Thompson & Thompson Genetics in Medicine, 8th Edition

Case 18. Type I (Non-Neuronopathic) Gaucher Disease (GBA1 Mutation, MIM 230800)

Autosomal Recessive


• Variable expression

• Asymptomatic homozygotes

Major Phenotypic Features

• Age at onset: Childhood or early adulthood

• Hepatosplenomegaly

• Anemia

• Thrombocytopenia

• Bone pain

• Short stature

History and Physical Findings

An 8-year-old Ashkenazi Jewish girl presented to clinic with easy bleeding and bruising, excessive fatigue, short stature, and enlargement of the belly. Abdominal ultrasound examination showed enlarged liver and spleen; complete blood count showed pancytopenia, and skeletal survey showed Erlenmeyer flask deformity Her parents were healthy and had another 6-year-old healthy child. Neither parent had a family history of bone anomalies, blood disease, or liver and spleen disease. Consistent with her clinical history and physical features, she had decreased β-glucocerebrosidase activity in leukocytes. DNA testing identified an Asn370Ser homozygous mutation in GBA1.


Disease Etiology and Incidence

Type 1 (non-neuronopathic) Gaucher disease (MIM 230800) is the most prevalent lysosomal storage disorder as well as the most common Gaucher disease phenotype, accounting for more than 90% of all Gaucher disease patients. It is an autosomal recessive disorder caused by mutations in GBA1 gene causing β-glucocerebrosidase deficiency. Type 1 Gaucher disease has a prevalence worldwide of 1 in 50,000 to 1 in 100,000, but it is as high as approximately 1 in 480 to 1280 in individuals of Ashkenazi heritage.


The defect in Gaucher disease is an inherited deficiency of the lysosomal enzyme acid β-glucosidase (glucocerebrosidase), which results in the accumulation of glucocerebroside within lysosomes of macrophages. Systemic accumulation of these glycolipid-lipid engorged cells (known as Gaucher cells) results in variable combinations of splenomegaly with associated abdominal discomfort; anemia associated with chronic fatigue; bleeding due to thrombocytopenia and/or Gaucher disease–related coagulopathy; hepatomegaly; abnormal results for tests of liver function; and a diverse pattern of bone disease. Increased susceptibility to infections may result from impaired neutrophil function and neutropenia. Rarely, the lungs, lymphatic system, skin, eyes, kidneys, and the heart are involved and, in the rare neuronopathic forms, neurodegenerative disease results. Gaucher disease is traditionally classified into three broad phenotypic categories: type 1 (non-neuronopathic disease); type 2 (MIM 230900), a fulminant neuronopathic disease that is fatal during infancy; and type 3 (MIM 231000), chronic neuronopathic disease, which usually results in death in childhood or early adult life. More than 350 GBA1 mutations have been identified to date. The GBA1 mutation spectrum varies widely according to ethnic group, and homozygosity for the Asn370Ser mutation is the most common genotype in the Ashkenazim, in whom it accounts for 70% of all disease alleles. The most common disease allele of GBA1 worldwide is the Leu444Pro mutation, which occurs in the sequence of the closely linked pseudogene; it is believed that gene conversion leads to the mutation in the active gene. The most frequent genotype of type 1 Gaucher disease in populations of European descent is Asn370Ser/Leu444Pro. This genotype generally leads to more severe disease compared with Asn370Ser homozygosity.

Phenotype and Natural History

The broadest phenotypic spectrum in Gaucher disease with respect to age of onset, rate of progression, and organs affected occurs in type 1 Gaucher disease. Symptoms may present in early childhood, and asymptomatic grandparents may be identified by their symptomatic grandchildren. Patients are often identified by splenomegaly in childhood or early adulthood. Hepatomegaly is usually not as severe as splenomegaly. Thrombocytopenia and anemia are easily observed, and skeletal findings such as osteopenia, osteonecrosis, bone pain, short stature, scoliosis, and multiple fractures are also noted. B-cell lymphoma is an atypical manifestation, but multiple myeloma may occur as a late complication.


A bone marrow or liver biopsy is sometimes done to diagnose Gaucher disease by revealing typical Gaucher cells, macrophages filled with lipid material, but the gold standard is to confirm deficient β-glucocerebrosidase activity in leukocytes. This noninvasive test is both sensitive and specific. Genetic tests can be used as an effective tool for diagnosis as well, but molecular analysis of GBA1 is complicated by the presence of a highly homologous pseudogene that harbors several mutations, which, if present in the active gene, would lead to Gaucher disease. A negative screen for common GBA1 mutations does not exclude Gaucher disease. Thus, sequencing of the entire coding region of GBA1 is recommended in patients strongly suspected of Gaucher disease when a screen for common mutations is negative. Mutation analysis of the GBA1 may provide some prognostic information, although there is considerable variation of disease severity among patients with identical GBA1 genotypes. Increased activity of biomarkers, such as acid phosphatase, angiotensin-converting enzyme, chitotriosidase, and ferritin, can also be used to identify disease activity.

Since 1993, when recombinant β-glucocerebrosidase became available, enzyme replacement treatment (ERT) has remarkably improved the clinical outcome of Gaucher disease patients (Fig. C-18). Particularly, hepatosplenomegaly and hematological abnormalities show notable improvement under ERT in patients with both the non-neuronopathic and chronic neuronopathic types. ERT is currently the standard treatment for non-neuronopathic Gaucher disease, and notably, levels of biomarkers (including chitotriosidase, acid phosphatase, and angiotensin-converting enzyme) decrease with ERT. However, because the recombinant enzyme cannot cross the blood-brain barrier, it cannot prevent neurological deterioration in patients with neuronopathic Gaucher disease. Other variants of macrophage-targeted enzyme replacement therapies for this disorder are undergoing clinical trials: velaglucerase, a human fibroblast–derived enzyme, was recently approved for treatment of type 1 Gaucher disease and taliglucerase, a plant-derived enzyme is in clinical trials.


FIGURE C-18 A, T1-weighted coronal image of the pelvis and femurs of a 5-year-old child with Gaucher disease before treatment with enzyme therapy. There is classic Erlenmeyer flask deformity of the distal femurs and abnormal marrow distribution with intermediate signal in the proximal and distal femoral epiphyses and diaphyses. B, T1-weighted coronal image of the femurs approximately 1 year after initiating enzyme therapy for treatment of Gaucher disease. The marrow distribution shows increased signal, indicating it has returned to normal. Erlenmeyer flask deformities of the femora remain, however. See Sources & Acknowledgments.

Substrate reduction therapy (SRT; miglustat [Zavesca]) is approved for patients with mild Gaucher disease who are unable to receive ERT. SRT with N-butyldeoxynojirimycin (miglustat), a small iminosugar molecule, reversibly inhibits glucosylceramide synthase, the ceramide-specific glucosyltransferase that catalyzes the first committed step in glycosphingolipid synthesis, and in this way reduces intracellular storage of glucosylceramide. Recent data confirmed miglustat efficacy in the long-term maintenance therapy of type 1 Gaucher disease with a positive impact of miglustat on both bone marrow and bone tissue. A more specific and potent inhibitor of glucosylceramide synthesis, eliglustat tartrate, is currently in Phase III trials, having shown efficacy and safety in Phase II trials.

Inheritance Risk

For unaffected parents with a child affected with type 1 Gaucher, the risk for recurrence in their future children is 25%, and knowledge of the GBA1 mutation in a proband facilitates family screening for genetic counseling purposes because heterozygote carriers cannot be reliably identified by enzyme assays. Penetrance, however, can be very variable.

Questions for Small Group Discussion

1. Name and discuss other disorders for which enzyme replacement therapy has been used.

2. How do the mutations in GBA1 affect mRNA and protein production?

3. The reason for the a high rate of asymptomatic homozygotes for the N370S mutation in GBA1 is unknown. What possible explanations might there be for this finding?

4. How has chemical chaperone therapy been used in Gaucher disease?


Desnick RJ, Schuchman EH. Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet. 2012;13:307–335.

Mignot C, Gelot A, De Villemeur TB. Gaucher disease. Handb Clin Neurol. 2013;113:1709–1715.

Pastores GM, Hughes DA. Gaucher disease. [Available from]

Thomas AS, Mehta A, Hughes DA. Gaucher disease: haematological presentations and complications. Br J Haematol. 2014;165:427–440.