Lysosomal Storage Diseases Flashcards
Ceramide
• R group: H
Sphingomyelin
•R group: phosphocholine
Cerebroside
- glycosphingolipid
- R group: monosaccharide (glucose or galactose)
- Cerebrosides, the simplest glycolipid, contain a single hexose, which is either a galactose or a glucose residue. Galactocerebrosides (also known as galactosylceramides) are mostly found in the brain as part of myelin. Glucocerebrosides (also known as glucosylceramides) are located mostly in extraneural tissues, though they usually are found as an intermediate in the synthesis or degradation of globosides or gangliosides.
Globoside
- glycosphingolipid
- R group: twpor or more sugars (galactose, glucose, N-acetylglucosamine, fucose)
- One prominent globoside is lactosylceramide, a constituent of the erythrocyte membrane. The globoside ceramide trihexoside (also known as ceramide galactosyllactoside) is unusual because the terminal galactose is linked in its -anomer configuration unlike the usual -anomer configuration. Globosides also form the basis of the ABO blood group characteristics.
Gangliosides
- glycosphingolipid
- R group: three or more sugars plus one sialic acid (N-acetylneuraminic acid; NANA)
- Gangliosides are named for their high concentration in ganglions of the CNS, especially in nerve endings. Gangliosides are identified by code names (e.g., GM3) with subscripts of M, D, T, or Q to indicate the number of sialic acid residues attached being 1 to 4, respectively. The number in the subscript (1, 2 or 3) codes for the carbohydrate sequence attached to ceramide. For instance subscript 3 refers to Gal-Glc-ceramide. Thus GM3 is the simplest ganglioside with two hexose residues and one sialic acid residue. Some gangliosides serve as cell surface receptors. GM1, located in human intestinal mucosal cells, is a receptor for cholera toxin with an affinity in the picomolar (10-12) range. The pathogenesis of cholera will be covered in the Immunity and Infection block (Vibrio, Campylobacter, Helicobacter). The effects of cholera toxin on cyclic AMP production are covered in DMH (G-protein Function and Adrenergic Receptors). Another example of linking gangliosides to bacterial infection is the ability of GM3 to bind uropathogenic E. coli R45. This interaction plays an important role in women with a history of recurrent E. coli urinary tract infections (see Immunity and Infection, Urinary Tract Infections). Hence GM3 is important in the pathogenesis of this disease.
Gaucher Disease
- glucocerebroside (cerebroside)
- heptosplenomegaly, accumulates in other tissues such as bone marrow and brain. These accumulations are associated with bone pain and skeletal features such as erosion of the long bones and the pelvis, as well as to mental deficiency. Other major symptoms include severe neurologic complications (type II) and swelling of lymph nodes.
- Type I, II, III
Type I Gaucher
•Type 1 Gaucher disease is the most common form of the three types. At onset, patients commonly have splenomegaly, anemia, or thrombocytopenia. They may also show chronic fatigue, hepatomegaly, bone pain, or pathologic fractures. Osteoporosis can develop. Patients may bruise easily because of thrombocytopenia. Splenomegaly is progressive and can become massive. Characteristic Gaucher cells are lipid-laden macrophages that resemble crumpled tissue paper. Type 1, unlike types 2 and 3, has no neural involvement.
Type II Gaucher
•Type 2 Gaucher disease, the rarest form, is associated with rapid progression of neurovisceral storage disease and death during infancy or during the first years of life.
Type III Gaucher
•Type 3 Gaucher disease also is characterized by progressive neurovisceral storage disease though les rapid than in type 2. Various associated clinical courses have been reported, some of which cause death in childhood or early adulthood
Gaucher Management
•Management: Enzyme (glucocerebrosidase) replacement therapy (ERT) for type 1 Gaucher disease includes imiglucerase (Cerezyme) amongst others. Most patients receive this recombinant enzyme. This treatment effectively reverses visceral and hematologic manifestations of the disease and especially has a remarkable effect on hepatosplenomegaly. Skeletal disease responds slowly. ERT generally is administered every other week and is typically indicated for patients exhibiting clinical signs and symptoms. Presymptomatic treatment with ERT remains controversial especially because of the high cost of the therapy (~$300,000 per year). Patients with bone crises require pain relief, hydration, and close monitoring. Another treatment involves use of inhibitors of synthesis of glucosylceramide, the substrate for glucocerebrosidase (Figure 2). These inhibitors include miglustat (Zavesca) and eliglustat (Cerdelga). Miglustat is a monotherapy for treatment of adults with mild-to-moderate type 1 disease for whom ERT is not a therapeutic option. Eliglustat is a first-line treatment for the longterm care of adults with type 1 disease.
Krabbe Disease
- galactocerebroside (cerbroside)
- Krabbe disease is associated with breakdown of the myelin coating largely affecting white matter though there can be damage to cortical gray matter. Overall there is resulting destruction of brain cells. A major feature of this disorder is impairment of the growth or development of the myelin sheath leading to severe degeneration of mental and motor skills. Krabbe disease is a leukodystrophy of globoid cells, which are multi-nucleated. Generally, leukodystrophies are those diseases associated with abnormalities of myelin.
- Symptoms of Krabbe disease include irritability, limb stiffness, feeding difficulties, vomiting, and slowing of mental and motor development. Secondary consequences include muscle weakness, spasticity, deafness, and blindness. Most common onset is before 6 months. Death typically occurs before age 2.
Management of Krabbe
•There is no cure. Hematopoietic stem cell transplantation (HSCT) is a potential early treatment of infants using with umbilical cord blood stem cells from unrelated donors prior to symptom onset. HSCT is considered in those with late-onset or slowly progressive disease and those with infantile-onset disease
Metachromatic Leukodystrophy
- arylsulfatase A
- The three types of the disease include late infantile (most common), juvenile, and adult. With the late infantile form, children have difficulty walking. Other symptoms can include muscle weakness and rigidity, eventual blindness, difficulty swallowing, convulsions and paralysis. Coma can result as well and most patients die before age 5. The juvenile form first appears as diminished performance in school, mental deterioration and a slower development of symptoms than seen in the infantile form. The adult form first appears in late teens as a psychiatric or neurological problem such as progressive dementia.
management of Metachromatic Leukodystrophy
•: HSCT (see Krabbe disease) is the only possible therapy for primary CNS manifestations. The best results are obtained in those with the juvenile or adult forms who are presymptomatic or exhibiting very early symptoms.
Niemann Pick A, B
- sphingomylelinase
- Type A (most common) is the classic infantile form and often fatal in the first 18 months. Lesions in the liver and spleen lead to hepatosplenomegaly. Liver malfunction causes jaundice. The enlarged spleen traps platelets and other blood cells leading to anemia and related problems. Profound brain damage results from excessive storage of sphingomyelin in the nervous system. Patients exhibit neurologic symptoms including ataxia, speech impediment, difficulty swallowing, dystonia, seizures and dementia. Clouding of the cornea occurs and a cherry-red spot develops around the center of the retina (macula). Lipid-laden macrophages (foam cells) are also characteristic. Type B is less severe, lacks neurological manifestations and with hepatosplenomegaly delayed until pre-teen years.
- Management Type A: Infants may benefit from physical and occupational therapy, assessment of nutritional status and possible use of a gastrostomy tube.
- Management Type B: Patients are assessed every 6-12 months for nutrition, growth in children, weight changes, extent of activity, bleeding, abdominal pain and neurologic function. Lab tests that are monitored are platelet count, liver enzymes, lipid profile, pulmonary function and chest radiography. In patients with hyperlipidemia, correction of elevated total cholesterol is recommended.
