Since GD manifestations are variable, a high level of suspicion is required to ensure a timely diagnosis.
By Dr. Sankar VH
A rare lysosomal storage disease (LSD), Gaucher disease (GD) affects less than 20,000 people globally, with some remaining undiagnosed. An inherited genetic disorder, it was first described by French physician Philippe Gaucher in 1882.
Significantly, GD is considered one of the most frequent LSD among all ethnic groups. The natural history and clinical manifestations of GD remain highly heterogeneous, showing extreme ethnic and geographic variations. The metabolic defect manifests due to a deficiency of acid β-glucosidase (lysosomal glucocerebrosidase) because of biallelic mutations in the GBA gene. This leads to the accumulation of glucocerebroside in lysosomes, typically in tissue macrophages.
In layman’s terms, people with GD lack an enzyme that breaks down lipids or fatty substances. The lipids then begin building up in specific organs such as the spleen and liver.
Immune cells, hepatocytes and osteoblasts are among other cells linked to disease pathophysiology. Gaucher cells (glucocerebroside-laden macrophages) that accumulate across the body characterise its multi-systemic disease manifestations.
Disease Burden in India
Given the convention of consanguineous weddings in some parts of India, the occurrence of GD in the country could be higher. Of 300-plus GD mutations classified in India, L444P seems the most prevalent.
Broadly, Gaucher disease is categorised into three phenotypes, depending on the presence or lack of neurological manifestations and their severity. Type 1 is the most common, affecting around 95% of those with the disorder. Such patients lack adequate platelets in their blood, making them prone to bruising easily and feeling fatigued.
Manifestation and Complications
Those with type 1 GD in India manifest the symptoms in early infancy up to late childhood, with 3.6 years being the median age. Without treatment, this extremely aggressive phenotype with cytopenia, spleno-hepatomegaly, irritability, bone issues and failure to thrive is linked to early mortality.
Type 2 is a form of GD that affects infants within the first three to six months. Since it is fatal, these children don’t survive more than two years. As for type 3, unlike in Western nations, it is comparatively common in India. In such patients, a common, early neurological manifestation includes oculomotor apraxia. To help differentiate between type 1 and 3 GD, this ocular sign needs to be evaluated in every patient during each clinic visit.
A range of complications arises in GD. These include splenic rupture; bleeding diathesis due to thrombocytopenia and acquired coagulopathy; hypersplenism and pancytopenia; fractures and collapsed vertebral bodies; hepatic fibrosis; portal hypertension; avascular osteonecrosis, chronic bone pain and bone crisis; haematological malignancies (multiple myeloma and hepatocellular carcinoma); hepatopulmonary syndrome; Parkinson’s disease with Lewy body dementia; and progressive neurodegenerative disease in GD type 2 and 3.
Diagnosis and Treatment
Since GD manifestations are variable, a high level of suspicion is required to ensure a timely diagnosis. Due to frequent diagnostic delays, patients can develop severe and irreversible complications. As a result, it is mandatory to undertake leucocyte acid β-glucosidase activity to establish GD diagnosis.
Management of GD includes ERT (enzyme replacement therapy) and SRT (substrate reduction therapy). For GD type 1 and 3, ERT is the preferred standard of care. With early therapy initiation, the favourable outcomes can be achieved before irreversible and potentially life-threatening complications emerge.
But ERT is not recommended in cases of progressive neurological symptoms such as neuro-regression and seizures, as the blood-brain barrier cannot be breached. Herein, the recommendations are for diagnosis, therapy initiation, monitoring and follow-ups of patients. Additionally, in India, preventing the recurrence of GD through prenatal diagnosis and genetic counselling is imperative because of the consistently severe phenotypes that occur in the local populace.
ERT greatly improves haematological and skeletal manifestations while ameliorating organomegaly and preventing avascular necrosis. Usually, GD patients in India are affected more severely with earlier disease onset than those in the West. Therefore, ERT can be considered even after the occurrence of avascular osteonecrosis since studies show that it reduces the risk of these complications.
A lifelong treatment, ERT is given once every 14 days as an intravenous infusion. As a recombinant enzyme that needs reconstitution before infusion, one must strictly adhere to the precautions stated in the pack insert to obtain optimum drug activity. Yet, as disease manifestations are heterogeneous, personalised modification of doses on a need basis could be necessary.
Coming to SRT, this works by partially blocking the body from making glucocerebroside – the fatty chemical that accumulates in the bodies of GD patients. While excess glucocerebroside is broken down by ERT, SRT works differently. While ERT helps the body in recycling more waste (glucocerebroside), SRT assists it in producing less of this. Although it doesn’t wholly shut down production, it allows the present enzymes to keep one’s body in balance.
Ultimately, the management of GD requires a multidisciplinary approach. This team generally includes a geneticist, gastroenterologist, haematologist, paediatrician, neurologist, orthopaedic surgeon and occupational therapist. By following the standard therapy guidelines, physicians and allied healthcare providers can ensure the efficient management of patients with Gaucher disease.
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