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Zellweger Spectrum Disorder

Adrenoleukodystrophy autosomal neonatal form, NALD, Cerebrohepatorenal syndrome, ZSD, PBD, Refsum disease- infantile form, Peroxisome Biogenesis Disorder, Adrenoleukodystrophy- autosomal- neonatal form, Zellweger Spectrum Disorders, Zellweger syndrome

Overview

Zellweger spectrum disorder is a group of conditions that have overlapping signs and symptoms and affect many parts of the body. This group of conditions includes Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease. These conditions were once thought to be distinct disorders but are now considered to be part of the same condition spectrum. Zellweger syndrome is the most severe form of the Zellweger spectrum disorder, NALD is intermediate in severity, and infantile Refsum disease is the least severe form. Because these three conditions are now considered one disorder, some researchers prefer not to use the separate condition names but to instead refer to cases as severe, intermediate, or mild.

Symptoms - Zellweger Spectrum Disorder

Individuals with Zellweger syndrome, at the severe end of the spectrum, develop signs and symptoms of the condition during the newborn period. These infants experience weak muscle tone (hypotonia), feeding problems, hearing and vision loss, and seizures. These problems are caused by the breakdown of myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is called white matter. Destruction of myelin (demyelination) leads to loss of white matter (leukodystrophy).

Children with Zellweger syndrome also develop life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys. They may have skeletal abnormalities, including a large space between the bones of the skull (fontanelles) and characteristic bone spots known as chondrodysplasia punctata that can be seen on x-ray. Affected individuals have distinctive facial features, including a flattened face, broad nasal bridge, and high forehead. Children with Zellweger syndrome typically do not survive beyond the first year of life.

People with NALD or infantile Refsum disease, which are at the less-severe end of the spectrum, have more variable features than those with Zellweger syndrome and usually do not develop signs and symptoms of the disease until late infancy or early childhood. They may have many of the features of Zellweger syndrome; however, their condition typically progresses more slowly. Children with these less-severe conditions often have hypotonia, vision problems, hearing loss, liver dysfunction, developmental delay, and some degree of intellectual disability. Most people with NALD survive into childhood, and those with infantile Refsum disease may reach adulthood. In rare cases, individuals at the mildest end of the condition spectrum have developmental delay in childhood and hearing loss or vision problems beginning in adulthood and do not develop the other features of this disorder.

Causes - Zellweger Spectrum Disorder

Mutations in at least 12 genes have been found to cause Zellweger spectrum disorder. These genes provide instructions for making a group of proteins known as peroxins, which are essential for the formation and normal functioning of cell structures called peroxisomes. 

Peroxisomes are sac-like compartments that contain enzymes needed to break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production of fats (lipids) used in digestion and in the nervous system. Peroxins assist in the formation (biogenesis) of peroxisomes by producing the membrane that separates the peroxisome from the rest of the cell and by importing enzymes into the peroxisome.

Mutations in the genes that cause Zellweger spectrum disorder prevent peroxisomes from forming normally. Diseases that disrupt the formation of peroxisomes, including Zellweger spectrum disorder, are called peroxisome biogenesis disorders. If the production of peroxisomes is altered, these structures cannot perform their usual functions. The signs and symptoms of Zellweger syndrome are due to the absence of functional peroxisomes within cells. NALD and infantile Refsum disease are caused by mutations that allow some peroxisomes to form.

Mutations in the PEX1 gene are the most common cause of Zellweger spectrum disorder and are found in nearly 70 percent of affected individuals. The other genes associated with Zellweger spectrum disorder each account for a smaller percentage of cases of this condition.

Prevention - Zellweger Spectrum Disorder

Zellweger spectrum disorder cannot be prevented.

Diagnosis - Zellweger Spectrum Disorder

Zellweger spectrum disorder can be diagnosed by showing peroxisome abnormalities that can be monitored in body fluids. The primary step in Zellweger spectrum disorder 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 Zellweger spectrum disorders; 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 Zellweger spectrum disorders, in contrast to biochemical tests, will also identify carriers for Zellweger spectrum disorders, which will allow reliable genetic counseling of families and may also assist with eligibility for future clinical trials.

Prognosis - Zellweger Spectrum Disorder

Although a rough genotype-phenotype correlation exists for several PEX genes, such as PEX1 and PEX26, the severity and progression of the disease is difficult to predict for individual patients. This will become more relevant as newborn screening is implemented. As a consequence of newborn screening for X-ALD by C26:0-lysoPC in several countries ZSD will also be diagnosed at birth. Children with the severe phenotype (neonatal-infantile presentation with severe clinical symptoms) have a poor prognosis and these patients usually die within the first year of life. Patients that present in childhood or adolescence usually have a better prognosis, but can develop progressive liver disease or leukodystrophy and deteriorate. If progressive liver disease or leukodystrophy occurs prognosis is poor. The remaining milder individuals can reach adulthood without progression or with long periods of stabilization. When progression occurs, it is mainly related to peripheral neuropathy and pyramidal signs, while cognition remains stable.

Treatment - Zellweger Spectrum Disorder

Treatment of manifestations: 

The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal in infancy, glasses, vitamin supplementation, primary bile acid therapy, adrenal replacement, antiepileptic drugs, and possibly monitoring for hyperoxaluria.

Surveillance:

Annual hearing and ophthalmologic evaluations, monitoring of liver function and coagulation factors, ACTH/cortisol. A baseline brain MRI is recommended; a loss of motor and cognitive milestones could indicate a leukodystrophy.

Resources - Zellweger Spectrum Disorder

Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines- N.E Braverman et al. Molecular Genetics and Metabolism 117 (2016) 313-321

Case Report: Diagnosis of a mild peroxisomal phenotype with next-generation sequencing- M.J. Ventura et al./ Molecular Genetics and Metabolism Reports 9 (2016) 75-78

https://www.understandingzsd.com/

 

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