Zellweger Spectrum Disorder

Zellweger spectrum disorder is a group of autosomal recessive peroxisome biogenesis disorders caused by biallelic variants in PEX genes, ranging from the severe Zellweger syndrome through neonatal adrenoleukodystrophy to the milder infantile Refsum disease. PEX1 is the commonest gene involved.

Pathophysiology. PEX genes encode peroxins, which assemble functioning peroxisomes. Failure of import of peroxisomal enzymes causes deficiency of plasmalogens and bile acid synthesis, with accumulation of very long chain fatty acids, phytanic acid, pristanic acid and bile acid intermediates.

Defects in bile acid synthesis cause liver disease and fat soluble vitamin deficiency.

Severity correlates with the residual peroxisomal function.

• Severe neonatal hypotonia, poor feeding and seizures
• Dysmorphism: a high forehead, flat facial profile, large anterior fontanelle, and epicanthic folds
• Liver disease: hepatomegaly, cholestasis and coagulopathy
• Renal cortical cysts, and calcific stippling of the patella and other epiphyses
• Retinopathy and cataracts, sensorineural hearing loss
• Adrenal insufficiency
• Developmental delay or regression, and leukodystrophy
• Milder phenotypes: hearing loss, retinal dystrophy, mild developmental problems and enamel defects
• Fat soluble vitamin deficiency with bleeding, rickets and night blindness

• Plasma very long chain fatty acids, phytanic acid, pristanic acid, and plasmalogens in red cells, with bile acid intermediates in plasma or urine.
• PEX gene sequencing, usually in a panel or exome sequencing, with deletion and duplication analysis.
• Brain MRI: cortical migration defects, hypomyelination and subependymal cysts.
• Liver tests, clotting studies and vitamin levels (A, D, E, K).
• Cortisol and ACTH to assess adrenal function.
• Ophthalmology, audiology and renal ultrasound.
• Prenatal diagnosis by testing of chorionic villi or amniotic fluid in a family with known variants.

Differential diagnosis.

• Isolated single enzyme peroxisomal disorders (D-bifunctional protein deficiency, acyl-CoA oxidase deficiency)
• Rhizomelic chondrodysplasia punctata
• Congenital disorders of glycosylation
• Neonatal cholestasis from other causes
• X-linked adrenoleukodystrophy and Smith-Lemli-Opitz syndrome

• Bile acid therapy: cholic acid 5 to 15 mg/kg orally daily in one or two doses to suppress abnormal bile acid synthesis, with monitoring of liver enzymes and bile acids. Ursodeoxycholic acid 10 to 15 mg/kg twice daily may be added for cholestasis.
• Fat soluble vitamins: vitamin K 1 to 5 mg orally daily, vitamin D 400 to 800 international units daily (higher doses for deficiency), vitamin A 5000 international units daily, and vitamin E 10 to 15 international units/kg daily, with levels checked every 3 to 6 months.
• Adrenal insufficiency: hydrocortisone 8 to 10 mg/m2 daily in three divided doses, increased during illness, and in crisis 50 to 100 mg/m2 (maximum 100 mg) intravenously.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with other agents by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Feeding and nutrition: gastrostomy and a calorie dense diet.
• Sensory care: cataract surgery when indicated, hearing aids or cochlear implants.
• Kidney and bone care: monitor kidney function, and treat rickets and hypocalcaemia.
• Development and communication: early intervention, physiotherapy, and special education.
• Palliative care input in severe forms, with attention to comfort and feeding.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Milder phenotypes (infantile Refsum disease): hearing loss and retinal disease dominate; check vitamin levels and plan sensory support.

Monitoring. Liver tests, clotting studies and bile acids every 3 months on cholic acid. Vitamin levels every 3 to 6 months, cortisol response yearly, and audiology and eye review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine, hepatology and neurology. Emergency for bleeding, adrenal crisis or prolonged seizures.