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Overview of Lysosomal Storage Diseases

Overview of Lysosomal Storage Diseases

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: Apr 24, 2025

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Overview

Definition

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.

Epidemiology

  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: approximately 1 per 5,000–10,000 live births (includes all types of lysosomal storage diseases)
  • The incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency 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 Inheritance pattern.
  • Some are X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy:
    • Men are impacted.
    • Women are not impacted but carry the defective 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.

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 Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles are extensive in macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation and other cells of the mononuclear phagocyte system.
  • The role of lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles 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: Anatomy 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: Anatomy become enlarged.
    • The accumulation of certain glycolipids Glycolipids Lipid attached to carbohydrate, outward-facing. The Cell: Cell Membrane or phospholipids Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Lipid Metabolism in various organs (particularly the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification) 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 Categorization Types of Variables 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 their associated genetic deficit

Inborn errors of metabolism with the associated genetic deficit

Image: “Inborn errors of metabolism” by Huckfinne. License: Public Domain
Table: Types of lysosomal storage diseases
Group Subgroup Description
Sphingolipidoses GM2-gangliosidosis
  • Accumulation of ganglioside Ganglioside A subclass of acidic glycosphingolipids. They contain one or more sialic acid (n-acetylneuraminic acid) residues. Using the svennerholm system of abbreviations, gangliosides are designated g for ganglioside, plus subscript m, d, or t for mono-, di-, or trisialo, respectively, the subscript letter being followed by a subscript arabic numeral to indicated sequence of migration in thin-layer chromatograms. Fatty Acids and Lipids GM2 due to a defect in the hexosaminidase system
  • Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease is the most common: 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 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 the α-subunit of the hexosaminidase A Hexosaminidase A A mammalian beta-hexosaminidase isoform that is a heteromeric protein comprised of both hexosaminidase alpha and hexosaminidase beta subunits. Deficiency of hexosaminidase A due to mutations in the gene encoding the hexosaminidase alpha subunit is a case of Tay-sachs disease. Deficiency of hexosaminidase A and hexosaminidase B due to mutations in the gene encoding the hexosaminidase beta subunit is a case of Sandhoff disease. Tay-Sachs Disease (HEXA) enzyme
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
  • The most prevalent of the sphingolipidoses
  • Glucocerebroside accumulates in the cells of the mononuclear macrophage system.
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
  • 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 Inheritance disease
  • 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 GALC GALC An enzyme that hydrolyzes galactose from ceramide monohexosides. Deficiency of this enzyme may cause globoid cell leukodystrophy. Krabbe Disease 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 galactosylceramidase Galactosylceramidase An enzyme that hydrolyzes galactose from ceramide monohexosides. Deficiency of this enzyme may cause globoid cell leukodystrophy. Krabbe Disease
  • Deficiency in the lysosomal enzyme galactocerebrosidase Galactocerebrosidase An enzyme that hydrolyzes galactose from ceramide monohexosides. Deficiency of this enzyme may cause globoid cell leukodystrophy. Krabbe Disease
Disseminated lipogranulomatosis (Farber disease)
  • 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 Inheritance disorder of lipid metabolism Lipid Metabolism Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component production. Lipid metabolism uses fats from dietary sources or from fat stores in the body. A complex series of processes involving digestion, absorption, and transport are required for the proper metabolism of lipids. Lipid Metabolism
  • Deficiency of acid ceramidase leading to an accumulation of ceramide
Niemann–Pick disease
  • 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 Inheritance disorder
  • Sphingomyelin Sphingomyelin A class of sphingolipids found largely in the brain and other nervous tissue. They contain phosphocholine or phosphoethanolamine as their polar head group so therefore are the only sphingolipids classified as phospholipids. Neonatal Respiratory Distress Syndrome accumulates in many organs due to a deficiency of sphingomyelinase.
Oligosaccharidoses Sialidosis
  • Deficiency of neuraminidase Neuraminidase An enzyme that catalyzes the hydrolysis of alpha-2, 3, alpha-2, 6-, and alpha-2, 8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. Antivirals for Influenza (sialidase)
  • Mutations in the NEU1 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
Galactosialidosis
  • A progressive neurodegenerative disease
  • Deficiency of neuraminidase Neuraminidase An enzyme that catalyzes the hydrolysis of alpha-2, 3, alpha-2, 6-, and alpha-2, 8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. Antivirals for Influenza (sialidase) and β-galactosidase
Fucosidosis
  • 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 Inheritance disorder
  • Deficiency of the lysosomal enzyme α-1-fucosidase
Mannosidosis 2 types:
  • α-mannosidosis 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 MAN2B1 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 α-mannosidase
  • β-mannosidosis 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 MANBA 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-mannosidase
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
  • 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 GNPTAB 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
  • 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 Inheritance neurodegenerative disorder
  • Caused by a deficiency of uridine-diphosphate-N-acetylglucosamine-1-phosphotransferase

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6:01
Lysosome

Pathophysiology

  • The role of lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles is to break down nutrients and cellular waste substrates through specific enzymatic cascades.
  • Lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles 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 Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids, glycoproteins Glycoproteins Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins. Basics of Carbohydrates, and mucopolysaccharides Mucopolysaccharides Heteropolysaccharides which contain an n-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1, 4- and 1, 3-linkages consisting of either n-acetylglucosamine or n-acetylgalactosamine. Basics of Carbohydrates. 
  • 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 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 the enzyme.
  • As a result of the enzymatic deficiency or error Error Refers to any act of commission (doing something wrong) or omission (failing to do something right) that exposes patients to potentially hazardous situations. Disclosure of Information, an overaccumulation of metabolic intermediates occurs within the lysosome, leading to cell apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage.
  • A defect in the following types of proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis may cause a lysosomal storage disease:
    • Lysosomal enzyme 
    • Posttranslational modification
    • Membrane transport proteins Transport proteins Proteins and Peptides
    • Enzyme protection proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
    • Transmembrane proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
Gaucher disease leads to bone necrosis

Gaucher disease leads to bone necrosis:
Connective tissue is infiltrated with numerous Gaucher cells (vacuolated, lipid-laden reticuloendothelial cells with enlarged granular cytoplasm and round, displaced nuclei).

Image: “Microscopic findings from surgical biopsy” by Ahmadieh A, Farnad F, Sedghizadeh PP. License: CC BY 4.0

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.
Table: Signs and symptoms of different etiologies in lysosomal storage disorders
Group Subgroup Signs and symptoms
Sphingolipidoses GM2-gangliosidosis
  • Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease usually results in death by 4 years of age.
  • Deterioration of mental and physical capabilities
GM1-gangliosidosis
  • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions eruptions
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
  • Irritability
  • Inability to walk
  • Knee hyperextension Knee Hyperextension Osgood-Schlatter Disease
  • Gradual muscle wasting Muscle Wasting Duchenne Muscular Dystrophy
  • Weakness
  • Hypotonia Hypotonia Duchenne Muscular Dystrophy
  • Nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism
  • Optic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation
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
  • Irritability
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Hypertonia Hypertonia Abnormal increase in skeletal or smooth muscle tone. Skeletal muscle hypertonicity may be associated with pyramidal tract lesions or basal ganglia diseases. Neurological Examination
  • Optic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation
  • Developmental delay
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
  • Swelling Swelling Inflammation throughout the body
  • Coarse facial features
  • Hip dislocation
  • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
Galactosialidosis
Fucosidosis
  • Coarse facial features
  • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
  • Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Deterioration of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 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: Anatomy
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
  • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
  • Developmental delay
  • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
  • Respiratory tract infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

Diagnosis

Work-up is based on the specific lysosomal storage disease, but some general principles are important to understand:

  • Prenatal screening Screening Preoperative Care via amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios and chorionic villus biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is becoming a more common route of diagnosis.
  • Laboratory studies:
    • Demonstration of specific enzymatic deficiency in peripheral blood leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology or cultured fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis
    • 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 Screening Preoperative Care study.
  • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification imaging: frequently obtained during evaluation of infants and children
  • Skeletal radiography: Skeletal abnormalities in GM1 gangliosidosis are similar to 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 and include anterior “beaking” of vertebrae, enlargement of the sella turcica Sella turcica A bony prominence situated on the upper surface of the body of the sphenoid bone. It houses the pituitary gland. Pituitary Gland: Anatomy, 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies:
    • Diagnostic: may allow for carrier Carrier Vaccination identification Identification Defense Mechanisms 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis are the gold standard test.
    • Individuals clinically suspected of disease with normal enzyme activity can be tested for enzyme activators.
Neimann-pick cell from a sample of the liver showing swollen kupffer cells with foamy cytoplasm

A Niemann-Pick cell from a liver sample showing swollen Kupffer cells with foamy cytoplasm, which is typical for Niemann-Pick disease type C

Image: “Histopathological liver biopsy findings” by Degtyareva AV, Mikhailova SV, Zakharova EY, Tumanova EL, Puchkova AA. License: CC BY 4.0

Management

Management depends upon the specific disorder. The general principles of management include:

  • Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID) therapy:
    • Replace the deficient or absent enzyme.
    • To improve cardiac and lung function
    • Does not penetrate the blood-brain barrier Blood-brain barrier Specialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. Systemic and Special Circulations
  • Substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes reduction therapy:
    • Substances reduce substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes 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 Synthesis Polymerase Chain Reaction (PCR) of the substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes, which inhibits the enzyme 
  • Antiinflammatory medications: to reduce inflammatory cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response such as IL-1
  • Hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation:
    • Engrafts are used to produce the deficient enzyme in organs.
    • Penetration Penetration X-rays is not good in the cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy, 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. Bones: Structure and Types.
  • 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 therapy:
    • The individual’s stem cells are taken.
    • The correct 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 is put into the cells.
    • After a chemotherapy Chemotherapy Osteosarcoma regimen, the cells are reintroduced into the individual.
  • Medications for seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures and movement disorders
  • Benefits from individualized learning plans due to special educational needs. Occupational therapy Occupational Therapy Skilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living. Fetal Alcohol Spectrum Disorder and physical therapy Physical Therapy Becker Muscular Dystrophy 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 Hydrocephalus Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial. Subarachnoid Hemorrhage 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.
Shunt in lysosomal storage disorder

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 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:

  • Alexander disease: leukodystrophy characterized by myelin sheath destruction, abnormal protein deposits, and Rosenthal fibers Rosenthal Fibers Hemangioblastoma found in astrocytes Astrocytes A class of large neuroglial (macroglial) cells in the central nervous system – the largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from ‘star’ cells) are irregularly shaped with many long processes, including those with ‘end feet’ which form the glial (limiting) membrane and directly and indirectly contribute to the blood-brain barrier. They regulate the extracellular ionic and chemical environment, and ‘reactive astrocytes’ (along with microglia) respond to injury. Nervous System: Histology. The condition often presents early in life (before 2 years of age). The signs and symptoms of the disease include macrocephaly Macrocephaly Cowden Syndrome, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and spasticity Spasticity Spinal Disk Herniation. 
  • 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 Mucopolysaccharides Heteropolysaccharides which contain an n-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1, 4- and 1, 3-linkages consisting of either n-acetylglucosamine or n-acetylgalactosamine. Basics of Carbohydrates. Due to the accumulation of sugar within cells, a variety of health problems may ensue.
  • Pelizaeus-Merzbacher disease: a rare X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) genetic disorder affecting the CNS. The disease involves abnormalities of the white matter White Matter The region of central nervous system that appears lighter in color than the other type, gray matter. It mainly consists of myelinated nerve fibers and contains few neuronal cell bodies or dendrites. Brown-Séquard Syndrome of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 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: Anatomy 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 Proteolipid Protein-lipid combinations abundant in brain tissue, but also present in a wide variety of animal and plant tissues. In contrast to lipoproteins, they are insoluble in water, but soluble in a chloroform-methanol mixture. The protein moiety has a high content of hydrophobic amino acids. The associated lipids consist of a mixture of glycerophosphates; cerebrosides; and sulfoglycosphingolipids; while lipoproteins contain phospholipids; cholesterol; and triglycerides. Orthopoxvirus 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 Galactosylceramidase An enzyme that hydrolyzes galactose from ceramide monohexosides. Deficiency of this enzyme may cause globoid cell leukodystrophy. Krabbe Disease protein. Saposin A deficiency is a very rare condition and may cause encephalopathy Encephalopathy Hyper-IgM Syndrome. 

References

  1. Abelleyra Lastoria, D. A., Rodríguez, M. F., & Lo Russo, R. M. (2025). Current and emerging therapies for lysosomal storage disorders. Drugs, 85(2), 171–192. https://doi.org/10.1007/s40265-025-02145-5
  2. Berg, J. M., Tymoczko, J. L., Gatto, G. J., & Stryer, L. (2023). Biochemistry (10th ed.). W. H. Freeman and Company.
  3. Borges, B., Martín, A., & Herrera, L. (2025). Prenatal delivery of enzyme replacement therapy to fetuses affected by early-onset lysosomal storage diseases. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, e32132. https://doi.org/10.1002/ajmg.c.32132
  4. Kumar, V., Abbas, A. K., & Aster, J. C. (2021). Robbins & Cotran pathologic basis of disease (10th ed.). Elsevier.
  5. Lerussi, G., Moretti, M., & Donati, A. (2025). Extracellular vesicles as tools for crossing the blood–brain barrier to treat lysosomal storage diseases. Life, 15(1), 70. https://doi.org/10.3390/life15010070
  6. Ludlaim, A. M., Fischer, D. R., & McCarthy, B. A. (2025). Unifying biology of neurodegeneration in lysosomal storage diseases. Journal of Inherited Metabolic Disease, 48(1), e12833. https://doi.org/10.1002/jimd.12833
  7. Parenti, G., Andria, G., & Ballabio, A. (2021). The rapidly evolving view of lysosomal storage diseases. EMBO Molecular Medicine, 13(2), e12836. https://doi.org/10.15252/emmm.202012836
  8. UpToDate. (2025, May 20). Overview of inherited disorders of glucose and glycogen metabolism. https://www.uptodate.com/contents/overview-of-inherited-disorders-of-glucose-and-glycogen-metabolism

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