An Insight into the Gaucher phenomenon 1 Shaw, MSc ; Ankit
2 Banik, MSc
Karishma 1Department of Biochemistry and Molecular Biology, Pondicherry University 2Department of Biotechnology, Pondicherry University
Abstract
Gaucher and Cancer
Gaucher disease is a rare, inherited, autosomal recessive disorder, caused due to the deficiency of
Chronic stimulation of the B-lymphocytes by accumulation of GCB: leading to multiple myeloma, chronic
glucocerebrosidase (GCBS) resulting in accummulation of glucocerebroside (GCB), throughout the body
lymphatic leukemia, chronic myeloid leukemia and lymphoma. Features:
especially in spleen , liver and bone marrow.
The accumulated GCB in the lysosomes upon diacylation, diffuses into the cytosol. The sphingosine, one of the by-products of β‐glucosylsphingosine, can aggregate together to exhibit some
It is a lysosomal storage disorder and is also called Gaucher splenomegaly. The symptoms vary greatly from patients to patients and whereas few may be asymptomatic, the others may
kind of carcinogenic activity. The activated macrophages release pro-inflammatory and anti-inflammatory cytokines, chemokines and
develop serious complications. The main goal of the therapies prevalent so far, is to improve the patient’s quality of life by permitting them to
hydrolases.Interleukin-6 and CCL-18 release has been suggested as source molecules to promote gammopathies, and act as signal transducing agent in multiple myeloma.
carry out their normal daily or to reduce the severity of the complications. The study here elucidates the symptoms , diagnosis and the correlation between Gaucher and other severe
Patients with β-glucosidase folding mutation in N370S homozygotes renders them more prone to monoclonal
diseases like cancer and Parkinson’s in order to understand the underlying molecular mechanism.
gammopathy
Gaucher’s and Parkinson’s
Introduction
As the research on Gaucher continues, a higher likelihood of Parkinson’s like symptoms with type 1 Gaucher
Also called cerebroside lipidosis syndrome, it is a rare , inherited lysosomal storage disorder.
disease was seen in patients older than 60.
Accumulation of GCB occur due to deficiency of GCBS.
In the parents of people diagnosed with Gaucher disease or other relatives who are known to be Gaucher
It is the second most common type of lysosomal storage disorder. First discovered by Phillipe Gaucher.
carriers, there ia a higher prevalence of Parkinson’s disease compared to people with comparable age who do
Three distinct types, depending on absence(type 1); presence and extent (type 2 and 3) of neurological
not have Gaucher mutations. The physiologic and biochemical connection between the two is “the autophagic lysosomal system”.
complications. Additionally, perinatal-lethal form and cardiovascular form.
Dysfunction in this system cause Gaucher’s disease or accummulation of GCB in brain
Overview of Gaucher disease: accumulation of glucocerebroside Once the GCB is made , it becomes a part of some cell’s membrane.
These cells eventually become old and are engulfed by macrophages.
The macrophages contain lysosomes , where , the enzyme GCBS breaks GCB.
In Gaucher’s disease, mutation in the GBA gene leads to reduced GCBS production.
GCB iaccumulates in the lysosomes of the macrophages , giving them a ‘crumpled tissue paper appearance.’
Gaucher cell
Symptoms Type 1: bruises, chronic fatigue and hepatosplenomegaly.
The perinatal lethal form: severe and associated with
Also infarction to bones leading to oesteoporosis, in rare
death before 3 months of age or even in womb. The
cases, the kidneys and lungs are also involved.
fetus may have edema hydrops fetalis, intracranial
Type 2: splenomegaly, hypotonia, spasticity, strabismus,
hemorrhage, non-bollous ichthyosiform erythroderma.
dysphagia, retroflexion. Life threatening conditions like
The
ichthvosiform changes in skin and respiratory distress.
calcification of mitral and aortic valves and increase in
Type 3: mental retardation, ataxia, myoclonic seizures,
blood pressure.
cardiovascular
form:
oculomotor
This leads to accumulation and aggregation of αsynuclein in brain, causing Parkinsonism.
Therapeutic management Enzyme replacement therapy (ERT)
• Intravenous infusions to correct the underlying enzyme deficiency that causes Gaucher disease. • Balances low levels of GCBS enzyme with a modified version. • This enzyme breaks down GCB, the fatty chemical that accumulates in the body of patients with Gaucher disease.
Substrate reduction therapy (SRT) • There are currently 2 FDA-approved oral SRT drugs for patients with Gaucher disease: Cerdelga and Zavesca.. • SRT partially blocks the body from producing GCB, the fatty chemical that builds up in the bodies of patients with Gaucher disease.
Chemical Chaperones • Selective binding to a specific target protein. • Lysosomal enzymes are folded in the ER with the aid of cellular chaperones, and then translocated to the lysosome. • Mutation and enzyme misfolding can lead to premature endoplasmic reticulum-associated degradation (ERAD) and never reach the lysosome
Histone Deacetylase (HDAC) inhibitors • Mutant GCBS results in a reduction of protein stability, but not disruption of enzymatic activity. • The mutation leads to aberrant protein conformation that results in altered chaperone binding, making the GCBS vulnerable to proteasomeassociated degradation.
apraxia,
pulmonary and interstitial lung disease.
Suggested hypothesis Recent studies suggests the importance of RIP3 in the pathological effects of Gaucher’s disease where its deficiency is associated with improved survival.
Diagnosis
The role of RIP3 is also suggested in Parkinson’s disease, where
BGL tests that measure acid beta glucosidase activity in WBCs of fibroblasts.
kinase domain-like protein (MLKL),a key event for
Genetic testing where DNA analysis is done for the identification of causal gene defects. Amniocentesis or CVS for prenatal diagnosis is possible if a known GBA gene ,mutation is present in the family.
RIP3 phosphorylates the S345 of mixed lineage
necroptosis. RIP3 may also accelerate Ripoptosome assembly and caspase-8 activation, facilitating apoptosis..
Drugs in use Drugs in use :
The hypothesis is to see if RIP3 deletion could protect the neurodegeneration in dopaminergic neurons by preventing apoptosis or necroptosis and if this would help in delaying
Eliglustat, Miglustat, iminosugar-N-butyldeoxynojirimycin, Velaglucerase alfa (a human
Parkinsonism associated with Gaucher’s disease.
recombinant glucocerebrosidase enzyme replacement therapy).
Incidence of Gaucher’s disease on age.
Age at which patients taking part
References
Coles V., Chan G., Palczewski K., Lewis K., Ho J. An Unexpected Link Between Gaucher Disease and Parkinson’s Disease. Illustrated by Cindy Nguyen. Rare Disease Review. March 2018. DOI:10.13140/RG.2.2.27808.07680.
FDA Prescription and Over-the-Counter Drug Product List. 32ND Edition Cumulative Supplement Number 3: March 2012.
in the US patient survey were
diagnosed with Gaucher disease.Age at which patients taking part in the US patient survey were diagnosed with Gaucher disease (N = 212). Age at which patients taking part in the US patient survey were diagnosed with Gaucher disease (N = 212). Khan, Mohammed, et al. Gaucher’s Disease: Prenatal and Post Natal Diagnostic Dilemma and Biochemical N=212 Aid – Case Series and Review of Literature. British Journal of Medicine and Medical Research. 2017;19(5): 1-11. doi:10.9734/bjmmr/2017/29680
Cox, T. M. (2010). Gaucher disease: clinical profile and therapeutic developments. Biologics: targets & therapy, 4, 299.
www.gaucherdisease.org