Osteonecrosis and osteochondritis
Ashley W. Blom, David Warwick, Michael R. Whitehouse in Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Gaucher’s disease (see also Chapter 8) is a familial metabolic disorder caused by inherited deficiency of lysosomal enzyme glucocerebrosidase and characterized by accumulation of glucosylceramide in the lysosomes of reticuloendothelial cells to produce Gaucher’s cells. The effects are seen chiefly in the liver, spleen and bone marrow. Accumulation of Gaucher’s cells in the bone marrow triggers a series of events that lead to skeletal pathology, of which osteonecrosis is the worst. The hip is most frequently affected, but lesions also appear in the distal femur, the talus and the head of the humerus. Bone ischaemia is usually attributed to the increase in medullary cell volume and sinusoidal compression, but it is likely that other effects (abnormal cell emboli and increased blood viscosity) are equally important.
Case 43
Atul B. Mehta, Keith Gomez in Clinical Haematology, 2017
Bone marrow aspirate and trephine biopsy show macrophages laden with lipids – typical Gaucher cells – suggesting she is suffering from Gaucher disease of the chronic adult type (type I). Types II and III Gaucher disease also affect the central nervous system. Gaucher disease is due to mutations within the glucocerebrosidase gene, which causes a deficiency of lysosomal beta-glucocerebrosidase. This in turn leads to accumulation of glucocerebroside in tissues. The different types of Gaucher disease have different degrees of residual enzyme activity. Type II disease has zero or extremely low activity and is incompatible with life – subjects die in utero or within the first year of life and have severe visceral disease and neurological impairment presenting as impaired consciousness, seizures and severe motor abnormalities. Type III is an intermediate form and subjects have variable neurological manifestations, ranging from mild ophthalmoplegia to cognitive impairment with seizures and failure to thrive. Type I Gaucher is the most common form. The condition has an increased prevalence among the Ashkenazi Jewish population (carrier rate approximately 1:12 and population incidence approximately 1:900). The enzyme deficiency manifests principally in reticuloendothelial cells and substrate accumulation causes hepatosplenomegaly and deposition of substrate in the bone marrow (reducing haemopoiesis) and skeleton. The overall incidence of the condition is approximately 1:30,000 individuals and it is one of the most common lysosomal storage disorders.
Erlenmeyer Flask Deformity
Michael E. Mulligan in Classic Radiologic Signs, 2020
Philippe Gaucher1 described the condition that now bears his name in 1882. This cerebroside disorder leads to packing of the bone marrow with lipid-laden reticuloendothelial cells and causes modeling abnormalities that are especially well demonstrated in the metaphyses of the long bones. The earliest detailed descriptions of the clinical, radiologic and pathologic findings were presented in two separate articles2,3, from the same case material, in 1926. The radiologist involved, Sven Junghagen (Rontgeninstitut Lund), described the abnormal contour of the ends of the long bones in a 3-year-old girl who had clinical and radiographic follow up over a 2-year period. However, it was A.W. Fisher (University of Frankfurt) who seems to have first used the term flask-shaped (flaschenformige) in an article 2 years later4 (Figure 1). He discussed the long bone changes, especially those in the distal femur, in 16 cases. Nine of the patients had a diagnosis of Gaucher’s disease. The others had diagnoses that included: Picks disease, chronic osteomyelitis, arthritis deformans and pernicious anemia. Fisher emphasized that the differences and similarities between cases, that may occur in the shape of the distal femur, are dependent upon the specific disease process involved. Thus, this Erlenmeyer flask-shaped deformity is not specific for Gaucher’s disease. It can be seen with many other disorders especially marrow-packing disorders. The long bone radiographic changes in what is now known as Niemann-Pick’s disease are indistinguishable from those due to Gaucher’s disease.
N-Methyl-D-Aspartate (NMDA) receptor modulators: a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Hazem Ahmed, Ahmed Haider, Simon M. Ametamey
Gaucher’s disease (GD) is a genetic disorder caused by a mutation in the GBA1 gene and is the most common out of the 50 lysosomal storage diseases. A patent filed by Yeda Research and Development Company in 2015 claimed the use of established NMDA receptor antagonists in treating the neuropathic forms of GD, i.e., type 2 and 3 [237]. Using 15 different mouse strains, the inventors discovered that GRIN2B polymorphisms are associated with the life expectancy of GD mice, and that administering an NMDA receptor antagonist surprisingly increased their life span [238]. They unraveled a single nucleotide variation (SNP ID rs29869040) in the non-coding area of the GRIN2B that correlated with GD prognosis. In addition, they showed that NMDA receptor agonists such as D-cycloserine reduced survival rate contrary to NMDA receptor antagonists (dizocilpine, memantine, and ifenprodil) which increased the GD mice life span. NMDA receptor antagonists claimed were not necessarily selective toward NMDA receptors, for example concurrently targeting sigma-1 receptors, neither only toward a specific subunit. The claim list included memantine, nitromemantine, neramexane, ketamine, amantadine, dextromethorphan, traxoprodil, ifenprodil, and Ro 25–6981 amongst others, whether alone or as a combination therapy.
Is Gene Editing Harmless? Two Arguments for Gene Editing
Published in The American Journal of Bioethics, 2022
Julian Savulescu, Marcos Alonso
Consider a child born with genetic disorder like Gaucher’s Disease or cystic fibrosis. A pill has been developed that must be given soon after birth. It will perfectly replace the missing protein/s in the disorder. It has no side effects but must be given each day or the child will suffer. There is a moral obligation to give such a pill, just as there is a moral obligation to give a life saving blood transfusion to a child bleeding to death, even if the parents who are Jehovah’s Witnesses refuse it. If a parent refuses to give the pill, a court order should be obtained to administer the pill, and prevent damage to the child, in just the same way that the objections to blood transfusions of Jehovah’s Witnesses are overridden.
Hematological manifestations and complications of Gaucher disease
Published in Expert Review of Hematology, 2021
Shoshana Revel-Vilk, Jeff Szer, Ari Zimran
Gaucher disease (GD) is an autosomal recessive condition caused by inherited mutations in the GBA1 gene leading to reduced activity of the lysosomal enzyme-glucocerebrosidase. Glucocerebrosidase is required for degradation of the major glycolipid glucocerebroside into glucose and ceramide and the minor lipid glucosylsphingosine (lyso-Gb1) into sphingosine and glucose [1]. The activated macrophages, or ‘Gaucher’ cells, harbor the accumulated undegraded glucocerebroside and the population of these cells expands, leading to hepatosplenomegaly, thrombocytopenia, anemia, and bone involvement, but also to the overexpression of various cytokines and chemokines, resulting in inflammation and immune dysregulation.
Related Knowledge Centers
- Anemia
- Fatigue
- Glucocerebrosidase
- Glucocerebroside
- Sphingolipid
- Spleen
- Platelet
- Liver
- Macrophage
- Genetic Disorder