Gaucher

General symptoms include anemia, thrombocytopenia, chronic fatigue, bleeding, splenomegaly, and bone involvement. Type 1 is the most common and least severe form, typically presenting in adulthood with hepatosplenomegaly, anemia, thrombocytopenia, bone pain, osteopenia, and fractures. Type 2 and type 3 are more severe and usually present in infancy or childhood. Type 2 presents with severe neurological symptoms such as seizures, strabismus, oculomotor apraxia, and hypertonia, while type 3 has neurological symptoms that develop more slowly, most often including slowing of the horizontal saccadic eye movements, and may not be as severe as in type 2. All types can present with osteoporosis, avascular necrosis of the femur, pancytopenia, pulmonary manifestations, and failure to thrive.¹

The nonspecific and often hematologic presenting symptoms of GD1 frequently lead to a delay in the correct diagnosis and appropriate treatment. Misdiagnoses lead to underlying symptom progression, often in the skeletal system, and negative effects on patient health and QoL. Often, other hematologic malignancies are considered first, leading to burdensome specialist referrals and bone marrow biopsies.

Gaucher disease can be diagnosed by enzyme assay, DNA testing, bone marrow biopsy, organ biopsy, or a combination of these methods.

Enzymatic testing of peripheral blood samples is the definitive diagnostic tool; results of the assay directly identify the causal enzyme deficiency in leukocytes. However, false negatives or positives are not uncommon (up to 30%) when enzyme testing is used to detect carrier status.²

The decreased acid β-glucosidase activity of <30% of the normal values in peripheral blood leukocytes or cultured skin fibroblasts is diagnostic for Gaucher. Enzyme testing is diagnostic but not predictive of clinical course; residual enzyme activity is not associated with clinical outcomes.

Gene sequencing can be used to confirm Gaucher diseases carriers and gives additional insight into disease progression associated with particular allele combinations as well.

Biochemical markers such as chitotriosidase and chemokine CC motif ligand 18 (CCL18) may be used as supplementary diagnostic tools.³ Elevations in the chemokine CCL18 are indicative of Gaucher disease but may not proportionally reflect symptom severity.

Another key biomarker, glucosylsphingosine (Lyso-GL1) has also been identified as a promising indicator of disease burden and treatment response in patients with GD1.

The treatment of Gaucher’s disease aims to manage the clinical signs and symptoms of the disease.

Two treatment approaches aimed at lowering GL-1 levels are currently available for Gaucher disease Type 1: enzyme replacement therapy (ERT) with recombinant acid β-glucosidase, which augments the deficient enzyme activity in patients and catabolizes stored GL-1 in lysosomes, and substrate reduction therapy (SRT), which acts by partially inhibiting the enzyme glucosylceramide synthase (GCS), thereby reducing the rate of synthesis of GL-1 to better match the impaired rate of catabolism.

Treatment typically involves enzyme replacement therapy (ERT) which can help reduce symptoms and prevent complications.

Bone marrow transplantation may also be considered in certain cases.

The complications of Gaucher disease can lead to premature mortality; estimated life expectancy among patients with GD1 is about 9 years lower compared with the US general population.

Delays in the diagnosis of Gaucher disease can lead to severe, sometimes irreversible complications, including bone complications (e.g., chronic bone pain, osteonecrosis, osteofibrosis, lytic lesions, AVN, and bone crises), severe and life-threatening bleeding, growth failure, and functional and symptomatic consequences of visceromegaly (e.g., acute abdominal pain).

Common complications include Parkinson disease   and increased risk of malignancy such as multiple myeloma and lymphoma. Type II Gaucher disease, also known as infantile Gaucher disease, has a poor prognosis with death occurring within the first years of life. Neurodegeneration is a common complication in type III Gaucher disease, also known as juvenile Gaucher disease.