A child with a rare disease presented in clinic for well child care and the mother reminded the pediatrician of another family she had taken care of while a resident. This family had come from another state to attend a professional conference and see their extended family. Their infant son came to the emergency room of the children’s hospital because of breathing difficulties and was noted to have hepatosplenomegaly and developmental delay. He was admitted to the intensive care unit because of poor respiratory effort and new onset seizures. He was eventually diagnosed with Gaucher Disease but at that time there was no treatment available. The pediatrician remembers the conversation when the family was told and the grief yet calmness on the mother’s face. She was a strong and practical woman, who took her time asking questions, but eventually keyed in on how she could get her baby home to die. The pediatrician had been tasked with arranging the medical transport and remembered the mother putting a special blanket over the child as they left the unit to travel to the airport.
Gaucher disease (GD) was first described by Philippe Gaucher in 1882. It was the first lysosomal storage disease (LSD) described and is the comparison prototype for many variations and their treatment. There are about 50 LSD and more well-known ones include Fabry, Niemann-Pick and Pompe diseases. LSDs currently have more than 300 different enzymes or membrane proteins affected which cause central nervous system and visceral disease. Overall the frequency of LSDs in aggregate is 1:3000 – 7000 live births. GD has an estimated prevalence of 1:57,000 – 111,000. It is higher within the Ashkenazi Jewish population (~1:850).
GD is an autosomal recessive disease whose main enzyme defect is acid β-glucosidase which causes accumulation of glucosylceramide, an indigestible lipid. This occurs in macrophage-lineage organs. Activated macrophages also affect a number of inflammatory pathways. Therefore organ systems are affected by lipid accumulation but also inflammation. Primary systems affected are the liver, spleen, bone marrow, lungs and central nervous system but other systems are also affected depending on the phenotype.
GD diagnosis may not occur until later ages when clinical manifestations occur. Splenomegaly is the presenting symptom for 95-99% of patients depending on the age. Diagnosis is by showing deficient enzyme activity in an appropriate tissue such as peripheral blood leukocytes. Genotyping can be helpful to help determine natural history and for genetic counseling. Genetic screening of high risk populations such as Ashkenazi Jews is performed as is newborn screening in certain US states. There are 3 types of GD.
- GD type 1
- 95% of cases
- Sometimes described as adult disease but usually diagnosed by age 20 because of some symptoms in childhood especially hepatomegaly, splenomegaly, and bone disease
- Clinical manifestations include hepatomegaly, splenomegaly, avascular bone disease or bone marrow fibrosis, delayed puberty, delayed growth, and pancytopenia
- GD type 2
- Acute neuronopathic GD
- Newborns and infant
- Severely affected with oculomotor, brainstem problems, hypotonia, spasticity and seizures. Lung involvement with respiratory distress is common.
- Usually die within 2 years
- GD type 3
- Chronic neuronopathic disease with 3 of its own subtypes
- Clinical manifestations include hepatosplenomegaly, poor growth, delayed puberty, ocular (especially saccadic movement) and cerebral involvement. May also affect other organs such as the heart
GD was the first lysosomal disease treated by enzyme replacement therapy (ERT) used mainly for Type 1. It’s availability came not long after the patient encounter above. ERT uses a mannose receptor which then allows delivery of the enzyme to the lysosomes. Unfortunately enzymes are large molecules and are not capable of crossing the blood-brain barrier and therefore are not effective against neurological manifestations of GD. Response to ERT is measured by changes in spleen and liver sizes which are sensitive indicators. Gene therapy is being tried for Type II as well.
Questions for Further Discussion
1. What is in the differential diagnosis of splenomegaly? A review can be found here
2. What is in the differential diagnosis of hepatomegaly? A review can be found here
3. What is in the differential diagnosis of anemia? A review can be found here
4. What is in the differential diagnosis of thrombocytopenia? A review can be found here
5. What is in the differential diagnosis of lymphopenia? A review can be found here
- Disease: Gaucher’s Disease
- Symptom/Presentation: Genetic Disorder | Inborn Error of Metabolism | Mass or Swelling | Respiratory Distress
- Age: Infant
To Learn More
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Di Rocco M, Andria G, Deodato F, Giona F, Micalizzi C, Pession A. Early diagnosis of Gaucher disease in pediatric patients: proposal for a diagnostic algorithm. Pediatr Blood Cancer. 2014;61(11):1905-1909. doi:10.1002/pbc.25165
Gupta P, Pastores G. Pharmacological treatment of pediatric Gaucher disease. Expert Rev Clin Pharmacol. 2018;11(12):1183-1194. doi:10.1080/17512433.2018.1549486
Grabowski GA. Gaucher disease and other storage disorders. Hematol Am Soc Hematol Educ Program. 2012;2012:13-18. doi:10.1182/asheducation-2012.1.13
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa