A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

Abstract

Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).

Gaucher’s disease Type I: a case report

“…Thus, Type 1 is differentiated from others based on the absence of neurological impairment, but in recent years few neurological manifestations particularly Parkinson's disease and peripheral neuropathies have been reported. Ocular motor impairment, progressive myoclonic epilepsy, cerebellar ataxia, spasticity and dementia are well documented in juvenile subacute neurological Gaucher's disease Type 3; whereas opisthotonus, bulbar palsy, trismus, psychomotor retardation and hypertonia are mostly reported in paediatric Gaucher's disease Type 2 [4].…”

“…Due to non-availability of resources these genetic tests were not performed. These gene-mutations cause loss of function or decreased level of glucocerebrosidase resulting in slowdown of lysosomal α-synuclein degradation and accumulation of intracellular-glucocerebroside which further inhibits glucocerebrosidase activities or its production by blocking trafficking from the endoplasmic reticulum to the golgi leading to accumulation of α-synuclein containing cells and, later, form insoluble aggregates of Lewy bodies [4,5]. These toxic aggregates increase in the substantia nigra of the mid-brain resulting in symptoms of Parkinson's disease and the frontotemporal (Hippocampal) region resulting in progressive neuro-psychiatric symptoms.…”

“…These toxic aggregates increase in the substantia nigra of the mid-brain resulting in symptoms of Parkinson's disease and the frontotemporal (Hippocampal) region resulting in progressive neuro-psychiatric symptoms. The onset and progression of these symptoms principally depend on the site where these substances are initially deposited [4].…”

“…According to previous studies, osteopenia and bone marrow infiltration and bone pain regress with intravenous enzyme replacement therapy. However, none of the above treatments seems to improve the neurological symptoms of Gaucher's disease [4].…”

Encore! Oral therapy for type 1 Gaucher disease

“…The 3 products currently approved in the United States, imiglucerase (1995), velaglucerase alfa (2010), and taliglucerase alfa (2012), differ slightly in amino acid structure and glycosylation, but are similar in terms of efficacy and safety. Exogenous glucocerebrosidase augments the attenuated activity of the patient's mutant glucocerebrosidase, thus restoring sphingolipid homeostasis 6 (see figure).…”