Zellweger Spectrum Disorder

Etiology

Zellweger spectrum disorder 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 proteins called peroxins (a peroxisome assembly protein). The most common mutations are the PEX1 or PEX6 gene, seen in approximately 65% of patients.[3] These genes encode ATPases 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:

• Zellweger spectrum disorder, neonatal adrenoleukodystrophy, and infantile Refsum disease are 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 spectrum disorder 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 the proper assembly of peroxisomes, and mutations in the peroxin gene (PEX) result in a defect in peroxisomal formation 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 spectrum disorder is thus characterized by increased accumulation of VLCFA and 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 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 almost all cells. 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, patients are divided into 3 groups.[6]

1. Neonatal-infantile presentation: Most children present with hypotonia, reduced spontaneous movements, and a weak 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, and broad nasal bridge. Ocular abnormalities include glaucoma, cataracts, and retinopathy; these patients can have varying degrees of sensorineural deafness. 
2. Childhood presentation: Children present with 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).
3. Adolescent and adult presentation: Individuals may present with developmental delay, neuroregression, cerebellar ataxia, peripheral neuropathy, adrenal insufficiency, and leukodystrophy.

Evaluation

The initial diagnostic step identifies clinical features and demonstrates 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] Patients with mild disease 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 spectrum disorder 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 reported include:

• 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 Zellweger spectrum disorder. However, its replacement was not associated with improved neurological symptoms or visual disturbances in randomized controlled trials.[13]
• 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 patients.[14][15]
• Cholic acid: This is a 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 Zellweger spectrum disorder, fat-soluble vitamins are deficient, and the use of cholic acid has been tried in other hepatic function disorders. The FDA has approved it for use in patients. However, there is little evidence regarding its efficacy.[16]
(A1)

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 diagnoses of Zellweger spectrum disorder based on the main presenting symptom are listed below.

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 [6]

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

Complications of Zellweger spectrum disorder include the following:

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