Presentation on theme: "A Proteopathy Disease: Gaucher’s Disease Diane Lokou Chem 4700 – Protein Structure Dr. Michael Kirberger Spring 2015."— Presentation transcript:
A Proteopathy Disease: Gaucher’s Disease Diane Lokou Chem 4700 – Protein Structure Dr. Michael Kirberger Spring 2015
Where does the name Gaucher come from? The disease obtained its name from its discoverer, Phillipe Charles Ernest Gaucher, a French physician in the 1800s when he discovered the disease. In 1882, he described for the first time the symptoms of a disease, later known as Gaucher Disease. Other names such as Gaucher splenomegaly, Glucosylceramide lipidosis, and Kerasin histiocytosis are used to name the disease.
Background of Gaucher’s Disease Hereditary disease. The mutations occur in a single gene called GBA; these changes cause very low levels of glucocerebrosidase The recessive mutation is seen in males and females. It is an autosomal recessive disorder of metabolism due to the lack of glucocerebrosidase also known as acid β-glucosidase, a lysosomal enzyme which catalyzes glycolipid glucocerebroside hydrolysis to ceramide and glucose. Gaucher’s Disease results from the accumulation of fatty substances in cells and some organs because of the deficiency of the enzyme, mainly in macrophages family or monocytes as the macrophages fail to eliminate the waste product. Glucosylceramide is a component of white and red blood cells’ membrane. - In type 1, it accumulates in visceral organs (liver, spleen, bone marrow). - In type 2 and 3, it accumulates in the central nervous system.
Statistics of Gaucher’s Disease The disease is more frequent among people who are of Ashkenazi Jewish ancestry. Occurrence in about 1 in 50,000 to 1 in 100,000 individuals in the general population. Type 1 is present 1 in 500 to 1 in 1000 people of Ashkenazi Jewish ancestry About 1 in 14 Ashkenazi Jews is a carrier. Type 2 and Type 3 of the disease are not as common. About 6,000 people in the United States are estimated to have the type 1 of Gaucher’s Disease.
Enzyme Description Acid β-glucosidase is encoded by the gene GBA which is 7.6 kb long and located at 1q21 locus (long (q) arm of chromosome 1 at position 21). GBA gene is located from base pair 155,234,447 to base pair 155,244,861 on chromosome 1. GBA protein is 497 amino acids long with a molecular weight of 55.6KD.
GBA gene location
Glucosidase, Beta, Acid PyMOL Viewer Beta strands and alpha-helices
Location of the mutations Almost 200 mutations have been identified in Gaucher’s Disease; these four changes are found in all 3 types: L444P: major SNP (single nucleotide polymorphisms: single nucleotide variations in the genome that occur at a frequency of more than 1%) associated with GBA gene. V460V D409H A456P SNPs occur around every 3000 base pairs in human genome. N370S, L444P, and R463C were the most common mutations identified in preceding findings in 60 patients with types 1 and 3 of the disease. E326K mutation had also been identified in patients with all three types, but in each case it was found on the same allele with another GBA mutation. PyMOL Viewer
Symptoms of Gaucher’s Disease Although the symptoms vary among people with this disorder, the common clinical symptoms are: - Hepatosplenomegaly - Anemia - Thrombocytopenia - Bone pain and fractures
Depending on the type of Gaucher disease, other symptoms are involved Type 1 Gaucher disease: In addition to the major symptoms, there is also lung disease. This is the most common type and the symptoms may appear earlier or in adulthood and the signs are so mild in many individuals that they do not experience any problems from the disorder. Type 2 and Type 3 Gaucher disease: In addition to the major symptoms, there are also nervous system symptoms such as eye problems, seizures and brain damage. With type 2, the severe medical problems start in infancy and the individuals’ life span does not usually exceed age two; some die during the newborn period, often with excessive fluid accumulation or serious skin problems. With type 3, the symptoms may start before the age of two, but usually in a more slowly progressive disease process and the degree of brain involvement is rather variable. The individuals typically have slowing of their horizontal eye movements.
Diagnosis of Gaucher’s Disease The diagnosis is based on clinical symptoms and laboratory testing. A diagnosis based on clinical symptoms is supposed in individuals with: bone problems enlarged liver and spleen (hepatosplenomegaly) changes in red blood cell levels easy bleeding bruising from low platelets or signs of nervous system problems.
Diagnosis of Gaucher’s Disease A diagnosis based on laboratory testing: A blood test is done to measure the activity level of the enzyme glucocerebrosidase; this enzyme has very low levels of activity in individuals who have the disease. Another type of laboratory testing is the GBA gene DNA analysis for the four most common GBA mutations. Enzyme and DNA testing can be done prenatally; bone marrow or liver biopsy is not essential to establish the diagnosis.
Treatments for Gaucher’s Disease Enzyme replacement therapy (ERT) is not an option for all patients with Gaucher disease. Symptoms in type 1 individuals can be treated with available glucosylceramide synthase inhibitors like: Zavesca (miglustat) oral drug for adults. Genzyme’s Cerdelga (eliglustat) Capsules for long-term treatment for adults. Enzyme replacement therapy: Cerezyme® (imiglucerase for injection) in 1994 ELELYSO™ (taliglucerase alfa for injection), a hydrolytic lysosomal glucocerebroside-specific enzyme for long-term ERT for adults with a confirmed diagnosis of Type 1. Approved by FDA on May 1, VPRIV®, a hydrolytic lysosomal glucocerebroside-specific enzyme for long-term enzyme replacement therapy (ERT) for pediatric and adult patients with type 1 If ERT is not effective, some individuals may need surgery. Splenectomy Blood transfusions Pain medications Joint replacement surgery
References PyMOL ease Manickam M, Ravanan P, Singh P, Talwar P. In silico identification of genetic variants in glucocerebrosidase (GBA) gene involved in Gaucher's disease using multiple software tools. Frontiers In Genetics [serial online]. May 2014;5:1-10. Available from: Academic Search Complete, Ipswich, MA. Accessed March 14, 2015