Gaucher disease

Gaucher disease encompasses a clinical spectrum from perinatal-lethal disease to asymptomatic adult presentations. Three major clinical types are delineated by the absence (type 1) or presence (types 2 and 3) of primary central nervous system involvement. Type 1 predominantly causes visceral, haematological, and skeletal disease with onset across childhood, adolescence, and adulthood, whereas types 2 and 3 manifest in infancy with neuronopathic features. Bone disease is a major manifestation of type 1 Gaucher disease and ranges from asymptomatic osteopenia to focal lytic or sclerotic lesions, osteonecrosis, pathological fractures, and chronic bone pain. Haematological manifestations are common and include anaemia, thrombocytopenia, and, less frequently, leukopenia, occurring alone or in combination. Type 2 is characterised by bulbar and pyramidal signs in infancy, and type 3 by oculomotor apraxia and saccadic initiation failure. Affected individuals also have an increased risk of multiple myeloma and parkinsonism.

The estimated prevalence of Gaucher disease across types is 0.02-1.1:100,000 in European populations.

Gaucher disease is caused by biallelic germline pathogenic variants in GBA1 (locus 1q22), which encodes lysosomal acid glucocerebrosidase (also termed glucosylceramidase). Deficient enzyme activity leads to accumulation of the undegraded substrate glucosylceramide (GL1) and other glycolipids in cells of the monocyte/macrophage lineage of the reticuloendothelial system.

Gaucher disease is inherited in an autosomal recessive manner. Each pregnancy of two heterozygous parents carries a 25% risk of an affected child, a 50% risk of an asymptomatic heterozygous carrier, and a 25% chance of an unaffected non-carrier. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis is established by demonstration of 0-15% of normal glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells. Identification of biallelic pathogenic variants in GBA1 through molecular genetic testing confirms the molecular diagnosis.

Main differential diagnoses include:

• Saposin C deficiency: visceromegaly and GL1 accumulation with normal glucocerebrosidase activity in vitro; PSAP
• type C: hepatosplenomegaly with vertical supranuclear gaze palsy and foam cells rather than Gaucher cells; NPC1, NPC2
• Acid sphingomyelinase deficiency: hepatosplenomegaly with cherry-red spot on fundoscopy (type A) and absence of Gaucher cells; SMPD1

• Establishing the diagnosis: a confirmed molecular diagnosis ends the diagnostic odyssey, enables informed prognostic discussion, and provides a definitive basis for further management.
• Specific and individualised surveillance and clinical management: identification of the causative pathogenic variants enables condition-specific surveillance for emerging manifestations and adjustment of supportive measures, as a prerequisite for targeted medical care guided by the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variants enables predictive and carrier testing of at-risk relatives, supporting informed reproductive and family-planning decisions.

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