Gaucher Disease

Gaucher disease is the commonest lysosomal storage disorder, with an incidence of about 1 in 40,000 to 60,000 (1 in 800 in Ashkenazi Jews).

It is autosomal recessive, due to deficiency of glucocerebrosidase (beta glucosidase; GBA1, 1q21), causing lipid laden macrophages (Gaucher cells) in the spleen, liver, bone marrow and, in neuronopathic forms, the brain.

The common variants are N370S (type 1 protective for neurological involvement), L444P (neuronopathic types 2 and 3), 84GG, and IVS2+1G>A. GBA1 heterozygosity is a major risk factor for Parkinson disease.

Types: type 1 (non-neuronopathic; about 90% in the West), type 2 (acute neuronopathic, infantile), and type 3 (chronic neuronopathic, including the Norrbottnian type with horizontal supranuclear gaze palsy).

• Type 1: massive splenomegaly (with hypersplenism), hepatomegaly, anaemia, thrombocytopenia with bruising and bleeding, bone disease (bone pain crises, Erlenmeyer flask deformity of the distal femur, osteonecrosis, pathological fractures, osteopenia), fatigue, growth delay, and increased risk of myeloma, gammopathy (monoclonal and polyclonal), and Parkinson disease
• Type 2: onset before 6 months, with hepatosplenomegaly, severe neurological deterioration (retroflexion of the head, trismus, strabismus, laryngospasm, apnoea), and death by 2 years
• Type 3: variable onset, with hepatosplenomegaly, horizontal supranuclear gaze palsy, ataxia, myoclonic epilepsy, and cognitive decline
• Pulmonary hypertension, interstitial lung disease, and hepatopulmonary syndrome in severe cases

1. Glucocerebrosidase enzyme assay in leucocytes or dried blood spot (activity below 15% of normal; diagnostic).
2. GBA1 genotyping (sequencing, as pseudogene interference makes testing technically challenging), for prognosis, family counselling and carrier detection.
3. Biomarkers: plasma chitotriosidase (markedly elevated; unhelpful in chitotriosidase deficiency), CCL18/PARC, and glucosylsphingosine (lyso-Gb1; most sensitive and specific marker for diagnosis and monitoring).
4. Full blood count, ferritin (often elevated), liver function tests, protein electrophoresis (monoclonal gammopathy), and coagulation studies.
5. Imaging: MRI of spleen and liver volumes (multiples of normal), MRI of femora and spine (Bone Marrow Burden score), and DXA.
6. Bone marrow biopsy is not needed when enzyme tests are done (but shows Gaucher cells).

• Enzyme replacement therapy (first line for symptomatic type 1 and type 3): imiglucerase 30 to 60 units/kg IV every 2 weeks (lower starting doses of 2.5 units/kg three times a week are used in some regions), velaglucerase alfa 60 units/kg every 2 weeks, or taliglucerase alfa 60 units/kg every 2 weeks. Response: haemoglobin and platelet improvement in 6 to 12 months, spleen and liver reduction over 2 to 5 years, and prevention of bone disease with early treatment. Antibodies are uncommon.
• Substrate reduction therapy: eliglustat 84 mg once or twice daily by oral route in adults with type 1 (according to CYP2D6 metaboliser status; contraindicated in CYP2D6 ultra rapid metabolisers and with strong CYP2D6 or CYP3A inhibitors; QT monitoring), and miglustat 100 mg three times daily for patients unsuitable for ERT.
• Neuronopathic disease: ERT does not cross the blood brain barrier; venglustat is under investigation; haematopoietic stem cell transplantation is limited; supportive care with antiepileptics and palliative support for type 2.
• Bone disease: bisphosphonates (alendronate, zoledronic acid) for osteoporosis, analgesia for bone crises, joint replacement for osteonecrosis, vitamin D and calcium.
• Splenectomy is now rarely needed (reserved for refractory cytopenias or splenic rupture), because of increased bone, liver and pulmonary risk.
• Monitoring: haemoglobin and platelet count, spleen and liver volumes, biomarkers, and bone imaging every 6 to 12 months initially, then annually; Parkinson symptoms, gammopathy and myeloma surveillance.
• Pregnancy: ERT is continued, with haematological monitoring.
• Genetic counselling: 25% recurrence risk, with carrier screening in high risk groups.