Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations Genetic Mutations Carcinogenesis in the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups of lysosomal storage diseases include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Subgroups within the main diseases have different underlying mechanisms and clinical manifestations.
Last updated: 11 Nov, 2021
Lysosomal storage diseases are rare metabolic conditions caused by genetic mutations Genetic Mutations Carcinogenesis of lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, which lead to dysfunctional metabolism and the accumulation of glycosaminoglycans, glycoproteins Glycoproteins Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins. Basics of Carbohydrates, or glycolipids Glycolipids Lipid attached to carbohydrate, outward-facing. The Cell: Cell Membrane.
Disorders are due to a deficiency in a specific lysosomal hydrolase or the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes required for lysosomal function:
The disorders are considered as groups of individually rare inherited disorders of intracellular metabolism. Of the 40 classified disorders, 15 account for the majority of cases. Categorization Categorization Types of Variables is by accumulated metabolite intermediates:
Inborn errors of metabolism with the associated genetic deficit
Image: “Inborn errors of metabolism” by Huckfinne. License: Public DomainGroup | Subgroup | Description |
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Sphingolipidoses | GM2-gangliosidosis |
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GM1-gangliosidosis | Caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the GLB1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics encoding for β-galactosidase-1 | |
Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease |
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Fabry disease Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. Fabry Disease |
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Metachromatic leukodystrophy Metachromatic leukodystrophy Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder that affects myelin in the brain and spinal cord. Genetic mutations result in the creation of a dysfunctional arylsulfatase A (ARSA) enzyme, which is unable to break down cerebroside sulfate. The accumulation of this metabolite results in permanent damage to oligodendroglial and Schwann cells (myelin). Metachromatic Leukodystrophy | Deficiency in arylsulfatase A activity | |
Krabbe disease Krabbe disease Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme galactocerebrosidase. Accumulation of galactocerebroside results in destruction of myelin-producing cells throughout the peripheral and central nervous systems, leading to demyelination and clinical symptoms. Krabbe Disease |
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Disseminated lipogranulomatosis (Farber disease) |
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Niemann–Pick disease |
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Oligosaccharidoses | Sialidosis |
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Galactosialidosis |
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Fucosidosis |
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Mannosidosis | 2 types:
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Mucolipidoses | I-cell disease I-cell disease Inclusion-cell disease (I-cell disease, mucolipidosis II, or ML II) is caused by a defect in uridine diphosphate (UDP)-N-acetylglucosamine-1-phosphotransferase, an enzyme that transfers phosphate to mannose residues on specific proteins. This protein is essential, since it is responsible for the breakdown of oligosaccharides, lipids, and glycosaminoglycans. I-cell Disease |
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Gaucher disease
Gaucher disease
Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation.
Gaucher Disease leads to
bone
Bone
Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy.
Bones: Structure and Types
necrosis
Necrosis
The death of cells in an organ or tissue due to disease, injury or failure of the blood supply.
Ischemic Cell Damage:
Connective tissue
Connective tissue
Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix.
Connective Tissue: Histology is infiltrated with numerous
Gaucher cells
Gaucher cells
Gaucher Disease (vacuolated, lipid-laden reticuloendothelial cells with enlarged granular cytoplasm and round, displaced nuclei).
The presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables depending upon the etiology of the lysosomal storage disorder and may occur soon after birth or late into adulthood:
Group | Subgroup | Signs and symptoms |
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Sphingolipidoses | GM2-gangliosidosis |
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GM1-gangliosidosis |
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Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease |
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Fabry disease Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. Fabry Disease |
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Metachromatic leukodystrophy Metachromatic leukodystrophy Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder that affects myelin in the brain and spinal cord. Genetic mutations result in the creation of a dysfunctional arylsulfatase A (ARSA) enzyme, which is unable to break down cerebroside sulfate. The accumulation of this metabolite results in permanent damage to oligodendroglial and Schwann cells (myelin). Metachromatic Leukodystrophy |
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Krabbe disease Krabbe disease Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme galactocerebrosidase. Accumulation of galactocerebroside results in destruction of myelin-producing cells throughout the peripheral and central nervous systems, leading to demyelination and clinical symptoms. Krabbe Disease |
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Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease |
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Oligosaccharidoses | Sialidosis |
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Galactosialidosis |
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Fucosidosis |
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Mucolipidoses | I-cell disease I-cell disease Inclusion-cell disease (I-cell disease, mucolipidosis II, or ML II) is caused by a defect in uridine diphosphate (UDP)-N-acetylglucosamine-1-phosphotransferase, an enzyme that transfers phosphate to mannose residues on specific proteins. This protein is essential, since it is responsible for the breakdown of oligosaccharides, lipids, and glycosaminoglycans. I-cell Disease |
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Work-up is based on the specific lysosomal storage disease, but some general principles are important to understand:
A Niemann-Pick cell from a liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy sample showing swollen Kupffer cells Kupffer cells Specialized phagocytic cells of the mononuclear phagocyte system found on the luminal surface of the hepatic sinusoids. They filter bacteria and small foreign proteins out of the blood, and dispose of worn out red blood cells. Benign Liver Tumors with foamy cytoplasm, which is typical for Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease type C
Image: “Histopathological liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings” by Degtyareva AV, Mikhailova SV, Zakharova EY, Tumanova EL, Puchkova AA AA Amyloidosis. License: CC BY 4.0Management depends upon the specific disorder. The general principles of management include:
A shunt may be required for individuals with hydrocephalus Hydrocephalus Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial. Subarachnoid Hemorrhage due to a lysosomal storage disorder.
Image by Lecturio.While lysosomal storage disorders encompass a broad spectrum Broad Spectrum Macrolides and Ketolides of disease, various other conditions may overlap the disorders. Some conditions are subgroups within the umbrella of lysosomal storage disorders: