Sphingolipidoses

Related Terms and Conditions: Sphingolipidoses, Edema, lymphedema, Enzyme replacement therapy, Lysosome, Lysosomal storage disorder, Pharmacological chaperone, Sphingolipid, Sphingolipidosis, Substrate reduction therapy, amniocentesis, chromosome aberration, Fabry's disease, Krabbe disease, Metachromatic leukodystrophy, Glucocerebrosides, Gaucher's disease, Metachromatic leukodystrophy, Glucocerebrosides, mucopolysaccharidosis I, mucopolysaccharidosis II, Hunter Syndrome, mucopolysaccharidosis VI, Maroteaux-Lamy syndrome, Pompe disease, urler-Scheie, and Scheie syndromes, Sphingosine kinase, Sphingosine-1-phosphate, Immune cell, Inflammation, Monocytes/macrophage, Neutrophil, Mast cell, Lymphocytes, Signalling

Considered part of the lipid storage disease group, with symptoms appearing in childhood. For the classification of the more then 50 lysomal storage diseases, please refer to this page: Classification of Lysosomal Storage Diseases

Clinical features.

(1) Complex lipids containing ceramide accumulate in cells, particularly neurons, causing neurodegeneration and shortening the life span.

(2) The rate of synthesis of the stored lipid is normal.

(3) The enzymatic defect is in the lysosomal degradation pathway of sphingolipids.

Cause

Genetic based - hereditary

Symptoms

There are 34 recognized “symptoms” for Sphingolipidosis. These are Psychomotor degeneration, Reduced vision, Burning sensation in hands, Burning sensation in feet, Gastrointestinal problems, Fatigue, Anemia, Enlarged spleen, Enlarged liver, Seizures, Easy bruising, Enlarged abdomen, Telangiectasia, Paresthesia, Lymphedema, Hearing problems, Nausea, Vomiting, Diarrhea, Angina, Nystagmus, Low blood platelets, Skeletal abnormalities, Bleeding problems, Skin lesions, Bone fractures, Incoordination, Spasticity, Bone pain, Reduced muscle tone, Muscle weakness, Physical malformations, Mental retardation, Premature death (1)

Diagnosis

A combination of physical characteristics of (coarse facies, macroglossia), bony abnormalities (dysostosis multiplex), cardiac involvement (arrhythmia or cardiomegaly), hepatosplenomegaly, ophthalmologic signs (corneal clouding or macular cherry-red spot) should point the clinitian towards the possibility of a lysosomal storage disease.

Neuerological symptoms include: evelopmental delay, hypotonia, epilepsy (complex partial or myoclonic), peripheral neuropathy, intellectual disability, ataxia, and/or spasticity.

A blood smear can reveal white blood cell vacuoles (granular, fingerprint lipid whorls, zebra bodies, or autophagic vacuoles). Urine can be screened for elevated excretion of oligosaccharides (oligosaccharidoses) and glycosaminoglycans (mucopolysaccharidoses). Blood chitotriosidase (an enzymatic marker of macrophage activation) may be elevated.(3)

Definitive testing is most efficiently performed by enzymatic activity measurement in a reference laboratory,

Treatment

Currently, there is no cure for sphingolipidoses. Therapies like enzyme replacement, pharmacological chaperone, and substrate reduction therapy, which have been shown to be efficient in non-neuronopathic LSDs, are currently evaluated in clinical trials of neuronopathic sphingolipidoses. In the future, neural stem cell therapy and gene therapy may become an option for these disorders. (2)

For some lipid storage diseases, enzyme replacement therapy is effective, especially for Gaucher disease types I and III, Fabry disease, mucopolysaccharidosis I (Hurler, Hurler-Scheie, and Scheie syndromes), mucopolysaccharidosis II (Hunter syndrome), mucopolysaccharidosis VI (Maroteaux-Lamy syndrome), and Pompe disease.

Some evidence indicates that at least in certain disorders, combination ERT and hematopoietic stem cell transplantation together might be superior to hematopoietic stem cell transplantation alone in patients who are appropriate candidates (3)

Other treatment may be relevant to the co-morbities of the condition.

For the complication of lymhphedema (swelling), the patient should receive a referral to a certified lymhpedema therapist for a complete examination and evaluation. The protocol treatment is manual decongestive therapy with the wearing of compression garments to hold down the swelling.

Research is also being done on the possibility of gene therapy.

(1) Right Diagnosis

(2) Principles of Treatment of Sphingolipidoses

(3) eMedicine

Prognosis

Generally, the prognosis for a lysomal storage disease is based on the severity of the particular syndrome.

Related Disorders

Niemann–Pick disease

Xanthomas (Xanthomatosis)

Gaucher disease

Fabry’s disease see also: Fabry’s Disease

Farber’s disease

Wolman’s disease (acid lipase deficiency) GM2

Metachromatic leukodystrophy (acid lipase deficiency) GM2

Krabbé disease (acid lipase deficiency) GM2 - also known as globoid cell leukodystrophy and galactosylceramide lipidosis

Cholesteryl ester storage disease (acid lipase deficiency) GM2

Tay-Sachs disease GM1

Sandhoff disease (variant AB) GM1

Abstracts and Studies

Pathology and current treatment of neurodegenerative sphingolipidoses. Dec. 2010

Eckhardt M. Source Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, 53115 Bonn, Germany. eckhardt@ibmb.uni-bonn.de

Abstract

Keywords: Enzyme replacement therapy - Lysosome - Lysosomal storage disorder - Pharmacological chaperone - Sphingolipid - Sphingolipidosis - Substrate reduction therapy

Sphingolipidoses constitute a large subgroup of lysosomal storage disorders (LSDs). Many of them are associated with a progressive neurodegeneration. As is the case for LSDs in general, most sphingolipidoses are caused by deficiencies in lysosomal hydrolases. However, accumulation of sphingolipids can also result from deficiencies in proteins involved in the transport or posttranslational modification of lysosomal enzymes, transport of lipids, or lysosomal membrane proteins required for transport of lysosomal degradation end products. The accumulation of sphingolipids in the lysosome together with secondary changes in the concentration and localization of other lipids may cause trafficking defects of membrane lipids and proteins, affect calcium homeostasis, induce the unfolded protein response, activate apoptotic cascades, and affect various signal transduction pathways. To what extent, however, these changes contribute to the pathogenesis of the diseases is not fully understood. Currently, there is no cure for sphingolipidoses. Therapies like enzyme replacement, pharmacological chaperone, and substrate reduction therapy, which have been shown to be efficient in non-neuronopathic LSDs, are currently evaluated in clinical trials of neuronopathic sphingolipidoses. In the future, neural stem cell therapy and gene therapy may become an option for these disorders.

Springerlink

Sphingolipid synthetic pathways are major regulators of lipid homeostasis.

2011

Worgall TS.

Source

Department of Pathology, Columbia University, New York, New York, USA. tpw7@columbia.edu

Abstract

This chapter focuses on the role of sphingolipids in the regulation of sterol-regulatory element binding protein (SREBP) dependent lipid synthesis and ATP-binding cassette protein ABCA1 and ABCG1 mediated lipid efflux, key regulators of cellular lipid homeostasis. Sphingolipid synthesis activates SREBPs independently of whether sphingolipid synthesis occurs through recycling or de novo pathways. SREBPs are major transcription factors of lipid metabolism that regulate more than 30 genes of cholesterol, fatty acid and phospholipid synthetic enzymes and they required NADPH cofactors. SREBPs are downstream of sphingolipid synthesis and do not regulate activity of sphingolipid synthetic enzymes. Cells that cannot synthesize sphingolipids fail to increase SREBP in response to lipid depletion. Similar mechanisms are found in D. melanogaster in which SREBP activity depends on expression of a ceramide synthase analog. SREBP is inhibited by its end products cholesterol and unsaturated fatty acids. Ceramide decreases SREBP by inhibiting sphingolipid synthesis. Molecular mechanisms of regulation are related to the effect of sphingolipids on intracellular trafficking but are overall not clear. Several groups have investigated the effect of sphingolipids in the regulation of cholesterol efflux receptors ABCA1 and ABCG1, major regulators of plasma high-density lipoprotein (HDL) concentration, an important anti-atherogenic lipoprotein. Data indicate an inverse relationship between sphingolipid de novo synthesis and cholesterol efflux. Inhibition of sphingolipid de-novo synthesis increases ABCA1 mediated cholesterol efflux independent of sphingomyelin. Potential mechanisms include the physical interaction of subunit 1 of serine-palmitoyl transferase (SPT), the rate limiting enzyme of de-novo sphingolipid synthesis, with ABCA1. ABCG1 mediated efflux, in contrast, is dependent on sphingomyelin mass. Animal studies support the findings made in cultured cells. Inhibition of sphingolipid de novo synthesis increases anti-atherogenic lipoproteins and decreases atherosclerosis in mouse models. Together, manipulation of sphingolipid synthetic pathways is a potentially promising therapeutic target for treatment of low-HDL dyslipidemia and atherosclerosis.

Springerlink

Blood sphingolipids in homeostasis and pathobiology.

2011

Hammad SM.

Source

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA. hammadsm@musc.edu

Abstract Sphingolipids have emerged as key signaling molecules involved in the regulation of a variety of cellular functions including cell growth and differentiation, proliferation and apoptotic cell death. Sphingolipids in blood constitute part of the circulating lipoprotein particles (HDL, LDL and VLDL), carried by serum albumin and also present in blood cells and platelets. Recent lipidomic and proteomic studies of plasma lipoproteins have provided intriguing data concerning the protein and lipid composition of lipoproteins in the context of disease. Sphingolipids have been implicated in several diseases such as cancer, obesity, atherosclerosis and sphingolipidoses; however, efforts addressing blood sphingolipidomics are still limited. The development of methods to determine levels of circulating bioactive sphingolipids in humans and validation of these methods to be a routine clinical laboratory test could be a pioneering approach to diagnose disease in the population. This approach would probably evolve to be analogous in implication to determining “good” and “bad” cholesterol and triglyceride levels in lipoprotein classes.

Springerlink