Peroxisome biogenesis disorder-Zellweger syndrome spectrum

Other Names: Zellweger syndrome spectrum; Peroxisomal biogenesis disorders, Zellweger syndrome spectrum; PBD, ZSS; Zellweger spectrum disorders; PBD-ZSD; PBD-ZSS; Peroxisome biogenesis disorder; Peroxisome biogenesis disorder spectrum; PBD-Zellweger spectrum disorder; Zellweger spectrum

Zellweger spectrum refers to a group of related conditions that have overlapping signs and symptoms and affect many parts of the body. The spectrum includes Zellweger syndrome (ZS), the most severe form; neonatal adrenoleukodystrophy (NALD), an intermediate form; and infantile Refsum disease (IRD), the least severe form. The features of NALD and IRD often vary in nature and severity, and may not become apparent until late infancy or early childhood. Individuals with NALD or IRD may have hypotonia, vision and/or hearing problems, liver dysfunction, developmental delay and learning disabilities. Most individuals with NALD survive into childhood, and those with IRD may reach adulthood.

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

ndividuals 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.

ZS typically become apparent in the newborn period and may include hypotonia, feeding problems, hearing and vision loss, seizures, distinctive facial characteristics, and skeletal abnormalities.

Diagnosis

The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above and identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes.

Clinical findings Newborns with:

• Hypotonia
• Poor feeding
• Distinctive facies
• Brain malformations
• Seizures
• Renal cysts
• Hepatomegaly, cholestasis, and hepatic dysfunction
• Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones

Older infants and children with:

• Developmental delays with or without hypotonia (Note: Intellect can be normal.)
• Failure to thrive
• Hearing loss
• Vision impairment
• Liver dysfunction
• Adrenal dysfunction
• Leukodystrophy
• Peripheral neuropathy and ataxia

The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above and identification of biallelic pathogenic variants in one of the 13 PEX genes.

Molecular genetic testing approaches can include gene-targeted testing (multigene panel) or more comprehensive genomic testing (exome sequencing or genome sequencing).

When the patient's findings do not lead to consideration of ZSD, comprehensive genomic testing (when clinically available) is likely to be the diagnostic modality selected. Comprehensive genomic testing includes exome sequencing and genome sequencing.

Prenatal Testing and Preimplantation Genetic Testing Molecular genetic testing

Once the ZSD-PEX gene pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ZSD are possible.

Biochemical testing Biochemical testing in cultured fibroblasts is still valuable when molecular testing has not identified biallelic pathogenic variants in a ZSD-PEX gene. In these cases, a definitive abnormality confirmed in cultured fibroblasts could then be used for prenatal testing in cultured CVS samples or amniocytes.

Biochemical testing of cultured amniocytes may also be useful when abnormalities suggestive of ZSD are detected on prenatal ultrasound examination.

Treatment

Feeding and nutrition Supplying adequate calorie intake for affected children often entails the placement of a gastrostomy tube to allow simpler home management. A diet low in phytanic acid has been proposed, based mainly on the weak analogy with adult Refsum disease, in which accumulation of phytanic acid is pathogenic and treatment involves restricted dietary intake of phytanic acid (including avoidance of full-fat cow's milk products and high-fat meat products from ruminants). Its effectiveness in ZSD has never been proven. All standard infant formulas are already low in phytanic acid.

Hearing

Hearing aids should be used in children found to have hearing impairment.

Vision

Cataract removal in early infancy to preserve vision is appropriate. Glasses should be used as needed to correct refractive errors.

Liver

Supplementation of vitamin K and other fat-soluble vitamins is recommended.

• Cholbam(cholic acid) supplementation to treat the liver disease in patients with ZSD has been recently approved.

Neurologic

Early-intervention services should be provided for those with developmental delays.

Standard antiepileptic drugs (AEDs) may be used to treat seizures. No type of AED is contraindicated. Seizures may be difficult to control despite use of appropriate medication.

Bone

Evaluation of (1) bone density by dual-energy x-ray absorptiometry (DXA) and (2) vitamin D levels should be considered. The benefits of bisphosphonate treatment have been reported in a case report [Rush et al 2016].

Teeth

Semiannual dental visits are recommended.

Vaccination

In addition to the usual vaccination schedule for children, patients with ZSD should receive annual influenza and respiratory syncytial virus vaccines

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• cholic acid (Brand name: Cholbam)Treatment of bile acid synthesis disorders due to single enzyme defects and as adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption.

Epidemiology

It occurs in 1 in 50,000 individuals.

NIH genetic and rare disease info

• NIH info on Peroxisome biogenesis disorder-Zellweger syndrome spectrum

Peroxisome biogenesis disorder-Zellweger syndrome spectrum is a rare disease.

Peroxisome biogenesis disorder-Zellweger syndrome spectrum Resources
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