids, erythrocyte plasmalogens, pipecolic acid in plasma and/or urine, and the bile acid intermediates dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA) in plasma and/or urine. Testing for multiple biochemical functions in patients or obtaining biochemical studies on patient-derived fibroblasts and genetic testing may be necessary for proper diagnosis. Genetic diagnostics tests involving the sequencing of PEX genes and biochemical tests have also proven highly effective for the diagnosis of ZSD and other peroxisomal disorders.

Prognosis – ZSD

Patients with ZSDs can present a complex range of clinical characteristics that often results in shortened life spans.

Treatment – ZSD

Unfortunately, there is no way to stop ZSDs from progressing. Therapies available are largely supportive treatments for managing the many organs affected by ZSDs. Although current treatments can only help with symptoms and do not cure the disease, they may help improve comfort and quality of life for people with ZSDs.

Feeding and nutrition

Many children have feeding difficulties. Supplying adequate calorie intake for affected children may entail the placement of a G-tube inserted through the abdomen to deliver nutrients to the stomach. With many children having some degree of malabsorption due to bile acid deficiency, vitamins A, D, E, and K amino acid-based formulas may be better tolerated.

Liver

To help support liver function, daily supplementation of vitamin K is recommended. Bile acid metabolism is altered and primary bile acid therapy (cholic acid and chenodeoxycholic acid) may improve liver function by reducing the buildup of abnormal bile acids, such as DHCA and THCA. Recently, cholic acid has been approved by the United States Food and Drug Administration as a supportive therapy to treat liver dysfunction in Zellweger Spectrum Disorders.

Hearing

Many patients have some degree of hearing loss and should be evaluated annually. Hearing aids should be used in children found to have substantive hearing loss. Cochlear implants (device placed in ear) have been effectively placed in children when hearing loss is severe and cannot be compensated by hearing aids.

Vision

Vision deterioration or loss is commonly seen due to retinal dystrophy and optic nerve abnormalities. Therefore, ophthalmologic exams are encouraged and cataract removal or corrective lenses may be recommended by your ophthalmologist.

Neurological function

Seizures affect nearly all severe ZSD patients and have been reported to occur in less severe cases of ZSDs. Electroencephalogram (EEG) test can determine the frequency and duration of seizures and should be performed whenever changes in seizure activity are suspected. Therapy to control seizures include a range of anti-epileptic drugs.

Evaluation for early physical, occupational and speech therapy is recommended for all children.

Bone

Regarding treatment of bone disease, a recent study has reported successful treatment with bisphosphonate medications in a patient. Bisphosphonate therapy should be carefully considered in consultation with an experienced metabolic bone specialist. Additionally, weight bearing physical activity has shown to slow bone loss in children and therefore prevent fractures.

Teeth

Dental examination should be performed every 6 months. Many children have enamel abnormalities of permanent teeth and should receive appropriate dental care.

Kidney

Children affected by ZSD, particularly older children (≥4–6 years), should be monitored for kidney injury or abnormalities, which can lead to kidney stone formation and renal failure. Treatments may include increased fluid intake or urine alkalization injections

Resources – PBD-ZSD

See Research Publications

• Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines- E Braverman et al. Molecular Genetics and Metabolism 117 (2016) 313-321
• Case Report: Diagnosis of a mild peroxisomal phenotype with next-generation sequencing- J. Ventura et al./ Molecular Genetics and Metabolism Reports 9 (2016) 75-78

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Resources