Lysosomal Storage Diseases (LSDs) are a group of approximately 50 rare inherited metabolic disorders. They are caused by defects in lysosomal function.
Lysosome is a bag full of enzymes within a cell. There are hundreds of lysosomes in a cell. The lysosomal enzymes digest large molecules into fragments and recycle cellular debris. These large molecules are lipids, glycoproteins (sugar containing proteins) or mucopolysaccharides.
Due to alteration in the genetic material (mutation), one of the enzymes either produces too little or it is missing entirely. Therefore, large molecules will not be broken down and subsequently accumulate within the cells. That is why these diseases are called “storage diseases”.
The lysosomes are distorted by the accumulated molecules. Gradually, the cells lose their functions and affect the tissues and organs such as the skeleton, brain, skin, heart and central nervous system.
The symptoms of LSDs vary, depending on the degree of the deficiency or altered enzymes and other factors like age. The symptoms can be mild to severe and they are generally progressive over a period of time.
Developmental delay, movement disorders, seizures, dementia, deafness and/or blindness, hepatomegaly (enlarged livers) and splenomegaly (enlarged spleen), lung and heart problems and abnormal growth of bones are observed in these patients.
As LSDs are the results of genetic defects, patients inherit their diseases from their parents. Children are mostly affected and they often die young.
Individually, LSDs occur at the incidence of less than at 1 case per 100,000 population. The incidence rate as a group of diseases is about 1 case in 5,000 to 10,000 population.
Despite the progress in clinical trials to seek possible treatment for some the diseases, many diseases have yet to find the appropriate treatments. However, new LSDs continued to be discovered.
Classification of LSD
LSDs are classified by the nature of the primary stored material as follows.
|Sphingolipidoses||Faber Disease, Fabry Disease, Schindler Disease, Gaucher Disease, Niemann-Pick Disease|
|Mucopolysaccharidoses||Hurler Syndrome, Sheie Syndrome, Hurler-Scheie Syndrome, Hunter Sydrome, Sanfilippo Syndrome, Maroteaux-Lamy Syndrome, Sly Syndrome, Hyaluronidase Deficiency|
|Mucolipidoses||Sialidosis, I-cell Disease, Pseudo-Hurler Polydystrophy, Mucolipidin 1 Deficiency|
|Gangliosidoses||GM1 Gangliosidosis, GM2 Gangliosidosis, Tay-Sachs Disease, Sandhoff Disease|
|Glycogen storage||Pompe Disease, Danon Disease|
|Leukodystrophies||Metachromic Leukodystrophy, Krabbe’s Disease, Adrenoleukodystrophy|
|Glycoproteinosis||Mannosidosis, Fucosidosis, Sialidosis, Aspartylglucosaminuria|
|Others||Ceramidosis, Cholesterol Ester Storage Disease|
Role of laboratory in LSD diagnosis
Some of the LSDs can be debilitating. Thus, early diagnosis is critical to ensure that treatment is given early so the adverse health outcomes can be avoided or reversed. Detection of the diseases preferably should be made before the patients exhibit any symptoms.
Some countries such as United States have initiated population screening for Krabbe disease and Pompe disease among newborns. More than ten countries are currently conducting the voluntary and regional pilot studies among their population.
The initial approach to laboratory diagnosis and screening of LSDs is to measure the accumulated large molecules or the lysosomal enzyme. The samples for measuring lysosomal enzymes are blood, urine, amniotic fluid and cultured skin fibroblasts.
Commonly used screening tests for LSDs are
- Urinary oligosaccharides screening is performed by high-performance thin-layer chromatography.
- Urinary glycosaminoglycans (GAGs) are measured when mucopolysaccharidoses are suspected.
Lysosomal enzyme testing has been the gold standard for providing definitive diagnoses. Further confirmation via molecular techniques is carried out to identify disease-causing mutations. Many lysosomal enzymes in the blood sample can be tested using commercially available synthetic 4-methylumbelliferone (4-MU) substrates.
Definitive diagnosis of LSDs is accomplished by specialised laboratory biochemical and molecular genetic testing. The diagnostic process requires a significant amount of expertise and experience in identifying these diseases.
Other methods for testing the lysosomal enzymes are the spectrometric or radioactive substrates.
Diagnostic services for LSD in Malaysia
In Malaysia, the Biochemistry Unit of Institute for Medical Research (IMR) plays an important role in the development of new diagnostic methods. As a reference laboratory, it provides specialised diagnostics services for Inborn Error of Metabolism (IEM) disorders. LSDs is a subset of IEM.
The Biochemical Genetic Testing was developed and set up for confirmatory of LSDs. The unit also set up rapid screening for IEM with dried blood spot using the Tandem Mass Spectrometry.
The screening test and enzyme assay for LSDs was set up for mucopolysaccharidosis (MPS), oligosaccharidosis, Fabry disease, Pompe disease, Gaucher disease, Krabbe disease and Niemann-Pick disease. The full list of tests offered by IMR for LSDs can be found on the website.
The Biochemistry Unit also conducts research projects in the field of IEM and related diseases where one the objectives is determining the incidence of various types of IEM in Malaysian Children.
Future development of diagnostics tools for LSD
One of the main challenges is to identify and diagnose these rare diseases. The time taken for definitive diagnosis may be years. This may be because the symptoms of many LSDs are often similar to other more common diseases. In cases where the disease develops very slowly, the symptoms are subtle and easily overlooked. Even for the same disease, symptoms can vary from patient to patient to complicate the identification of the disease.
In recent years, development in molecular technology as the diagnostic tool in identifying the genetic cause for LSDs has taken place. The Next-Generation Sequencing (NGS), for instance, can produce diagnosis of LSDs in 4 – 6 weeks.
The precise molecular diagnosis is important as more newly developed treatments are targeting the specific types of LSDs and also patients who have the same specific types of mutations.
A polymeric microdevice was developed as a point-of-care system for diagnostics of Fabry disease. The device is reported to take 10 minutes to complete testing and it is inexpensive. Further works are carried out to devise similar system for the diagnosis of Gaucher disease.
- Meikle, P. J.; Hopwood, J. J.; Clague, A. E.; Carey, W. F. Prevalence of lysosomal storage disorders. JAMA. 1999. 281 (3): 249–254.
- Institute of Medical Research. http://www.imr.gov.my/index.php/en/sdc/55-english-content/centre/sdc/biochemistry-unit/173-activities-of-biochemistry-unit
- Lysosomal Storage Disorders. National Organization for Rare Disorders. http://rarediseases.org/rare-diseases/lysosomal-storage-disorders/
- Chunli Yu, Qin Sun and Hui Zhou. Enzymatic screening and diagnosis of Lysosomal Storage Diseases. N Am J Med Sci (Boston). 2013; 6(4): 186 – 193.
- Komlosi, K, Sólyom, A and Beck, M. The role of Next-Generation Sequencing in the diagnosis of Lysosomal Storage Disorders. Journal of Inborn Errors of Metabolism and Screening. Oct 12, 2016.
- Kwapiszewski, R., Chudy,M., Dybko, A., Brzozka, Z. Development of a point-of-care system for early diagnostics of genetic diseases. Biomedical Engineering. http://yadda.icm.edu.pl/yadda/element/bwmeta1.element.baztech./ Kwapiszewski.pdf
|Last Reviewed||:||31 October 2017|
|Writer||:||Katheleen Ng Li Fong|
|Accreditor||:||Lau Kim Bee|