Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited
metabolic disorders
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
that result from defects in lysosomal function.
Lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane p ...
s are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.
Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
of
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
s,
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glyco ...
s (sugar-containing proteins), or so-called
mucopolysaccharides. Individually, lysosomal storage diseases occur with incidences of less than 1:100,000; however, as a group, the incidence is about 1:5,000 – 1:10,000. Most of these disorders are
autosomal recessive
In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...
ly inherited such as
Niemann–Pick disease, type C
Niemann–Pick type C (NPC) (colloquially, "Childhood Alzheimer's") is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present b ...
, but a few are
X-linked recessively inherited, such as
Fabry disease
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. ...
and
Hunter syndrome (MPS II).
The lysosome is commonly referred to as the cell's recycling center because it processes unwanted material into substances that the cell can use. Lysosomes break down this unwanted matter by
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s, highly specialized
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s essential for survival. Lysosomal disorders are usually triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, substances accumulate in the cell. In other words, when the lysosome does not function normally, excess products destined for breakdown and recycling are stored in the cell.
Like other
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s, individuals inherit lysosomal storage diseases from their parents. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic – all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome.
Lysosomal storage diseases affect mostly children and they often die at a young age, many within a few months or years of birth.
Classification
Standard classification
The lysosomal storage diseases are generally classified by the nature of the primary stored material involved, and can be broadly broken into the following: (
ICD-10
ICD-10 is the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD), a medical classification list by the World Health Organization (WHO). It contains codes for diseases, signs and symptoms ...
codes are provided where available)
* (E75)
Lipid storage disorder
A lipid storage disorder (or lipidosis) is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one o ...
s
**
Sphingolipidoses, including
Gaucher's and
Niemann–Pick disease
Niemann–Pick disease is a group of severe inherited metabolic disorders, in which sphingomyelin accumulates in lysosomes in cells (the lysosomes normally degrade material that comes from out of cells).
These disorders involve the dysfunctional ...
s (E75.0-E75.1)
**
Gangliosidosis (including
Tay–Sachs disease
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around three to six months of age, with the baby ...
(E75.2)
**
Leukodystrophies
* (E76.0)
Mucopolysaccharidoses
Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells ...
, including
Hunter syndrome and
Hurler disease
Hurler syndrome, also known as mucopolysaccharidosis Type IH (MPS-IH), Hurler's disease, and formerly gargoylism, is a genetic disorder that results in the buildup of large sugar molecules called glycosaminoglycans (GAGs) in lysosomes. The in ...
* (E77)
Glycoprotein storage disorders
* (E77.0-E77.1)
Mucolipidoses
Also,
glycogen storage disease type II
Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of th ...
(Pompe disease) is a defect in lysosomal metabolism as well, although it is otherwise classified into E74.0 in ICD-10.
Cystinosis
Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosom ...
is an lysosomal storage disease characterized by the abnormal accumulation of the amino acid cystine.
By type of defect protein
Alternatively to the protein targets, lysosomal storage diseases may be classified by the type of protein that is deficient and is causing buildup.
Lysosomal storage disorders
Lysosomal storage diseases include:
Sphingolipidoses
*
Ceramidase
**
Farber disease
**
Krabbe disease
*** Infantile onset
*** Late onset
*
Galactosialidosis
*
Gangliosides:
gangliosidoses
Gangliosidosis contains different types of lipid storage disorders caused by the accumulation of lipids known as gangliosides. There are two distinct genetic causes of the disease. Both are autosomal recessive and affect males and females equall ...
**
Alpha-galactosidase
α-Galactosidase ( EC 3.2.1.22, α-GAL, α-GAL A; systematic name α-D-galactoside galactohydrolase) is a glycoside hydrolase enzyme that catalyses the following reaction:
: Hydrolysis of terminal, non-reducing α-D-galactose residues in α-D ...
***
Fabry disease
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. ...
(alpha-galactosidase A)
***
Schindler disease (alpha-galactosidase B)
**
Beta-galactosidase
β-Galactosidase (EC 3.2.1.23, lactase, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase), is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides.
β ...
/
GM1 gangliosidosis
The GM1 gangliosidoses, usually shortened to GM1, are gangliosidoses caused by mutation in the GLB1 gene resulting in a deficiency of beta-galactosidase. The deficiency causes abnormal storage of acidic lipid materials in cells of the central and ...
*** Infantile
*** Juvenile
*** Adult / chronic
**
GM2 gangliosidosis
***
AB variant
*** Activator deficiency
***
Sandhoff disease
Sandhoff disease is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, ...
**** Infantile
**** Juvenile
**** Adult onset
***
Tay–Sachs
**** Juvenile hexosaminidase A deficiency
**** Chronic hexosaminidase A deficiency
*
Glucocerebroside
**
Gaucher disease
*** Type I
*** Type II
*** Type III
*
Sphingomyelinase
**
Lysosomal acid lipase deficiency
*** Early onset
*** Late onset
**
Niemann–Pick disease
Niemann–Pick disease is a group of severe inherited metabolic disorders, in which sphingomyelin accumulates in lysosomes in cells (the lysosomes normally degrade material that comes from out of cells).
These disorders involve the dysfunctional ...
*** Type A
*** Type B
*
Sulfatidosis
Sulfatidosis is a form of lysosomal storage disease resulting in a proliferation of sulfatide.
Causes
It is caused by a genetic insufficiency of sulfatase enzymes.
Diagnosis Types
Metachromatic leukodystrophy and multiple sulfatase deficiency
Mu ...
**
Metachromatic leukodystrophy
*** Saposin B deficiency
**
Multiple sulfatase deficiency
Mucopolysaccharidoses
Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells ...
* Type I
** MPS I
Hurler syndrome
** MPS I S
Scheie syndrome
Scheie syndrome is a disease caused by a deficiency in the enzyme iduronidase, leading to the buildup of glycosaminoglycans (GAGs) in the body. It is the most mild subtype of mucopolysaccharidosis type I; the most severe subtype of this diseas ...
** MPS I H-S
Hurler–Scheie syndrome
* Type II (
Hunter syndrome)
* Type III (
Sanfilippo syndrome
Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare autosomal recessive lysosomal storage disease that primarily affects the brain and spinal cord. It is caused by a buildup of large sugar molecules called gly ...
)
** MPS III A (Type A)
** MPS III B (Type B)
** MPS III C (Type C)
** MPS III D (Type D)
* Type IV (
Morquio)
** MPS IVA (Type A)
** MPS IVB (Type B)
* Type VI (
Maroteaux–Lamy syndrome
Maroteaux–Lamy syndrome, or Mucopolysaccharidosis Type VI (MPS-VI), is an inherited disease caused by a deficiency in the enzyme arylsulfatase B (ARSB). ASRB is responsible for the breakdown of large sugar molecules called glycosaminoglycans ...
)
* Type VII (
Sly syndrome
Sly syndrome, also called mucopolysaccharidosis type VII (MPS-VII), is an autosomal recessive lysosomal storage disease caused by a deficiency of the enzyme β-glucuronidase. This enzyme is responsible for breaking down large sugar molecules ca ...
)
* Type IX (
hyaluronidase deficiency)
Mucolipidosis
* Type I (
sialidosis)
* Type II (
I-cell disease
Inclusion-cell (I-cell) disease, also referred to as mucolipidosis II (ML II), is part of the lysosomal storage disease family and results from a defective phosphotransferase (an enzyme of the Golgi apparatus). This enzyme transfers phosphate to ...
)
* Type III (pseudo-Hurler polydystrophy /
phosphotransferase
Phosphotransferases are a category of enzymes ( EC number 2.7) that catalyze phosphorylation reactions. The general form of the reactions they catalyze is:
:A-P + B \rightleftharpoons B-P + A
Where ''P'' is a phosphate group and A and B are the d ...
deficiency)
* Type IV (
mucolipidin 1 deficiency)
Lipidoses
*
Niemann–Pick disease
Niemann–Pick disease is a group of severe inherited metabolic disorders, in which sphingomyelin accumulates in lysosomes in cells (the lysosomes normally degrade material that comes from out of cells).
These disorders involve the dysfunctional ...
**
type C
** Type D
*
Neuronal ceroid lipofuscinoses
Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These l ...
** Type 1
Santavuori–Haltia disease / infantile NCL (CLN1
PPT1)
** Type 2
Jansky–Bielschowsky disease
Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body ...
/ late infantile NCL (CLN2/LINCL
TPP1)
** Type 3
Batten–Spielmeyer–Vogt disease / juvenile NCL (
CLN3)
** Type 4
Kufs disease / adult NCL (
CLN4)
** Type 5 Finnish Variant / late infantile (
CLN5)
** Type 6 Late infantile variant (
CLN6)
** Type 7
CLN7
** Type 8 Northern epilepsy (
CLN8)
** Type 8 Turkish late infantile (
CLN8)
** Type 9 German/Serbian late infantile (unknown)
** Type 10 Congenital cathepsin D deficiency (
CTSD
Cathepsin D is a protein that in humans is encoded by the ''CTSD'' gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathe ...
)
*
Wolman disease
Oligosaccharide
An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sug ...
*
Alpha-mannosidosis
*
Beta-mannosidosis
*
Aspartylglucosaminuria
*
Fucosidosis
Lysosomal transport diseases
*
Cystinosis
Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosom ...
*
Pycnodysostosis
*
Salla disease / sialic acid storage disease
*
Infantile free sialic acid storage disease
Glycogen storage diseases
* Type II
Pompe disease
Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of th ...
* Type IIb
Danon disease
Other
*
Cholesteryl ester storage disease
Lysosomal disease
Signs and symptoms
The symptoms of lysosomal storage diseases vary depending on the particular disorder and other variables such as the age of onset, and can be mild to severe. They can include developmental delay, movement disorders,
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...
,
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
,
deafness
Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is written ...
, and/or
blindness
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...
. Some people with lysosomal storage diseases have
enlarged livers or
spleens,
pulmonary and
cardiac
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
problems, and bones that grow abnormally.
Diagnosis
The majority of patients are initially screened by enzyme assay, which is the most efficient method to arrive at a definitive diagnosis.
[ In some families where the disease-causing mutations are known, and in certain genetic isolates, mutation analysis may be performed. In addition, after a diagnosis is made by biochemical means, mutation analysis may be performed for certain disorders.
]
Treatment
No cures for lysosomal storage diseases are known, and treatment is mostly symptomatic, although bone marrow transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
and enzyme replacement therapy
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
ERT is availa ...
(ERT) have been tried with some success. ERT can minimize symptoms and prevent permanent damage to the body. In addition, umbilical cord blood
Cord blood (umbilical cord blood) is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders su ...
transplantation is being performed at specialized centers for a number of these diseases. In addition, substrate reduction therapy, a method used to decrease the production of storage material, is currently being evaluated for some of these diseases. Furthermore, chaperone therapy
Chaperone or Chaperon may refer to:
*Chaperone (social) or chaperon, a person who accompanies or supervises young people on social occasions
*Chaperone (clinical), a person who acts as a witness during a medical examination or procedure
*Chaperon ...
, a technique used to stabilize the defective enzymes produced by patients, is being examined for certain of these disorders. The experimental technique of gene therapy
Gene therapy is a Medicine, medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying ...
may offer cures in the future.
Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase, so it may be a useful therapeutic agent for both Gaucher disease and Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
. Ambroxol triggers the secretion of lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane p ...
s from cells by inducing a pH-dependent calcium release from acidic calcium stores. Hence, relieving the cell from accumulating degradation products is a proposed mechanism by which this drug may help.
History
Tay–Sachs disease
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around three to six months of age, with the baby ...
was the first of these disorders to be described, in 1881, followed by Gaucher disease in 1882. In the late 1950s and early 1960s, de Duve and colleagues, using cell fractionation techniques, cytological studies, and biochemical analyses, identified and characterized the lysosome as a cellular organelle responsible for intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
digestion and recycling of macromolecules
A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...
. This was the scientific breakthrough that would lead to the understanding of the physiological basis of the lysosomal storage diseases. Pompe disease
Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of th ...
was the first disease to be identified as an lysosomal storage disease in 1963, with L. Hers reporting the cause as a deficiency of α-glucosidase. Hers also suggested that other diseases, such as the mucopolysaccharidosis
Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cel ...
, might be due to enzyme deficiencies.
See also
* Mannosidosis Mannosidosis is a deficiency in mannosidase, an enzyme.
There are two types:
* Alpha-mannosidosis
* Beta-mannosidosis
See also
*Swainsonine
Swainsonine is an indolizidine alkaloid. It is a potent inhibitor of Golgi alpha-mannosidase II, an ...
* Molecular chaperone therapy
A pharmacological chaperone or pharmacoperone is a drug that acts as a protein chaperone. That is, it contains small molecules that enter cells and serve as a molecular scaffolding in order to cause otherwise- misfolded mutant proteins to fold a ...
References
External links
{{DEFAULTSORT:Lysosomal Storage Disease
*
Inborn errors of metabolism
Neurological disorders in children
Autosomal recessive disorders
X-linked recessive disorders