Wolman Disease

Wolman disease is the severe infantile form of lysosomal acid lipase deficiency, an autosomal recessive disorder due to biallelic null or near null variants in LIPA. It presents in the first weeks of life with vomiting, diarrhoea, failure to thrive, hepatosplenomegaly and adrenal calcification, and is fatal within months without enzyme replacement therapy.

Pathophysiology. Lysosomal acid lipase hydrolyses cholesteryl esters and triglycerides delivered to the lysosome by lipoproteins. Absent activity causes massive storage in the liver, spleen, intestine, adrenal glands and macrophages.

The storage causes malabsorption, adrenal failure and liver failure.

Haemophagocytic features occur in some infants.

• Onset in the first weeks with feeding intolerance, vomiting and diarrhoea
• Severe failure to thrive and abdominal distension
• Massive hepatosplenomegaly
• Adrenal calcification, with adrenal insufficiency in some
• Anaemia, thrombocytopenia, and fever
• Steatorrhoea and malabsorption
• Liver failure with cholestasis and coagulopathy
• Hyperferritinaemia and haemophagocytic lymphohistiocytosis in some
• Developmental regression is uncommon, as brain disease is not a main feature

• Lysosomal acid lipase activity in dried blood spots, leukocytes or fibroblasts: absent or very low.
• LIPA sequencing with deletion and duplication analysis.
• Imaging: abdominal ultrasound or CT for hepatosplenomegaly and bilateral adrenal calcification.
• Lipid profile: raised total cholesterol and triglycerides, with low HDL, though often only mildly abnormal.
• Liver tests, coagulation studies, ferritin, and blood count.
• Cortisol and ACTH to assess adrenal function.
• Prenatal diagnosis by enzyme assay or variant testing.

Differential diagnosis.

• Niemann-Pick disease type A or B and Gaucher disease
• Haemophagocytic lymphohistiocytosis (primary)
• Cystic fibrosis, congenital infection and other causes of infantile malabsorption
• Neuroblastoma or other causes of adrenal calcification

• Enzyme replacement therapy: sebelipase alfa 1 mg/kg intravenously once weekly for infants with rapidly progressive disease, increasing to 3 mg/kg weekly if response is inadequate, and then up to 5 mg/kg weekly. Premedicate with an antihistamine (cetirizine 2.5 mg twice daily for ages 1 to 5 years) if infusion reactions occur. Keep adrenaline 0.01 mg/kg (maximum 0.5 mg) intramuscularly available because anaphylaxis occurs.
• Nutrition: medium chain triglyceride based or elemental formula, parenteral nutrition for severe malabsorption, and fat soluble vitamin supplementation (vitamin D 400 to 800 international units daily and vitamin K 1 mg daily).
• 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.
• Haematopoietic stem cell transplantation: used before enzyme replacement was available, and still considered in some centres.
• Haemophagocytic lymphohistiocytosis: specialist treatment, and ferritin monitoring.
• Infection: prompt treatment of sepsis and vaccination.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Infants diagnosed in the first weeks: start enzyme replacement therapy urgently, because delay leads to irreversible organ damage.

Monitoring. Growth, liver size, transaminases and ferritin at each visit. Haemoglobin and platelet counts, lipid profile every 3 months, and antibody and infusion reaction surveillance.

Referral and escalation. Refer to clinical genetics, metabolic medicine, gastroenterology and haematology. Emergency for sepsis, bleeding, adrenal crisis or infusion reaction.