Gaucher Disease – Common among rare

Lysosomal Storage Disorders: rare but not alone. In the mid 1950s, biochemist Christian de Duve discovered ‘dense bodies, surrounded by a membrane’ within the cell. He called these organelles lysosomes (from lysis, to lyse and soma, body). We now know that the lysosomal system is a tightly regulated cellular compartment, responsible for the degradation and recycling of a variety of biomolecules.
Mutations in the genes encoding lysosomal proteins lead to a variegate group of genetic metabolic diseases called Lysosomal Storage Disorders (LSDs). These include more than 60 different disorders, which are mainly caused by accumulation of biological material in the cells throughout the body. LSDs share common clinical features with multi-organ presentation involving viscera, central and peripheral nervous system. Despite being individually rare, LSDs are collectively frequent with a combined prevalence of 1:7,000 people worldwide.

Gaucher: common among rare. Gaucher Disease (GD) is the most common LSD, with an approximate prevalence of 1 in 100,000 people. It was named after Philippe Gaucher, who first described the typical enlarged spleen cells in 1882. It was only in the 1950s that the condition was defined as a genetic disorder, characterised by mutations in the GBA gene and the inability of the defective lysosomal enzyme β-glucocerebrosidase (GCase) produced by it to degrade its substrate glucosylceramide (GluCer).
GD has been historically classified into three types. Type I is the most frequent form, characterised by enlargement of the spleen and liver, extensive blood and bone disease and pulmonary involvement. Symptoms have a wide range of onset, spanning from early infancy to adulthood. Type II is the acute neuropathic form of Gaucher (nGD). nGD presents with systemic manifestations accompanied by severe neurological symptoms. The onset is in the perinatal period and premature death occurs by two year of age. Type III is the chronic form, where the progression of the disease is slow and lifespan can be prolonged to early adulthood.
On a cellular level, defects in the GCase enzyme result in the build-up of lipids in various cell types, including cells of the nervous system. The accumulation process increases the production of activated immune cells (the so-called Gaucher cells), which contribute to inflammation, cell loss and disease progression.

Neurological components create a spectrum of phenotypes. GD presents a complex multi-systemic pathology. A more recent clinical assessment has revealed that Gaucher disease exhibits a continuum of phenotypes, where type I patients may also occasionally manifest neurological symptoms.
nGD is characterised by widespread accumulation of Gaucher cells throughout the brain, neuronal loss, atrophy, necrosis and extensive inflammation. As a consequence, activated immune cells release additional neurotoxic molecules further contributing to the rapid neurodegeneration.
In recent years, many studies have demonstrated that mutations in the GBA gene are an important risk factor for developing Parkinson’s disease. α-synuclein inclusions and loss of dopaminergic neurons have been found in Gaucher patients with parkinsonian symptoms. However, the exact mechanisms through which GBA mutations can promote Parkinson’s are still not fully understood.

Therapeutic options: from ERT to gene therapy. Currently there are different treatment options available for the non-neurological symptoms. Enzyme Replacement Therapy (ERT) is successfully administered in combination with other standard treatments, resulting in reduced systemic manifestations in the viscera. Although ERT has revolutionised the treatment of type I patients, it presents a number of drawbacks including the need for regular and expensive infusions for the duration of the patient’s life. Moreover, ERT is not a viable treatment for the brain pathology of type II and III patients.
Different pharmacological and gene therapy approaches suitable for nGD patients are currently under investigation. In particular, prenatal gene therapy has shown promising results preventing the severe neurological damage from occurring in the first place and therefore offering the earliest possible cure necessary to treat the severe nGD neuropathology.

For more information on Gaucher disease visit: https://www.gaucher.org.uk

Written by Giulia Massaro; Edited by Radhika Menon; Featured image by NGC/Design.

Giulia Massaro, PhD. Italian living abroad by choice, gene therapist by chance. I am a postdoctoral research associated with University College London, investigating novel treatments for rare neurological disorders. My work focuses on addressing the unmet need of life-changing therapies for lethal diseases and translating academic research to the clinic.

References:

Platt FM. Sphingolipid lysosomal storage disorders. Nature, 510 (2014).

Grabowsky GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet, 371 (2008).

Lal T. & Sidransky E. The spectrum of neurological manifestations associated with Gaucher disease. Diseases, 5 (2017).

Pastores GM. & Hughes DA. Gaucher disease. GeneReviews (2018).

Massaro G. et al. Fetal gene therapy for neurodegenerative diseases of infants. Nat Med, 24 (2018).