Continuing Education Activity

Zellweger syndrome, also known as cerebrohepatorenal syndrome, is a rare inherited disorder characterized by the absence or reduction of functional peroxisomes. It is autosomal recessive and is due to a defect in the PEX gene. It is a rapidly progressive disorder with a high mortality rate. With no curative treatment available, treatment options are limited to supportive care to improve quality of life. This activity describes the evaluation and management of Zellweger syndrome and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Describe the pathophysiology of Zellweger syndrome.
• Outline the typical clinical features that factor into the evaluation of a patient with Zellweger syndrome.
• Summarize management options available for Zellweger syndrome.
• Explain the importance of coordination and collaboration among the interprofessional team to enhance patient care and improve outcomes in Zellweger syndrome

Introduction

Zellweger syndrome (ZS), also known as cerebrohepatorenal syndrome, is a rare inherited disorder characterized by the absence/reduction of functional peroxisomes in cells, which are essential for beta-oxidation of very-long-chain fatty acids. It is autosomal recessive in inheritance, and the spectrum of the disease includes Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata type 1 (RCDP1) depending on the phenotype and severity.[1][2]

Etiology

Zellweger syndrome is caused by mutations in various genes required for peroxisome biogenesis. Mutations in at least 13 different PEX genes have been associated, and the PEX genes encode for proteins called peroxins (a peroxisome assembly protein). The most common mutations are PEX1 or PEX6 gene, which is seen in approximately 65 percent of patients.[3] These genes encode ATPases, which are needed to import the protein into peroxisomes from the cytosol outside.[4]

Peroxisomal disorders are subdivided into 3 groups based on functional disturbances in peroxisome as follows:

• ZS, neonatal adrenoleukodystrophy, and infantile Refsum’s disease associated with generalized loss of peroxisome function
• Adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN) associated with a single enzymatic defect in peroxisome
• Rhizomelic chondrodysplasia punctata associated with multiple enzymatic defects in peroxisome[5]

Epidemiology

Zellweger syndrome is the most common peroxisomal disorder that presents in early infancy with an incidence of 1 in 50,000 live births in the United States, but it varies between regions.[6] A higher incidence occurs in the region of Quebec (1 in 12,000) and a lower incidence in Japan (1 in 500,000). The overall incidence of peroxisomal disorder is about 1 in 50,000 to 100,000 live births.

Pathophysiology

Peroxisomes are single membrane-bounded organelles with a matrix, containing over 50 enzymes for fatty acid metabolism. All human cells except erythrocytes contain peroxisomes. The liver and kidney have peroxisomes in abundance in comparison to other organs. Peroxins are necessary for proper assembly of peroxisomes, and mutations in the peroxin gene (PEX) results in a defect in peroxisomal formation, which is associated with lower or undetectable levels of key internal enzymes. The peroxisomes are involved in beta-oxidation of very-long-chain fatty acids (VLCFA), alpha oxidation of branched-chain fatty acids, catabolism of amino acids, and ethanol, biosynthesis of bile acids, steroid hormones, gluconeogenesis and plasmalogen formation which are important constituents of the cell membrane and myelin. It is also involved in the degradation of cytotoxic hydrogen peroxide.[7]

Zellweger syndrome is thus characterized by increased accumulation of VLCFA, increased C26, and C22 fatty acids in plasma, fibroblasts, and amniocytes.[8] Reduced steroid biosynthesis and accumulation of VLCFA in adrenal gland cells cause decreased levels of adrenocorticotropic hormone (ACTH) and some other steroidal hormones.[9] Reduced degradation of cytotoxic hydrogen peroxide and abnormal accumulation of VLCFA causes neuronal membrane injury and demyelination.[10]

Major abnormalities are present in the kidney (cortical cysts), liver (fibrotic), and brain (demyelination, centrosylvian polymicrogyria) - hence the name cerebrohepatorenal syndrome.

History and Physical

The disorder affects almost every organ system as peroxisomes are present in all organelles. Manifestations include severe craniofacial abnormalities, hypotonia, severe neurodevelopmental delay, sensorineural hearing loss, ocular abnormalities, and enamel abnormalities. Hepatomegaly is present in 80% of cases with increased liver enzymes and bilirubin levels. Renal cortical cysts are present in 70% of cases.[11]

Depending on the age of presentation, ZS patients are divided into three groups.[6]

Neonatal-infantile presentation

• Most of these children will present with hypotonia, reduced spontaneous movements, and poor cry. They frequently have difficulty feeding, and seizures can be early onset during neonatal life.[6]
• They often have facial dysmorphism, including a high forehead, large fontanelles, wide sutures, hypoplastic supraorbital ridges, broad nasal bridge. Ocular abnormalities include glaucoma, cataracts, and retinopathy, and these patients can have varying degrees of sensorineural deafness. 

Childhood presentation

• Developmental delay, failure to thrive, eye and hearing abnormalities including varying levels of hepatic dysfunction, adrenal insufficiency, and renal calcium oxalate stones. They can have regression of previously attained neurological milestones secondary to demyelination (leukodystrophy).

Adolescent - adult presentation

• Developmental delay and neuroregression, cerebellar ataxia, peripheral neuropathy, adrenal insufficiency, leukodystrophy.

Evaluation

The initial diagnostic step is the identification of clinical features and a demonstration of elevated very-long-chain fatty acid (VLCFA) in blood during newborn screening. Genetic testing makes the diagnosis of PEX genes. The next step in evaluation is biochemical testing looking for elevated levels of VLCFA, phytanic and/or pristanic acid, pipecolic acid, bile acid intermediates, and reduced levels of plasmalogen in red blood cells.[12] Mild ZS patients may have normal biochemical tests, so confirmation in cultured skin fibroblasts at 40 degrees centigrade is required if clinical suspicion is high.[6] Genetic counseling and prenatal diagnosis are crucial.[2]

Treatment / Management

Zellweger syndrome is a rapidly progressive disorder with a high mortality rate. With no curative treatment available, treatment options are limited to supportive care to improve quality of life.[11] 

Various treatment modalities that have been tried include:

1. Docosahexaenoic acid - This is a long-chain unsaturated fatty acid essential for myelination, brain, and eye development. The levels of docosahexaenoic acid are low in the plasma of patients with ZS. However, its replacement was not associated with improvement in neurological symptoms or visual disturbances in randomized controlled trials.[13]

2. Lorenzo's oil - Lorenzo's oil is a mixture of glyceryl trioleate and glyceryl trierucate, and its use was initially attempted in patients with X linked adrenoleukodystrophy. It was shown to reduce VLCFA levels in plasma but did not affect disease progression in ZS patients.[14][15]

3. Cholic acid - This is 24 carbon bile acid, which is helpful in the absorption of fat-soluble vitamins. Due to liver dysfunction and lipoprotein synthesis impairment in patients with ZS, there is a deficiency of fat-soluble vitamins, and the use of cholic acid has been tried in other disorders of hepatic function. It has been approved by the US FDA for use in patients with ZS. However, there is little evidence regarding its efficacy.[16]

Supportive measures include:

• Hearing aids or cochlear implants for hearing loss
• Ophthalmologist referral, cataract removal, and glasses for vision impairment
• Standard antiepileptic drugs for seizures
• Vitamin K supplementation for coagulopathy
• Cortisone for adrenal insufficiency
• Gastrostomy for insufficient calorie intake
• Vitamin supplementation for low levels of fat-soluble vitamins (A, D, E)

Differential Diagnosis

Differential diagnosis of ZS based on the main presenting symptom includes the following:[6]

Hypotonia in newborns

• Chromosomal abnormalities (Down syndrome, Prader-Willi syndrome)
• Spinal muscular atrophy
• Hypoxic-ischemic encephalopathy
• Other peroxisomal disorders (acyl-CoA oxidase type 1 deficiency, D-bifunctional protein deficiency)

Sensorineural hearing loss with retinitis pigmentosa

• Usher syndrome type 1,2
• Cockayne syndrome
• Alport syndrome
• Waardenburg syndrome
• Classical Refsum disease

Bilateral cataract

• Lowe syndrome
• Galactosemia
• Congenital infections
• Rhizomelic chondrodysplasia punctate

Adrenocortical Insufficiency

• Adrenal hemorrhage
• X-linked adrenoleukodystrophy
• Infectious adrenalitis

Prognosis

Children presenting in the neonatal period have a very poor prognosis and usually die within the first year of life. Patients who present in later childhood can develop progressive liver disease/failure and have slightly longer survival after diagnosis as compared to the neonatal form. Patients who present in adolescence have a slightly longer survival but usually develop progressive neurological symptoms, including spasticity and peripheral neuropathy later in life.

Complications

• Gastrointestinal bleeding
• Liver failure
• Pneumonia
• Respiratory distress
• Infections

Deterrence and Patient Education

Zellweger syndrome is a fatal and progressive disease with multiple congenital anomalies. Even with improved care, the survival rate is poor. There are reports of affected children living up to 2 years depending on genetic-phenotypic variability, and they typically die from respiratory failure, apnea, or complications from an infection.

Due to poor outcomes and no specific treatment available, genetic testing and counseling for family planning should be offered to potential carriers prior to pregnancy. Prenatal or preimplantation genetic diagnosis is also available for potential carriers.[17]

Enhancing Healthcare Team Outcomes

Patients diagnosed with Zellweger syndrome should have interprofessional care with a medical team comprising a metabolic disease specialist, neurology, ophthalmology, otorhinolaryngology, and occupational and physical therapists with appropriate follow up arranged before hospital discharge. As ZS affects multiple organs, appropriate care would be possible by teamwork and collaboration among specialists from multiple disciplines. Additionally, the integration of palliative resources plays a key role in improving the quality of life for infants and parents. Genetic counseling is crucial for early diagnosis.