|Year : 2013 | Volume
| Issue : 1 | Page : 10-14
Lysosomal storage diseases: A review with dental abnormalities
Sudha Jimson, N Balachander, K. M. K. Masthan, C Priyadharsini
Department of Oral and Maxillofacial Pathology, Sree Balaji Dental College and Hospital, Bharath University, Chennai, India
|Date of Web Publication||13-Mar-2013|
Department of Oral and Maxillofacial Pathology, Sree Balaji Dental College and Hospital, Bharath University, Chennai
Source of Support: None, Conflict of Interest: None
Cells are made of many organelles. One of those organelles is lysosome, which are cellular organelles and are the first line of defense. They are found only in animal cells. Their main function is destroying foreign bodies that could harm the cell. They get rid of unwanted matter and also help in repair of damaged plasma membrane and seal the wound. Lysosomal storage diseases (LSD) are metabolic disorders caused by deficiency of a single gene. There are about 50 groups of diseases found which are mostly autosomal inherited and few are X-linked inheritance. No cure for LSDs has been found yet and they are mostly symptomatic. Recently, progress has been made in the treatment of LSDs.
Keywords: Gaucher′s disease, lysosome, metabolic disorder
|How to cite this article:|
Jimson S, Balachander N, Masthan K, Priyadharsini C. Lysosomal storage diseases: A review with dental abnormalities. J NTR Univ Health Sci 2013;2:10-4
|How to cite this URL:|
Jimson S, Balachander N, Masthan K, Priyadharsini C. Lysosomal storage diseases: A review with dental abnormalities. J NTR Univ Health Sci [serial online] 2013 [cited 2020 Apr 7];2:10-4. Available from: http://www.jdrntruhs.org/text.asp?2013/2/1/10/108505
| Introduction|| |
Lysosomal storage disease (LSD) is a group of fifty rare, inherited metabolic disorders. It is a metabolic disorder due to defects in the function of lysosomes. They happen when a particular enzyme is too small or missing, and the excess products accumulate in the cell. The first of these disorders was described as Tay-Sachs disease in 1881 and Gaucher's disease in 1882.  From 1950 to early 1960, Christian de Duve and his colleagues used cytological studies, biochemical analysis, and all fractionation techniques to identify lysosomes responsible for cellular digestion and recycling of macromolecules. Pompe disease was identified as LSD in 1963. There are numerous LSDs and are usually grouped biochemically. Subgroups include mucopolysaccharidoses, sphingolipidoses and mucolipidoses.  LSD is classified based on nature of primary stored material and protein defects [Table 1].
Based on nature of primary stored material
- Lipid storage disorders:
- Sphingolipidosis: Gaucher's disease, Niemann-Pick disease
- Gangliosidosis: Tay-Sachs disease
- Mucopolysaccharidoses: Hunter syndrome, Hurler syndrome
- Glycoprotein storage disorders
It is a deficiency of an enzyme that involves glycosaminoglycan (GAG) breakdown. These are polysaccharides that are found abundant in cell surface in extracellular matrix and structure. Inheritance is autosomal recessive. Accumulation of GAG in lysosomes causes changes in bone, soft tissue, and central nervous system (CNS). Common manifestations are neurodevelopmental delay, joint contractures, respiratory insufficiency, and skeletal changes.
Normal lipid components that accumulate in lysosomes cause neuronal, bone and other changes when the enzyme deficiency prevents their break down. Gaucher's disease is the most common among Niemann-Pick, Tay-Sachs, Fabry's, Krabbe and cholesterol ester disease.
The incidence rate is 1:100,000 and most of them are autosomal recessively inherited; only few are X-linked recessively inherited. It mostly affects children and they die at a young age. All are autosomal inherited except for Fabry disease, Hunter syndrome, and Danon disease, which are X-linked disorder.
Autosomal Recessive Inheritance
In human body all genes come in pairs, one inherited by each parent. A carrier of recessive condition has one dominant copy of gene (normal copy) and another copy of gene that is altered. If both parents are carriers then there is a 50% chance of child being a carrier and 25 % (1 in 4) chance of not having the disease. If one parent is a carrier, there is no chance of child getting the disease. 
These conditions are more common in males. For X-linked inheritance there is a 25% chance of male getting affected (1:4) and 25% of male are unaffected. The chance of female carrier is 1:4 and that of non-carrier is 1:4.  It is usually caused by the deficiency of a single enzyme that is required for metabolism of lipids and glycoproteins.
A baby affected by lysosome storage diseases may present with symptoms at birth while others appear normal at birth and progressively develop symptoms in the first few years. They include bone deformities, developmental delay, seizures, deafness, blindness, splenomegaly, hepatomegaly, cardiac problems, pulmonary problems, loss of speech and learning skills, and mental retardation.
Intralysosomal accumulation of metabolized substrates is the primary cause of LSD. But the symptoms indicate that many biochemical and cellular pathways must be activated. Accumulating metabolite, affects a secondary biochemical and cellular pathway, which then leads to tissue pathology, altered gene expression and the activation of territory biochemical pathways [Figure 1].
Explanation of lysosome storage disease pathology would be lysosomal stability, compromised permeability that leads to the release of hydrolases, and accumulating metabolites into the cytosol. Lysosomal proteases, cathespins are found in the cytosol during apoptosis. Lysosomotropic agents include apoptosis by inducing lysosomal leakage and the expression of certain proteins (such as amyloid Aβ1 -42) that results in the appearance of lysosomal enzymes (such cathespin D and β-hexoaminidase) in the cytosol. In sphingolipidoses defective signaling results in changes in the production of ceramide, an important lipid second messenger that could have a role in the development of pathology. In Niemann-Pick disease, which is caused by the defective activity of acid sphingomyelinase, ceramide is not produced in response to various ligands. The characteristic feature of Gaucher's disease is the change that occurs in the level of serum chitotrisidases or chemokine CCL18. The relationship between glucosylceramide accumulation and the secretion of these compounds is unknown. 
Oral and dental abnormalities of LSD
Lamy syndrome: Is a genetic disorder involving disturbances in mucopolysaccharides metabolism. It results in increased storage of mucopolysaccharides and deficiency of aryl sulfatase B that leads to accumulation of sulfatase in tissues. It is a progressive disorder involving multiple organs that often results in death in the second decade of life. It has several oral and dental abnormalities; they are large head, short neck, corneal opacity, open mouth, enlarged tongue, and enlargement of skull. Dental complications are dentigerous cyst, malocclusion, condylar defects, and gingival hyperplasia. 
Gaucher's disease: It is one of the lysosomal storage disorder caused by deficiency of glucocerebrosidase. High prevalence of this disease is found in Ashkenazi Jews. Genetic defects cause glucocerebroside and accumulation in macrophages forming Gaucher's cell. Gaucher's cell accumulates in perivascular spaces of brain causing gliosis. Common signs and symptoms are hepatomegaly, anemia, and bone deformities.  Oral and dental abnormalities are less common. They are asymptomatic, but can be detected by routine dental X-rays. There is mandibulo-maxillofacial involvement. Three types are known type I, type II, and type III. Type I is non neuropathic and affects individuals between 2 years to adulthood. Signs and symptoms are splenomegaly, delay in puberty, ecchymosis, and bone disease. Flaring of ends of bone is seen in radiographic examination. Type II is acute, non-neuropathic and is rare. It leads to progressive neurologic deterioration and finally death by the age of 2 years. Type III is subacute neuropathic. Onset occurs at childhood. Progressive dementia and ataxia are seen. 
Hurler syndrome : Rare autosomal recessive disorder. It is a deficiency of specific lysosomal enzyme with patients seen with open bite, class III skeletal base, dental spacing, ectopic tooth eruption, hypodontia and microdontia, enamel defects, tapering canine, and pointed or bulbous molar cusps. Roots are usually short in permanent and primary dentition, but seen mostly in primary dentition. 
Pyknodysostosis: It is a rare, genetic, autosomal recessive disorder. It is characterized by short statue, bone sclerosis, maxillary atresia, and an increase in mandibular angle. 
Niemann-Pick disease: It is a liposomal storage disorder caused by deficiency in sphingomyetinases activity. It is most often seen in Ashkenazi Jews. It has two types; type A and type B. Hepatomegaly and lymphadenopathy are commonly seen. Death usually occurs at 2 years of age. 
Pompe disease: Pompe disease causes progressive, often life-threatening musculoskeletal, respiratory, and cardiac symptoms. Early treatment can benefit infants with Pompe disease and it is also achieved by newborn scanning. 
Fabry's disease: It is a rare X-linked disorder and is caused by deficient activity of lysosomal enzyme α-galactosidases. Enzyme replacement therapy leads to significant clinical benefits in the affected patients. 
Neuropathic cystinosis : Cysteine accumulates intracellularly in many tissues, including kidney. Renal failure usually occurs at 10 years of age. Glomerular dysfunction can be slowed by oral administration of cysteamine. Visual activity is decreased, recurrent corneal erosion; central nervous system is also involved. 
Usually suspected by history and examination, hepatomegaly is usually seen. It can be confirmed by sphinomyelinase assay and enzyme analysis of WBC. In Gaucher's disease; cell macrophages in liver, bone marrow, and spleen show wrinkled tissue paper appearance. Biochemical and genetic diagnosis of LSD can be performed in specialized laboratories. Many clinical samples can be used for analysis such as blood, urine, amniotic fluid, and tissue biopsies. First approach of LSD when suspected is the measurement of accumulated substrate LSD. Secondary changes may also occur. Such changes may also be seen as a modification of cellular components that may be useful as markers of specific disease. Molecular analysis is also performed. Commonly used screening test are as follows.
It is performed by high performance thin layer chromatography technique (HPTLC). It provides initial indication and further investigations are needed to confirm the diagnosis. Disorders that present with abnormal HPTLC profile are aspartyglucosaminuria, GMI-gangliosidosis, GM2-gangliosidosis, fucosidoses, glycogen storage disease type II.
Mucopolysacchridoses may be suspected from urinary GAGs and by repeated perception, cetylpyridinium chloride GAGs are isolated and quantified by colorimeter assay. Method used to assess the amount of hexuronic acid contained in extracted GAGs.
Recognition of the high combined prevalence of LSD and increasing specific therapies has encouraged the search of biomarkers that can identify LSD in newborn.
Assessment of lysosmal enzyme activities
Lysosomal enzyme activities are determined by flurometric assay in cultured fibroblast, leucocytes using 4-methylumbelliferyl containing fluorescent assay.
It is useful for the identification of LSD and monitoring the effects of treatment.
The majority of LSD is autosomal recessive mode of inheritance. It enables prenatal and postnatal testing and allows provision of genetic counseling.
There is no particular cure for LSDs and it is mostly symptomatic. Today's enzyme replacement therapy was first introduced for the treatment of Gaucher's disease and has been the most successful therapeutic approach for LSD. Benefits of this therapy were not established for patients with very late onset of disease. Bone marrow transplantation has been tried out with some blood samples, umbilical cord blood transplantation, and substrate therapy [Figure 2]. Increase in awareness and diagnosis are important, as treatment is now feasible. Usually damage of an organ arises from accumulation of substrates for the missing enzyme. One of the treatments for LSD is splenectomy, which is relatively common in Gaucher's disease. However splenectomy can only reduce the symptoms. Some of the specific treatments for LSD (Fabry's disease) are renal transplantation or chronic hemodialysis. Gene therapy is the most effective treatment for LSD. However gene therapy will become a viable option in the future. Significant resources and researches have been challenged in gene therapy. 
| Conclusion|| |
These disorders are very rare and it makes the market potential for therapeutic products very small. The cost of research, development, clinical trial, and marketing involves much larger cost than the market potential. Clinical trials are also being conducted for LSD. There is no specific treatment for LSDs. Progress has been made in the treatment of various gene therapies. 
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[Figure 1], [Figure 2]