LIPID STORAGE DISEASES

CLASSIFICATION : Mucopolysaccharidoses (variable nervous system involvement) Mucolipidoses Glycoproteinoses Glycogen storage Sphingolipidoses Lipid storage disorders Multiple enzyme defects Transport defects Batten Disease (Red = nervous system involvement)

INBORN ERRORS OF PHOSPHOLIPID, SPHINGOLIPID METABOLISM Demyelination: Sclerosis multiplex White matter decrease of [phospholipid], [plasmenyl ethanolamine], [sphingolipid] Sphingolipidosis: Accumulation of complex lipids Synthesis of complex lipids is not effected Lack of specific (hydrolytic) lysomal enzymes All tissues are effected Multiple sulfatase deficiency Biosynthesis of membrane lipids and steroids 1

THE PRINCIPAL CLASSES OF STORAGE AND MEMBRANE LIPIDS Point out difference in 3rd position, fatty acid versus phosphate, phosphate versus sugar. All these lipids have either glycerol or sphingosine as the backbone.

LYSOSOMAL STORAGE DISEASES ( LSDs ) Are caused by defects in lysosomal hydrolases and proteins essential to lysosomal biogenesis/function Defects give rise to swollen lysosomes, developmental and degenerative defects with varying involvement of the nervous system due to ‘storage’ of material in the lysosome. LSDs cause death in childhood (generally) after normal infancy. LSDs are essentially incurable, but some are treatable to varying degrees.

LYSOSOMAL STORAGE DISEASE (Amaurotic Idiocy) Autosomal recessive diseases Individually rare Collectively occur @ 1/8000 live births Cause death in early to late childhood (after normal infancy) Varying involvement of the nervous system All ‘store’ material in the lysosome due to defects in substrate degradation or biogenesis of the lysosome

GENERAL OUTLINE OF LSD DYSFUNCTION: Mutations arising in hydrolytic enzyme, co-factor or factor essential of enzyme delivery to lysosome Also, factors essential for lysosome function and biogenesis (membrane proteins, channels and proteins of unknown function) plus factors for protein traffic to lysosome Material (substrate) continues to be delivered to lysosome resulting in ‘stored’ material, leads to swollen lysosomes Developmental dysfunction and early death: symptoms v. variable, varying involvement of different tissues

All tissues are effected - Usually, lack of an enzyme leads to accumulation of a particular lipid, causing symptoms such as enlarged spleen and liver, seizures, blindness, mental retardation and death Synthesis of complex lipids is not effected All tissues are effected

Degradation of sphingolipids by lysosomal enzymes (deficiencies result in lysosomal storage disease = sphingolipidoses) SPHINGOLIPIDOSES genetic mutations, mental retardation, death Name Deficient enzyme Acccumlated lipid Fucosidosis α-Fucosidase H-Isoantigen Generalized gangliosidosis GM1-β-Galactosidase GM1-Ganglioside Tay-Sachs disease Hexosaminidase A GM2-Ganglioside Tay-Sachs variant Hexosaminid. A and B Fabry disease α-Galactosidase Globotriaosylceramide Ceramide lactoside lipidosis Ceramide lactosidase Ceramide lactoside Metachromatic leukodystrophy Arylsulfatase A 3-Sulfogalactosylceramide Krabbe disease β-Galactosidase Galactosylceramide Gaucher disease β-Glucosidase Glucosylceramide Niemann-Pick disease Sphingomyelinase Sphingomyelin Farber disease Ceramidase Ceramide

GANGLIOSIDOSIS A disease of the accumulation of gangliosides is called "Gangliosidosis", which is a form of Lipid storage disorder. The gangliosidoses are two distinct genetic groups of diseases. Both are autosomal recessive and affect males and females equally. GM1 gangliosidoses GM2 gangliosidoses

GANGLIOSIDOSIS The GM1 gangliosidoses are caused by a deficiency of beta-galactosidase, with resulting abnormal storage of acidic lipid materials in cells of the central and peripheral nervous systems, but particularly in the nerve cells. GM1 has three forms: early infantile, late infantile, and adult.

THE GM2 GANGLIOSIDOSES cause the body to store excess acidic fatty materials in tissues and cells, most notably in nerve cells. these disorders result from a deficiency of the enzyme beta-hexosaminidase. the gm2 disorders include:

Tay-Sachs (GM2-gangliosidosis) First described in 1880’s from ‘cherry-red’ spot in fundus (retina) (lipid deposition in bipolar ganglion cells) Genetic defect: Hexosaminidase A (HEXA) storage material: GM2 ganglioside, globoside, glycolipids

Biosynthesis of membrane lipids and steroids 1 Tay – Sachs Disease . Glu Gal GalNAc Ceramid NANA hexosaminidase Biosynthesis of membrane lipids and steroids 1

TAY-SACHS DISEASE

Biosynthesis of membrane lipids and steroids 1 Tay – Sachs Disease Deficiency of Hexosaminidase A Hexosaminidase A hydrolyses the N-acetyl-galactosamine of GM2 ganglioside Mental retardation Macrocephalia Death at age 2-4 Frequency: Ashkenazi Jewish population 1:3500 Biosynthesis of membrane lipids and steroids 1

Tay-Sachs disease (also known as GM2 variant B). The incidence is particularly high among Eastern European and Ashkenazi Jewish populations, as well as certain French Canadians and Louisianan Cousins. Affected children appear to develop normally for the first few months of life. Symptoms begin by 6 months of age and include progressive loss of mental ability, dementia, decreased eye contact, increased startle reflex to noise, progressive loss of hearing leading to deafness, difficulty in swallowing, blindness, cherry-red spots in the retinas, and some paralysis. Seizures may begin in the child’s second year. Children may eventually need a feeding tube and they often die by age 4 from recurring infection. No specific treatment is available. Anticonvulsant medications may initially control seizures. Other supportive treatment includes proper nutrition and hydration and techniques to keep the airway open. A much rarer form of the disorder, which occurs in patients in their twenties and early thirties, is characterized by unsteadiness of gait and progressive neurological deterioration.

TAY-SACHS DISEASE

SANDHOFF DISEASE (VARIANT AB). This is a severe form of Tay-Sachs disease. Onset usually occurs at the age of 6 months and is not limited to any ethnic group. Neurological symptoms may include progressive deterioration of the central nervous system, motor weakness, early blindness, marked startle response to sound, spasticity, myoclonus (shock-like contractions of a muscle), seizures, macrocephaly (an abnormally enlarged head), and cherry-red spots in the eye. Other symptoms may include frequent respiratory infections, murmurs of the heart, doll-like facial features, and an enlarged liver and spleen. There is no specific treatment for Sandhoff disease. As with Tay-Sachs disease, supportive treatment includes keeping the airway open and proper nutrition and hydration. Anticonvulsant medications may initially control seizures. Children generally die by age 3 from respiratory infections.

A, Near end stage in a Spanish 13-year-old patient with GM2-gangliosidosis variant B1 (photograph courtesy of H.H. Goebel, Mainz ).

B, GM2-gangliosidosis in a 23-week-old fetus; and part of a cortical neuron; early stage of membranous cytoplasmic bodies (two clusters marked by crosses), i.e., lipid storing secondary lysosomes, ×36,000 (courtesy W. Schlote, Tübingen). .

C, The large cells are neurons distended by lysosomal storage in the medulla oblongata of a 1.5-year-old patient with GM1-gangliosidosis. The small dark bodies are nuclei from increased numbers of glial cells (“reactive gliosis”). .

D, Cherry red macular spot in an infantile patient with GM2-gangliosidosis variant B (Tay–Sachs disease). The dark red spot in the middle of the light central area is secondary to lipid storage in neuronal cells in this area; the storing cells have lost their processes that normally cover the fovea centralis. The fovea normally appears as yellow, but is changed to the red macular spot showing the color of the choroidea behind the retina.

Biosynthesis of membrane lipids and steroids 1 Sphingolipidoses Niemann-Pick Disease . Ceramide P-Choline sphingomyelinase Accumulation of sphingomyelin Biosynthesis of membrane lipids and steroids 1

Degradation of Sphingomyelin Sphingomyelin is degraded by sphingomyelinase, a lysosomal enzyme that hydrolytically removes phosphorylcholine, leaving a ceramide. The ceramide is, in turn, cleaved by ceramidase into sphingosine and a free fatty acid

TAY-SACHS DISEASE

SPHINGOMYELIN DEGRADATION Niemann-Pick disease is due to sphingomyelinase deficiency Sphingomyelin accumulates in the brain, spleen, and liver

NIEMANN-PICK DISEASE

Types of Niemann-Pick disease Niemann-Pick disease (Types A and B) Autosomal recessive disease Inability to degrade sphingomyelin The deficient enzyme is sphingomyelinase—a type of phospholipase C

Type A—less than 1% normal activity lipid deposit in liver and spleen  Increase size of liver and spleen , Neuron-degeneration Type B—5% or more of normal activity little to no damage to neural tissue, but lungs, spleen, liver, and bone marrow are affected Mostly commonly affect jews

Biosynthesis of membrane lipids and steroids 1 Gaucher’s - disease Accumulation of glucocerebrosides in reticuloendothelial cells of spleen, liver, and bone marrow the most common of lysosomal storage disease Mental retardation . Glu Ceramide b-glucosidase Biosynthesis of membrane lipids and steroids 1

TAY-SACHS DISEASE

Biosynthesis of membrane lipids and steroids 1 Krabbe disease Accumulation of Galactosyl ceramide Ceramide Gal . b-galactosidase Biosynthesis of membrane lipids and steroids 1

TAY-SACHS DISEASE

Biosynthesis of membrane lipids and steroids 1 Sphingolipidoses Fabry Disease Glu Gal Gal Ceramide a-galactosidase Biosynthesis of membrane lipids and steroids 1

Fabry Disease

ECONOMIC COST ERT is current most effective treatment (non neurodegenerative LSDs): Disease Treatment Annual Cost (per patient in $) Gaucher ERT 145,000 - 290,000 Gaucher SRT 91,000 Fabry ERT 156,000 Reasons: High regulatory costs Cost of research Lack of competition (Orphan Drug Act 1983, US)

Medical Condition Defective Enzyme Major Accumulating Metabolite SUMMARY OF DEFECTS IN GANGLIOSIDE CATABOLISM THAT CONTRIBUTE TO HUMAN DISEASE Medical Condition Defective Enzyme Major Accumulating Metabolite Generalized Gangliosidosis Beta-Galactosidase GM1 Tay-Sachs Disease Hexosaminidase A GM2 Gaucher’s Disease Glucocerebrosidase Glucosylcerebroside Niemann-Pick Disease Sphingomyelinase Sphingomyelin Sandhoff’s Disease Hexosaminidase A&B A Globoside* Fabry’s Disease Alpha-Galactosidase A A Globoside* *The globosides that are substrates for the defective enzymes in these diseases do not have specific names, but are referred to by the broad term globoside.

Some sphingolipidoses