Lysosomal storage diseases

Group of > 50 hereditary metabolic diseases caused by malfunctions in the lysosome. The lysosome is a cell organelle present in almost all eukaryotic cells. Lysosomes contain numerous acid hydrolases e.g. proteases, nucleases, lipases. Their most important task is the hydrolytic cleavage of foreign or endogenous substances (proteins, polysaccharides, nucleic acids, glycolipids). Lysosomes thus act as a kind of "garbage chute" that removes the cell's degradation products produced during metabolic processes.

In general, lysosomal storage diseases are divided into three groups::

• severe infantile
• moderate juvenile
• mild adult forms.

Depending on the accumulated substance class, a distinction is made between:

• Mucopolysaccharidoses
• Mucolipidoses (ML)
• sphingolipidoses
• Oligosaccharidoses
• Neuronal ceroid lipofuscinoses (amaurotic idiocy)
• other

Disease patterns known to date with mutated enzyme/transporter and the associated chromosome/gene locus

Mucopolysaccharidoses

Mucopolysaccharidoses are based on a defect in the lysosomal glycosidases. They lead to the accumulation of proteoglycans.

Pfaundler-Hurler disease (MPS I-H) Enzyme defect of the α-L-iduronidase (gene locus: 4p16.3)

Scheie disease (MPS I-S) Enzyme defect of α-L-iduronidase (gene locus:4q16.3)

Hurler-Scheie disease (MPS I-H/S) Enzyme defect of α-L-iduronidase (gene locus:4q16.3)

Hunter disease (MPS II) Enzyme defect of iduronate-2-sulfatase (gene locus:Xq27.3-28)

Sanfilippo syndrome type A (MPS IIIA) Enzyme defect of heparan sulfate sulfamidase (gene locus:17q25.3)

Sanfilippo syndrome type B (MPS IIIB) Enzyme defect of α-N-acetylglucose amidase (gene locus:17q21)

Sanfilippo syndrome type C (MPS IIIC) Enzyme defect of acetyl-CoA α-glucosaminide-N-acetyltransferase (gene locus:8p11.1)

Sanfilippo syndrome type D (MPS IIID) Enzyme defect of N-acetyl-glucosamine-6-sulfate sulfatase (gene locus:12q14)

Morquio syndrome type A (MPS IVA) Enzyme defect of N-acetyl-glucosamine-6-sulfate sulfatase (gene locus:16q24.3)

Morquio syndrome type B (MPS IVB) Enzyme defect of β-galactosidase (gene locus:3p21.3)

Morquio syndrome type C (MPS IVC)

Maroteaux-Lamy syndrome (MPS VI) Enzyme defect of arylsulfatase B (gene locus:5q11-13)

Sly syndrome (MPS VII) Enzyme defect of β-glucuronidase (gene locus:7q21.1-11)

Mucolipidoses (ML)

Mucolipidoses offer a combination of the symptoms of mucopolysaccharidoses (involvement of skin, cartilage, etc.) and lipidoses

Sialidosis type II (ML type I) Enzyme defect of neuraminidase (gene locus:6p21.3)

I-cell (disease (ML type IIα/β) Enzyme defect of phosphotransferase (gene locus:12q23.3)

Pseudo-Hurler polydystrophy (ML type IIIα/β) Enzyme defect of phosphotransferase (gene locus:12q23.3)

Sialolipidosis (ML type IV) Enzyme defect of mucolipin-1 (gene locus:19p13.3-p13.2 - MCOLN1)

Sphingolipidoses

Lipidoses are caused by a defect in the lysosomal lipases. Depending on the accumulated lipids, further subtypes are distinguished: sphingolipidoses (e.g. Gaucher's disease) and gangliosidoses (e.g. Fabry's disease). Sphingolipids are important components of membrane structures and play a role in the proliferation and differentiation of cells.

GM1 gangliosidosis type I Enzyme defect of the β-galactosidase (gene locus:3p21.3 - GLB1)

GM1 gangliosidosis type II enzyme defect of β-galactosidase (gene locus:3p21.3)

GM1 gangliosidosis type III Enzyme defect of β-galactosidase (gene locus:3p21.3)

Tay-Sachs disease Enzyme defect of β-hexosaminidase A (gene locus:15q23-24 - HEXA)

Sandhoff disease Enzyme defect of β-hexosaminidase A & B (gene locus:5q13 HEXB)

Tay-Sachs syndrome AB variant GM2 activator deficiency (gene locus:5q31.3-q33.1)

Fabry disease enzyme defect of α-galactosidase (gene locus:Xq22 GLA)

Gaucher disease (non-neuronopathic form) Enzyme defect of glucocerebrosidase (gene locus:1q22 GBA)

Gaucher disease (acute neuronopathic form) Enzyme defect of glucocerebrosidase (gene locus:1q22 GBA)

Gaucher disease (chroic neuronopathic form) Enzyme defect of glucocerebrosidase (1q22 GBA)

Gaucher disease perinatal lethal Enzyme defect of glucocerebrosidase (gene locus:1q22 GBA)

Multiple sulfatase deficiency Deficiency of Fgly-generating enzymes (gene locus:3p26 SUMF1)

Farber disease enzyme defect of acid ceramidase (gene locus:8p22-p21.3 ASAH)

Metachromatic leukodystrophy (MLD) Enzyme defect of arylsulfatase A (gene locus:22q13.3 ARSA)

Saposin B deficiency Deficiency of saposin B (gene locus:10q22.1 PSAP)

Krabbe disease enzyme defect of galactosylceramidase (gene locus:14q31 GALC)

Krabbe disease atypical deficiency of SAPOSIN-A (gene locus:10q22.1 PSAP)

Niemann-Pick disease type A Enzyme defect of sphingomyelinase (gene locus:11p15.4-p15.1 SMPD1)

Niemann-Pick disease type B Enzyme defect of sphingomyelinase (gene locus:11p15.4-p15.1 SMPD1)

Niemann-Pick disease type C1 Deficiency of NPC1 protein (gene locus:18q11-q12 NPC1)

Niemann-Pick disease type C2 Deficiency of NPC2 protein (gene locus:1424.3 NPC2)

Gaucher disease Saposin C deficiency Deficiency of saposin C (gene locus:10q22.1 PSAP

Oligosaccharidoses

Defects in the lysosomal oligosaccharidases are responsible. It leads to the accumulation of glycoproteins. They are very rare and mainly affect the CNS. They are often severe courses with seizures and muscle weakness, in addition to mental and motor regression.

α-Mannosidosis Enzyme defect of the α-mannosidase (gene locus:19cen-q12 MAN2B1)

β-mannosidosis enzyme defect of β-mannosidase (gene locus:4q22-q25 MANBA)

Fucosidosis enzyme defect of α-fucosidase (gene locus:1p34 FUCA1)

Aspartylglucosaminuria Enzyme defect of aspartylglucosaminidase (gene locus:4q32-33 AGA)

Kanzaki disease (syn. Schindler disease type I) Enzyme defect of aspartylglucosaminidase α-galactosaminidase (gene locus:22q11 NAGA)

Sialic acid storage disease infantile (ISSD) Defect of the sialic acid transporter (sialin)

(gene locus:6q14-15 SLC17A5)

Sialic acid storage disease adult (Salla disease) Defect of the sialic acid transporter (sialin) (gene locus:6q14-15 SLC17A5)

Galactosialidosis (Goldberg syndrome) Defect of the protective protein (gene locus:20q13.1 GLB2)

Neuronal ceroid lipofuscinoses (amaurotic idiocy)

Group of rare, hereditary, as yet incurable lysosomal storage diseases that can occur in different forms and at different ages. NCL is colloquially referred to as childhood dementia.

Neuronal ceroid lipofuscinosis 1 Defect in palmitoyl thio-esterase (gene locus:1p32 CLN1)

Neuronal ceroid lipofuscinosis 2 Defect of tripeptidyl peptidase 1 (gene locus:11p15.5 TPP1)

Neuronal ceroid lipofuscinosis 3 (Batten syndrome) (gene locus:16p12.1 CLN3)

Neuronal ceroid lipofuscinosis 4A

Neuronal ceroid lipofuscinosis 4B

Neuronal ceroid lipofuscinosis 5 (gene locus:13q21.1-q32 CLN5)

Neuronal ceroid lipofuscinosis 6 (gene locus:15q21-q23 CLN6)

Neuronal ceroid lipofuscinosis 7 (gene locus:4q28.1-q28.2 MFSD8)

Neuronal ceroid lipofuscinosis 8 (gene locus:8p23 CLN8)

Neuronal ceroid lipofuscinosis 8 (Nordic epilepsy) (gene locus:8p23 CDefect of LN8)

Neuronal ceroid lipofuscinosis 9

Neuronal ceroid lipofuscinosis 10 (gene locus:11p15.5 CTSD)

Other

Pycnodysostosis Enzyme defect of cathepsin K (gene locus:1q21 CTSK)

Pompe disease Defect of lysosomal α-glucosidase (gene locus:17q25.2-3 GAA)

Cystinosis, nephropathic Defect of the cystine transporter (gene locus:17p13 TAX1BP3 gene)

Cystinosis, adult, non-nephropathic Defect of the cystine transporter (gene locus:17p13 CTNS gene)

Wolman disease/CESD Defect in lysosomal acid lipase (gene locus:10q23.2-23.3 LIPA gene)

The total frequency of all lysosomal storage diseases is about 1/ 7500 - 8000 new births.

If the activity of a lysosomal enzyme is significantly reduced, the degradation of the macromolecules produced can no longer be catalysed or can only be catalysed much more slowly. The macromolecules to be degraded initially accumulate in the cell, and later in an uncontrolled manner in the extracellular matrix and thus in the entire organism. The reason for the reduced or missing enzyme activity are mutations of the coding genes that lead to a change in the protein's secondary or tertiary structure. Mucopolysaccharidosis type II (Hunter's disease) and Fabry's disease are inherited X-linked, all other autosomal recessive diseases. The liver, spleen and skin, but also the nervous system, cartilage and bones are affected by reduced enzyme activity.

In addition to the reduced enzyme activity, missing or defective membrane transporters can also lead to an accumulation (storage) of metabolic products in the cell. This has been demonstrated in 5 of the lysosomal storage diseases known to date.

Genetically engineered enzyme replacement therapies are available for some lysosomal storage diseases. These include Hunter's disease, idursulfase, Gaucher's disease, imiglucerase and alpha-galactosidase in Fabry's disease.