NH2

HO C13H27 OH

O LysosomalAcid Ceramidase HO R Farber’s Disease Storage Diseases A Cayman Chemical Company O In 1881, Tay-Sachs disease was described as the first lysosomal storage disease. A description of Gaucher disease soon HN R followed in 1882. Thus began the identification of a group of rare, inherited disorders that result in the accumulation HO C13H27 of compounds within the lysosome. -Glu Morecosi thandase 50 lysosomal storage disorders have now been OHidentified. Most of OH HO O these diseases are autosomal recessive,Gauc withhe ra Disefew thatase are X-linked recessive, and occur in about 1:8,000 cases.OH HO OH The lysosome is an organelle within the cell that is responsible for catabolizing and recycling many lipid compounds, as well as maintaining a proper balance of compounds in cells. Lysosomes have a low pH, and the enzymes present within lysosomes mostly function only in this acidic environment. Enzyme deficiencies within the lysosome resultO in the accumulation of various , which are toxic at high concentrations. OH HN R Glucosylcerebroside O HO O C13H27 HO Lysosomal storage diseases are classified according to the compounds accumulated in the lysosomes.OH This includesOH , oligosaccharidoses, mucolipidoses, mucopolysaccharidoses, lipoprotein storage disorders, lysosomal transport defects, and neuronal ceroid lipofuscinoses. Because the lysosome lacks sufficient enzyme activity -Galactosidase OHOH to metabolize a particular lipid compound, substrates in lysosomes accumulate. Disease can also resultO from an OH inability to transport a particular lipid out of the lysosome. Both of these issues stem from HOspecific mutations in an OH enzyme’s gene code.

O OHOH For many years, lysosomal storage diseases were untreatable, but now, with a clearer understandingOH of the mechanismsR O HN O involved, several effective therapies have been developed. There are two approachesHO to treatingO these diseases:O replacingC13H27 OH HO the defective enzymes or inhibiting the synthesis of the accumulated lipid. The most promising andOH most commonOH treatment is enzyme replacement therapy (ERT). However, this treatment is very expensive and requires the transport of enzymes across the blood-brain barrier. This limits the effectiveness of ERT in cases involving the (CNS). HO Another treatment in development isGa stemng celllioside transplantation, Neuraminidas either one its own or along with ERT.AcHN However, bone marrow HO O transplant has limited applications and cannot be applied to as many cases as ERT. A third treatment option, OHinhibiting the Sialidosis HO HO2C synthesis of the accumulated lipid, has seen some success in treating type I Gaucher disease by reducingOH the synthesis of glucosylceramide. However, this affects the synthesis of other downstream lipids, which are also critical for cellularO OHOH functions. It appears that, due to the complexity of the diseases encountered, a combination of therapeuticOH approachesR O HN O will be needed. O O O C13H27 OH HO GM OH 3 HO O CO2H OH Sphingolipidoses (sphingolipid lysosomal storage disorders) result in an accumulation of various in the AcHN lysosome. Ten main sphingolipidoses affect the pathway: Farber’s,HO Krabbe,OH Gaucher, Metachromatic OH , Fabry, Sandhoff, Niemann-Pick, Sialidosis, Tay-Sachs, and GM1 . All of these disorders OH OH are characterized by an accumulationHe ofxo sphingolipidssaminidase in theA lysosome due to enzyme deficiency or ineffectiveO transport of lipids from the lysosome. Tay-Sachs Disease HO OH Sandhoff Disease NHAc OH OH O O HO Turn to the next page to view sphingolipidoses pathways O OH OH R NHAc O HN detailing the enzymes associated with these disorders and the O GM O O O C13H27 2 OH HO OH sphingolipid products they produce. HO O CO2H OH

AcHN HO OH MATREYA, LLC · 2178 HIGH TECH ROAD · STATE COLLEGE, PA · 16803 OH TEL: 800-342-3595 · FAX: 814-355-1031 · WWW.MATREYA.COM Acid -Galactosidase OHOH O OH GM1 Gangliosidosis HO OH

OHOH OH OH O O O O O OH HO OH R GM NHAc O HN 1 OH O O O O C13H27 OH HO OH HO O CO2H OH

AcHN HO OH OH LYSOSOMAL STORAGE DISEASE BIOMARKERS Sphingosine and Ceramide Accumulation NH2 Sphingosine HO C13H27 Catalog No. Product Name OH

O 1802 D-erythro-Sphingosine Acid Ceramidase HO R Farber’s Disease 2079 D-erythro-Sphingosine, D9 1618 N-Dodecanoyl-NBD-D-erythro-sphingosine Ceramide O HN R erythro 2038 N-Heptadecanoyl-D- -sphingosine HO C13H27 -Glucosidase OH OH 2081 N-Hexanoyl-biotin-D-erythro-sphingosine HO O Gaucher Disease OH HO OH 1841 N-Hexanoyl-NBD-D-erythro-sphingosine

2201 N-omega-CD3-Octadecanoyl-D-erythro-sphingosine O OH HN R Glucosylcerebroside O HO O C13H27 HO Glucosylceramide Accumulation OH OH Catalog No. Product Name -Galactosidase OHOH O 1522 , plant Krabbe Disease OH HO OH 1521 Glucocerebrosides, buttermilk O OHOH OH R 1057 Glucocerebrosides, Gaucher's spleen O HN Lactosylceramide O HO O O C13H27 OH HO 1306 Glucosylsphingosine, buttermilk OH OH

1310 Glucosylsphingosine, plant HO AcHN Neuraminidase HO 2086 Glucosylsphingosine, synthetic O OH Sialidosis HO HO2C OH

1533 N-omega-CD3-Hexadecanoyl-glucopsychosine O OHOH OH R O HN O 2085 N-Hexanoyl-biotin-glucosylceramide O O O C13H27 OH HO GM OH 3 HO O CO2H OH 1622 N-Hexanoyl-NBD-glucosylceramide AcHN HO OH 2089 N-Glycinated glucosylsphingosine OH OH OH A O Tay-Sachs Disease HO OH Accumulation Sandhoff Disease NHAc OH OH O O HO Catalog No. Product Name O OH OH R NHAc O HN O O O 1050 , bovine GM O C13H27 2 OH HO OH HO O CO2H OH

1633 N-Dodecanoyl-NBD-galactosylceramide AcHN HO OH OH 2091 N-Glycinated galactosylsphingosine Acid -Galactosidase OHOH O 2203 N-Hexanoyl-biotin-galactosylceramide OH GM1 Gangliosidosis HO OH 1621 N-Hexanoyl-NBD-galactosylceramide OHOH OH OH O O O 1914 N-Octadecanoyl-D35-psychosine, (perdeuterated, C18:0 fatty acid) O O OH HO OH R GM NHAc O HN 1 OH O O O O C13H27 1335 N-Pentadecanoyl-psychosine OH HO OH HO O CO2H OH

1305 Psychosine (free amine form) AcHN HO OH OH 2087 Psychosine, synthetic

Lipid Accumulation Enzyme Deficiency Associated Disease

MATREYA, LLC · 2178 HIGH TECH ROAD · STATE COLLEGE, PA · 16803 TEL: 800-342-3595 · FAX: 814-355-1031 · WWW.MATREYA.COM Lactosylceramide Accumulation Sphingosine NH2 HO C13H27 Catalog No. Product Name OH

1500 Lactosylceramides, porcine RBC Acid Ceramidase O Farber’s Disease 1507 Lactosylceramides, bovine buttermilk HO R

1517 lyso-Lactosylceramide (bovine buttermilk)

2088 lyso-Lactosylceramide, synthetic O Ceramide HN R 2090 N-Glycinated lactosylsphingosine HO C13H27 OH 2205 N-Hexanoyl-biotin-lactosylceramide

OH 1534 N-omega-CD -Hexadecanoyl-lactosylceramide 3 -Glucosidase HO O Gaucher Disease HO OH 1629 N-Hexanoyl-NBD-lactosylceramide OH

1630 N-Dodecanoyl-NBD-lactosylceramide O

Glucosylcerebroside OH HN R Ceramide Trihexoside O HO O C13H27 HO () Accumulation OH OH Catalog No. Product Name -Galactosidase OHOH O OH Krabbe Disease HO 1067 Ceramide trihexosides; Gb3 (porcine) OH 1520 lyso-Ceramide trihexoside

1631 N-Dodecanoyl-NBD-ceramide trihexoside O OHOH OH R Lactosylceramide O HN O 1530 N-Glycinated lyso-ceramide trihexoside HO O O C13H27 OH HO OH OH 1523 N-Heptadecanoyl-ceramide trihexoside

1537 N-omega-CD -Octadecanoyl-ceramide trihexoside 3 -Galactosidase A OHOH O OH HO Accumulation OH Catalog No. Product Name OHOH 1068 (porcine) O Gb3 (CTH) HO O OHO OH OH R O HN Ganglioside Accumulation O HO O O C13H27 OH HO Catalog No. Product Name OH OH

+ 1061 Monosialoganglioside GM1 (NH4 salt) -Hexosaminidase A + B OH + Sandhoff Disease OH 1518 lyso-Monosialoganglioside GM1 (NH4 salt) O HO OH + NHAc 2050 N-omega-CD3-Octadecanoyl monosialoganglioside GM1 (NH4 salt)

2053 N-Hexanoyl-biotin-monosialoganglioside GM 1 OH OHOH OH + Gb O O 2051 N-omega-CD3-Octadecanoyl monosialoganglioside GM2 (NH4 salt) 4 HO O O NHAc OHO OH + OH R 2052 N-omega-CD -Octadecanoyl monosialoganglioside GM (NH salt) O HN 3 3 4 O HO O O C13H27 OH HO 2054 N-omega-CD3-Octadecanoyl disialoganglioside GD3 OH OH

2055 N-Hexanoyl-biotin-disialoganglioside GD 3 Lipid Accumulation Enzyme Deficiency Associated Disease

MATREYA, LLC · 2178 HIGH TECH ROAD · STATE COLLEGE, PA · 16803 TEL: 800-342-3595 · FAX: 814-355-1031 · WWW.MATREYA.COM NH2 Sphingosylphosphorylcholine Accumulation HO C13H27 OH Sphingomyelinase CH Catalog No. Product Name 3 O Niemann-Pick Disease O H C N+ 3 O PHO Types A and B R CH 1318 D-erythro-Sphingosylphosphorylcholine HO 3 OH O CH3 O HN R 1619 N-Dodecanoyl-NBD-sphingosylphosphorylcholine + O H3C N O P O C13H27 R CH3 1890 N-Heptadecanoyl-sphingosylphosphorylcholine HN OH OH HO C13H27 OH 2200 N-1-13C-Hexadecanoyl-D-erythro-sphingosylphosphorylcholine -Galactosidase OH OH Krabbe Disease O OH 1912 N-Hexanoyl-NBD-sphingosylphosphorylcholine HO OH

O Galactosylcerebroside Accumulation OH OH HN R O O C13H27 Catalog No. Product Name HO OH OH Metachromatic Leukodystrophy 1049 (bovine) 2- SO4 + 1904 lyso-Sulfatide (NH4 salt)

O 1632 N-Dodecanoyl-NBD-sulfatide OH Sulfatide OH HN R O O C13H27 2092 N-Glycinated lyso-sulfatide HO3SO OH OH 2207 N-Hexanoyl-biotin-sulfatide Lipid Accumulation Enzyme Deficiency Associated Disease

1536 N-omega-CD3-Octadecanoyl-sulfatide DISEASE CHARACTERISTICS Farber’s Disease Krabbe Disease · Excess lipid: · Excess lipids: galactosylcerebroside and psychosine · Enzyme deficiency: ceramidase · Enzyme deficiency: β-galactosidase · Systems affected: various organs and CNS · Systems affected: sheath and axons · Potential therapy: hematopoietic stem cell transplant · Potential therapy: bone marrow transplant

Fabry Disease

· Excess lipid: globotriaosylceramide (CTH) · Excess lipids: globoside and monosialoganglioside GM2 · Enzyme deficiency: α-galactosidase A · Enzyme deficiency: β-hexosaminidase A and B activity · Systems affected: CNS and heart · System affected: CNS · Potential therapy: inhibitors or viral vectors Niemann-Pick Disease Types A and B · Excess lipid: sphingomyelin Sialidosis · Enzyme deficiency: sphingomyelinase · Excess lipid: ; sialic acid-rich glycoproteins

· Systems affected: neurons and organs and oligosaccharides · Enzyme deficiency: α-N-acetyl neuraminidase GM Gangliosidosis 1 · System affected: nervous system

· Excess lipids: ganglioside GM1 and

asialoganglisoide GM1 Tay-Sachs Disease · Enzyme deficiency: β-galactosidase · Excess lipid: ganglioside GM2 · System affected: CNS · Enzyme deficiency: β-hexosaminidase A · Potential therapy: ERT and substrate reduction · System affected: CNS · Potential therapy: ERT MATREYA, LLC · 2178 HIGH TECH ROAD · STATE COLLEGE, PA · 16803 TEL: 800-342-3595 · FAX: 814-355-1031 · WWW.MATREYA.COM