Gaucher Disease                     

Epidemiology

GD is a rare disease with a frequency of about 1 in 50,000 to 1 in 100,000 worldwide, but it’s particularly more common in the Ashkenazi Jewish population (1 in 800 to 1 in 1,000).^6,8 Due to its inheritance pattern, it tends to affect males and females equally.³ The onset of symptoms can vary depending on disease type and severity with milder forms presenting in adulthood and a significant number of individuals with type 1 never receiving any medical attention.^9,10

GD is generally categorized into 3 types: type 1 is the most prevalent, accounting for more than 90% of all cases, and is characterized by the presence of bone disease and the lack of neurologic features. Type 2 and Type 3 both typically involve neurodegeneration.^{7,10,11,12,13}

Pathophysiology

GD is an autosomal recessive inherited disorder that causes a deficiency in the β-glucocerebrosidase enzyme, which is required for glycosphingolipid metabolism.^1,2,3 GD has been associated with >350 different variants in the Glucosylceramidase Beta 1 (GBA1) gene and results in lysosomal accumulation of glucosylceramide within cells, leading to its multisystemic manifestations.⁶

The manifestations of Type 1 GD are caused by the accumulation of engorged macrophages in visceral tissues.¹¹ By contrast, Types 2 and 3 GD have a pathophysiology that leads to neuronal death, possibly due to the inability to break down glucosylceramide, and the accumulation of a derivative neurotoxin, glucosylsphingosine.⁶

Diagnosis

Identifying patients for diagnostic testing remains a challenge in clinical practice, contributing to diagnostic delays and misdiagnoses.^14,15

Although patients are commonly diagnosed in childhood or adolescence, the average age at diagnosis for the most common type of GD (type 1) is 30-40 years of age.⁹

Initial diagnosis is based on laboratory testing and physical examination including:¹⁶

• hematologic (complete blood count, liver function test)
• skeletal (bone mineral density, magnetic resonance imaging (MRI) of hip/spine)
• visceral (MRI of spleen/liver)
• cardiopulmonary (electrocardiogram, chest x-ray)
• central nervous system (neurological exams)

However, a definitive diagnosis requires enzymatic analysis of glucocerebrosidase and can also be supplemented by detection of genetic defects.¹⁷

Type 2 GD, with substantial CNS involvement, is typically diagnosed in infancy, with bulbar signs and oculomotor paresis, while Type 3 GD is typically diagnosed in childhood or adolescence, often with a progression of CNS involvement.¹¹

Navigating Gaucher Disease

Several factors are consistently elevated in GD and can therefore be used as potential biomarkers to:⁸

• Aid in the diagnosis and monitoring of disease progression^8,18
• Provide insight into disease pathophysiology¹⁹
• Aid in the development of GD-specific treatments^19,20

Traditional biomarkers (chitotriosidase and CCL18) have demonstrated low sensitivity and lack specificity.²¹ Glucosylsphingosine (Lyso-Gb1) has been associated with 100% sensitivity/specificity, is correlated with liver volume and bone marrow fat fraction, and with severity of variants in the GBA gene.^4,18,21