Overview
Definition
Lysosomal storage diseases are rare metabolic conditions caused by genetic mutations 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, or glycolipids.
Epidemiology
- Incidence: approximately 1 per 5,000–10,000 live births (includes all types of lysosomal storage diseases)
- The incidence of a single lysosomal storage disorder is < 1 per 100,000 live births.
- The majority is inherited in an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancepattern.
- Some are X-linked recessive:
- Men are impacted.
- Women are not impacted but carry the defective gene.
Etiology
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:
- Lysosomes are extensive in macrophages and other cells of the mononuclear phagocyte system.
- The role of lysosomes is to break down nutrients and cellular waste substrates through specific enzymatic cascades.
- Substrates not metabolized due to enzyme deficiency accumulate in various organs of the body:
- The 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 and spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen become enlarged.
- The accumulation of certain glycolipids or phospholipids in various organs (particularly the brain) underlies a form of sphingolipidosis.
Classification
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 is by accumulated metabolite intermediates:
- Lipid storage disorders:
- Sphingolipidoses
- Gangliosidoses
- Leukodystrophies
- Mucopolysaccharidoses Mucopolysaccharidoses The mucopolysaccharidoses, a subset of the lysosomal storage diseases, are a group of inherited disorders characterized by absent or defective enzymes needed to break down carbohydrate chains called glycosaminoglycans (GAGs). These disorders lead to the accumulation of GAGs within cells. Mucopolysaccharidoses
- Glycoprotein storage disorders
- Mucolipidoses
Inborn errors of metabolism with the associated genetic deficit
Image: “Inborn errors of metabolism” by Huckfinne. License: Public Domain| Group | Subgroup | Description |
|---|---|---|
| Sphingolipidoses | GM2-gangliosidosis |
|
| 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 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 |
|
|
| 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 |
|
|
| 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 |
|
|
| Disseminated lipogranulomatosis (Farber disease) |
|
|
| Niemann–Pick disease |
|
|
| Oligosaccharidoses | Sialidosis |
|
| Galactosialidosis |
|
|
| Fucosidosis |
|
|
| Mannosidosis | 2 types:
|
|
| 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 |
|
Pathophysiology
- The role of lysosomes is to break down nutrients and cellular waste substrates through specific enzymatic cascades.
- Lysosomes depend upon a number of 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 to metabolize lipids, glycoproteins, and mucopolysaccharides.
- A lysosomal storage disorder is a result of a deficiency or malfunctioning of an enzyme, often 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 gene encoding for the enzyme.
- As a result of the enzymatic deficiency or error, an overaccumulation of metabolic intermediates occurs within the lysosome, leading to cell apoptosis.
- A defect in the following types of proteins may cause a lysosomal storage disease:
- Lysosomal enzyme
- Posttranslational modification
- Membrane transport proteins
- Enzyme protection proteins
- Transmembrane proteins
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.
Structure of Bones necrosis:
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 is infiltrated with numerous Gaucher cells (vacuolated, lipid-laden reticuloendothelial cells with enlarged granular cytoplasm and round, displaced nuclei).
Clinical Presentation
The presentation 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:
- Children are generally born without any abnormalities.
- The CNS is most often affected early.
- Recurrent fetal deaths may be a sign of an undiagnosed lysosomal storage disease within a family.
| Group | Subgroup | Signs and symptoms |
|---|---|---|
| Sphingolipidoses | GM2-gangliosidosis |
|
| GM1-gangliosidosis |
|
|
| 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 |
|
|
| 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 |
|
|
| 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 |
|
|
| 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 |
|
|
| 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 |
|
|
| Oligosaccharidoses | Sialidosis |
|
| Galactosialidosis |
|
|
| Fucosidosis |
|
|
| 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 |
|
Diagnosis
Work-up is based on the specific lysosomal storage disease, but some general principles are important to understand:
- Prenatal screening via amniocentesis and chorionic villus biopsy is becoming a more common route of diagnosis.
- Laboratory studies:
- Demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts
- Urine glycosaminoglycans (GAG) elevation is indicative of a mucopolysaccharidosis.
- Elevated creatinine kinase (CK) is indicative of Pompe disease.
- A dried blood spot test is often used as a screening study.
- Brain imaging: frequently obtained during evaluation of infants and children
- Skeletal radiography: Skeletal abnormalities in GM1 gangliosidosis are similar to mucopolysaccharidoses and include anterior “beaking” of vertebrae, enlargement of the sella turcica, and thickening of the calvaria.
- Chest radiography: Individuals with sphingomyelinase deficiency ( 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 A and type B) show fine reticulonodular infiltrates.
- Abdominal radiography: calcification of the adrenal gland in Wolman disease
- Genetic testing:
- Diagnostic: may allow for carrier identification and prenatal diagnosis
- Genotype-phenotype correlations can be made in 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.
- Cultured skin fibroblasts are the gold standard test.
- Individuals clinically suspected of disease with normal enzyme activity can be tested for enzyme activators.
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 sample showing swollen Kupffer cells 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 biopsy findings” by Degtyareva AV, Mikhailova SV, Zakharova EY, Tumanova EL, Puchkova AA. License: CC BY 4.0Management
Management depends upon the specific disorder. The general principles of management include:
- Enzyme replacement therapy:
- Replace the deficient or absent enzyme.
- To improve cardiac and lung function
- Does not penetrate the blood-brain barrier
- Substrate reduction therapy:
- Substances reduce substrate formation.
- To inhibit 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 catalyzing the synthesis of the substrate, which inhibits the enzyme
- Antiinflammatory medications: to reduce inflammatory cytokines such as IL-1
- Hematopoietic stem cell transplantation:
- Engrafts are used to produce the deficient enzyme in organs.
- Penetration is not good in the cornea, heart valves, and 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. Structure of Bones.
- Gene therapy:
- The individual’s stem cells are taken.
- The correct gene is put into the cells.
- After a chemotherapy regimen, the cells are reintroduced into the individual.
- Medications for seizures and movement disorders
- Benefits from individualized learning plans due to special educational needs. Occupational therapy and physical therapy will also be required.
- Cardiac surgery Cardiac surgery Cardiac surgery is the surgical management of cardiac abnormalities and of the great vessels of the thorax. In general terms, surgical intervention of the heart is performed to directly restore adequate pump function, correct inherent structural issues, and reestablish proper blood supply via the coronary circulation. Cardiac Surgery may be required for valve replacement.
- A shunt may be necessary if hydrocephalus develops.
- Speech pathology: to avoid aspiration and improve speech
- Other ancillary services such as social services and hospice may be required based upon the specific needs of the individual.
A shunt may be required for individuals with hydrocephalus due to a lysosomal storage disorder.
Image by Lecturio.Clinical Relevance
While lysosomal storage disorders encompass a broad spectrum of disease, various other conditions may overlap the disorders. Some conditions are subgroups within the umbrella of lysosomal storage disorders:
- Alexander disease: leukodystrophy characterized by myelin sheath destruction, abnormal protein deposits, and Rosenthal fibers found in astrocytes. The condition often presents early in life (before 2 years of age). The signs and symptoms of the disease include macrocephaly, seizures, and spasticity.
- Mucopolysaccharidoses Mucopolysaccharidoses The mucopolysaccharidoses, a subset of the lysosomal storage diseases, are a group of inherited disorders characterized by absent or defective enzymes needed to break down carbohydrate chains called glycosaminoglycans (GAGs). These disorders lead to the accumulation of GAGs within cells. Mucopolysaccharidoses: a group of inherited conditions in which the body cannot break down mucopolysaccharides. Due to the accumulation of sugar within cells, a variety of health problems may ensue.
- Pelizaeus-Merzbacher disease: a rare X-linked genetic disorder affecting the CNS. The disease involves abnormalities of the white matter of the brain and spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord due to 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 proteolipid protein 1, a myelin protein. The most noteworthy symptom is little or no movement in the arms or legs. Individuals experience difficulty with breathing and have left-to-right eye movement.
- Saposin A deficiency: almost identical to 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, but involves a defect in saposin A rather than galactosylceramidase protein. Saposin A deficiency is a very rare condition and may cause encephalopathy.
References
- Sun, A. (2018). Lysosomal storage disease overview. Ann Transl Med. 6(24), 476. https://pubmed.ncbi.nlm.nih.gov/30740407/
- Ferreira, C.R., Gahl, W.A. (2017). Lysosomal storage diseases. Transl Sci Rare Dis. 2(1–2), 1–71. https://pubmed.ncbi.nlm.nih.gov/29152458/
- Rajkumar, V., Dumpa, V. (2020). Lysosomal Storage Disease. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved October 18, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK563270/
