What is Wolman disease?
Wolman disease (WD) (Online Mendelian Inheritance in Man number - 278000) is a rare genetic disorder characterized by complete absence of an enzyme known as lysosomal acid lipase (LIPA). Wolman disease, also known as cholest erol ester storage disease is an autosomal recessive disease and has an estimated incidence of 1 in 500,000 live births. The affected neonates present with failure to thrive, vomiting, diarrhoea, jaundice, anemia, hepatospleenomegaly and septicaemia. Milder late onset form is also observed but is less recognised due to lack of awareness about the late onset phenotype. Lysosomal acid lipase is coded by the LIPA gene on chromosome 10q23.3. The gene is encoded by 10 exons spanning 36 kb. A variety of pathogenic variants have been reported to cause LAL deficiency, including missense variants, nonsense variants, single- and double-nucleotide insertions and deletions, complex insertion/deletions, and splice site variants
Lysosomal acid lipase is coded by the LIPA gene on chromosome 10q23.3. The gene is encoded by 10 exons spanning 36 kb. A variety of pathogenic variants have been reported to cause LAL deficiency, including missense variants, nonsense variants, single- and double-nucleotide insertions and deletions, complex insertion/deletions, and splice site variants
When to suspect? What are the clinical features?
WD is a severe, early-onset condition involving massive storage of triglycerides and cholesteryl esters in the liver, intestines, spleen, adrenals and other monocyte-macrophage system cells. This deposition leads to malabsorption, hepatosplenomegaly, liver failure, adrenal cortical insufficiency and death in early infancy. Calcified adrenal glands are characteristic and present in seventy percent of the patients. The disease can sometimes present in the fetus (hepatomegaly, ascitis, and calcified adrenal glands).
There is a milder form presenting in children and adults as hepatomegaly, dyslipemia, and cirrhosis. These patients are at risk of atherosclerosis. Statins and other lipid-lowering medications are not effective in correcting dyslipemia and liver disease which progresses to cirrhosis. increased aminotransferases
How is the disease diagnosed?
The diagnosis is based on finding almost total deficient activity of lysosomal acid lipase in peripheral blood leukocytes and sequencing of LIPA gene (gold standard) to find biallelic pathogenic variants.
What is the treatment?
The treatment has mainly been supportive. It is most important to improve malabsorption, treat liver failure (liver transplantation has been done) and manage adrenal insufficiency. The life expectancy with aggressive symptomatic treatment is only around one year. In 2015, the U.S. Food and Drug Administration (FDA) approved Kanuma (sebelipase alfa) as the first treatment for lysosomal acid lipase (LAL) deficiency. Use of enzyme replacement therapy with recombinant human LAL in short-term studies has shown to be safe and effective. Hematopoietic stem cell transplantation (HSCT) has also been tried and yielded overall mixed results, but is associated with considerable morbidity and mortality
What are the implications for the relatives of the patient?
Being an autosomal recessive disease, the risk of recurrence is 25% in the sibling of a child with WD. Prenatal diagnosis can be performed by measuring enzymatic activity of lysosomal acid lyase or by mutational analysis (gold standard) of chorionic villus samples, once the disease causing mutation is identified in the proband.
Each normal sibling of an affected individual has a 50% chance of being an asymptomatic carrier, and carrier testing for such individulas and others at-risk family members can also be provided by targeted analysis after the disease causing mutation has been identified in the affected family member. Carrier screening is useful especially in families with consanguineous marriages.
Efficacy of recently approved drug, Serelipase alpha in normalizing aminotransferases and improvement in serum lipid profile is remarkable and appears to treat the basic cause. The drug is likely to change the lethal outcome of the disease in infants. With the availability of the drug, more awareness about late onset disease in children and adults is necessary; so that this rare disease with common presentations like hepatomegaly and hyperlipidemia is diagnosed and treated.
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Dr. Shubha R Phadke
Sanjay Gandhi Postgraduate Institute of Medical Sciences